Nasopharyngeal Shedding of Severe Acute Respiratory Syndrome—Associated Coronavirus Is Associated with Genetic Polymorphisms
Identifieur interne : 000071 ( Istex/Corpus ); précédent : 000070; suivant : 000072Nasopharyngeal Shedding of Severe Acute Respiratory Syndrome—Associated Coronavirus Is Associated with Genetic Polymorphisms
Auteurs : Wei-Ju Chen ; Jyh-Yuan Yang ; Jih-Hui Lin ; Cathy S. J. Fann ; Valeriy Osyetrov ; Chwan-Chuen King ; Yi-Ming Arthur Chen ; Hsiao-Ling Chang ; Hung-Wei Kuo ; Fong Liao ; Mei-Shang HoSource :
- Clinical Infectious Diseases [ 1058-4838 ] ; 2006.
Abstract
Background. A high initial or peak severe acute respiratory syndrome (SARS)—associated coronavirus (SARS-CoV) load in nasopharyngeal specimens was shown to be associated with a high mortality rate. Because all infected individuals were devoid of preeexisting protective immunity against SARS-CoV, the biological basis for the variable virus burdens in different patients remains elusive. Methods. The nationwide SARS database in Taiwan was analyzed, and genotyping of 281 single-nucleotide polymorphisms (SNPs) of 65 genes was performed for 94 patients with SARS, to identify SNPs for which distribution between patients with or without detectable nasopharyngeal shedding of SARS-CoV was biased. Results. Titers of SARS-CoV shed in nasopharyngeal specimens varied widely, ranging from nondetectable to 108 SARS-CoV RNA copies/mL, and they were correlated positively with a high mortality rate (P < .0001, by trend test) and with early death (i.e., death occurring within 2 weeks of the onset of illness) (P = .0015, by trend test). Virus shedding was found to be higher among male patients (P = .0014, by multivariate logistic regression) and among older patients (P = .015, by multivariate logistic regression). Detectable nasopharyngeal shedding of SARS-CoV was associated with polymorphic alleles of interleukins 18 (P = .014) and 1A (P = .031) and a member of NFκB complex (reticuloendotheliosis viral oncogene homolog B [RelB]) (P = .034), all of which are proinflammatory in nature, as well as the procoagulation molecule fibrinogen-like protein 2 (P = .008). Conclusion. The SARS-CoV load is a determinant of clinical outcomes of SARS, and it is associated with polymorphisms of genes involved in innate immunity, which might be regulated in an age- and sex-dependent manner. The findings of the present study provided leads to genes involved in the host response to SARS-CoV infection; if substantiated with functional studies, these findings may be applicable to other newly emerged respiratory viruses (e.g., the influenza pandemic strain).
Url:
DOI: 10.1086/503843
Links to Exploration step
ISTEX:9C32D2577E261A285735FBF93EC3393DFED7E0BDLe document en format XML
<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title>Nasopharyngeal Shedding of Severe Acute Respiratory Syndrome—Associated Coronavirus Is Associated with Genetic Polymorphisms</title><author><name sortKey="Chen, Wei Ju" sort="Chen, Wei Ju" uniqKey="Chen W" first="Wei-Ju" last="Chen">Wei-Ju Chen</name><affiliation><mods:affiliation>Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan</mods:affiliation></affiliation></author><author><name sortKey="Yang, Jyh Yuan" sort="Yang, Jyh Yuan" uniqKey="Yang J" first="Jyh-Yuan" last="Yang">Jyh-Yuan Yang</name><affiliation><mods:affiliation>Center for Disease Control, Taipei, Taiwan</mods:affiliation></affiliation></author><author><name sortKey="Lin, Jih Hui" sort="Lin, Jih Hui" uniqKey="Lin J" first="Jih-Hui" last="Lin">Jih-Hui Lin</name><affiliation><mods:affiliation>Center for Disease Control, Taipei, Taiwan</mods:affiliation></affiliation></author><author><name sortKey="Fann, Cathy S J" sort="Fann, Cathy S J" uniqKey="Fann C" first="Cathy S. J." last="Fann">Cathy S. J. Fann</name><affiliation><mods:affiliation>Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan</mods:affiliation></affiliation></author><author><name sortKey="Osyetrov, Valeriy" sort="Osyetrov, Valeriy" uniqKey="Osyetrov V" first="Valeriy" last="Osyetrov">Valeriy Osyetrov</name><affiliation><mods:affiliation>Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan</mods:affiliation></affiliation></author><author><name sortKey="King, Chwan Chuen" sort="King, Chwan Chuen" uniqKey="King C" first="Chwan-Chuen" last="King">Chwan-Chuen King</name><affiliation><mods:affiliation>Graduate Institute of Epidemiology, National Taiwan University, Taipei, Taiwan</mods:affiliation></affiliation></author><author><name sortKey="Chen, Yi Ming Arthur" sort="Chen, Yi Ming Arthur" uniqKey="Chen Y" first="Yi-Ming Arthur" last="Chen">Yi-Ming Arthur Chen</name><affiliation><mods:affiliation>Institute of Public Health, National Yang-Ming University, Taipei, Taiwan</mods:affiliation></affiliation></author><author><name sortKey="Chang, Hsiao Ling" sort="Chang, Hsiao Ling" uniqKey="Chang H" first="Hsiao-Ling" last="Chang">Hsiao-Ling Chang</name><affiliation><mods:affiliation>Center for Disease Control, Taipei, Taiwan</mods:affiliation></affiliation></author><author><name sortKey="Kuo, Hung Wei" sort="Kuo, Hung Wei" uniqKey="Kuo H" first="Hung-Wei" last="Kuo">Hung-Wei Kuo</name><affiliation><mods:affiliation>Center for Disease Control, Taipei, Taiwan</mods:affiliation></affiliation></author><author><name sortKey="Liao, Fong" sort="Liao, Fong" uniqKey="Liao F" first="Fong" last="Liao">Fong Liao</name><affiliation><mods:affiliation>Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan</mods:affiliation></affiliation></author><author><name sortKey="Ho, Mei Shang" sort="Ho, Mei Shang" uniqKey="Ho M" first="Mei-Shang" last="Ho">Mei-Shang Ho</name><affiliation><mods:affiliation>Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan</mods:affiliation></affiliation><affiliation><mods:affiliation>Graduate Institute of Epidemiology, National Taiwan University, Taipei, Taiwan</mods:affiliation></affiliation><affiliation><mods:affiliation>Institute of Public Health, National Yang-Ming University, Taipei, Taiwan</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: homs@ibms.sinica.edu.tw</mods:affiliation></affiliation><affiliation><mods:affiliation>Reprints or correspondence: Dr. Mei-Shang Ho, IBMS, Academia Sinica, Taipei, 11529 Taiwan (homs@ibms.sinica.edu.tw).</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:9C32D2577E261A285735FBF93EC3393DFED7E0BD</idno><date when="2006" year="2006">2006</date><idno type="doi">10.1086/503843</idno><idno type="url">https://api.istex.fr/ark:/67375/HXZ-HB5XDM1W-T/fulltext.pdf</idno><idno type="wicri:Area/Istex/Corpus">000071</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">000071</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main">Nasopharyngeal Shedding of Severe Acute Respiratory Syndrome—Associated Coronavirus Is Associated with Genetic Polymorphisms</title><author><name sortKey="Chen, Wei Ju" sort="Chen, Wei Ju" uniqKey="Chen W" first="Wei-Ju" last="Chen">Wei-Ju Chen</name><affiliation><mods:affiliation>Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan</mods:affiliation></affiliation></author><author><name sortKey="Yang, Jyh Yuan" sort="Yang, Jyh Yuan" uniqKey="Yang J" first="Jyh-Yuan" last="Yang">Jyh-Yuan Yang</name><affiliation><mods:affiliation>Center for Disease Control, Taipei, Taiwan</mods:affiliation></affiliation></author><author><name sortKey="Lin, Jih Hui" sort="Lin, Jih Hui" uniqKey="Lin J" first="Jih-Hui" last="Lin">Jih-Hui Lin</name><affiliation><mods:affiliation>Center for Disease Control, Taipei, Taiwan</mods:affiliation></affiliation></author><author><name sortKey="Fann, Cathy S J" sort="Fann, Cathy S J" uniqKey="Fann C" first="Cathy S. J." last="Fann">Cathy S. J. Fann</name><affiliation><mods:affiliation>Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan</mods:affiliation></affiliation></author><author><name sortKey="Osyetrov, Valeriy" sort="Osyetrov, Valeriy" uniqKey="Osyetrov V" first="Valeriy" last="Osyetrov">Valeriy Osyetrov</name><affiliation><mods:affiliation>Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan</mods:affiliation></affiliation></author><author><name sortKey="King, Chwan Chuen" sort="King, Chwan Chuen" uniqKey="King C" first="Chwan-Chuen" last="King">Chwan-Chuen King</name><affiliation><mods:affiliation>Graduate Institute of Epidemiology, National Taiwan University, Taipei, Taiwan</mods:affiliation></affiliation></author><author><name sortKey="Chen, Yi Ming Arthur" sort="Chen, Yi Ming Arthur" uniqKey="Chen Y" first="Yi-Ming Arthur" last="Chen">Yi-Ming Arthur Chen</name><affiliation><mods:affiliation>Institute of Public Health, National Yang-Ming University, Taipei, Taiwan</mods:affiliation></affiliation></author><author><name sortKey="Chang, Hsiao Ling" sort="Chang, Hsiao Ling" uniqKey="Chang H" first="Hsiao-Ling" last="Chang">Hsiao-Ling Chang</name><affiliation><mods:affiliation>Center for Disease Control, Taipei, Taiwan</mods:affiliation></affiliation></author><author><name sortKey="Kuo, Hung Wei" sort="Kuo, Hung Wei" uniqKey="Kuo H" first="Hung-Wei" last="Kuo">Hung-Wei Kuo</name><affiliation><mods:affiliation>Center for Disease Control, Taipei, Taiwan</mods:affiliation></affiliation></author><author><name sortKey="Liao, Fong" sort="Liao, Fong" uniqKey="Liao F" first="Fong" last="Liao">Fong Liao</name><affiliation><mods:affiliation>Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan</mods:affiliation></affiliation></author><author><name sortKey="Ho, Mei Shang" sort="Ho, Mei Shang" uniqKey="Ho M" first="Mei-Shang" last="Ho">Mei-Shang Ho</name><affiliation><mods:affiliation>Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan</mods:affiliation></affiliation><affiliation><mods:affiliation>Graduate Institute of Epidemiology, National Taiwan University, Taipei, Taiwan</mods:affiliation></affiliation><affiliation><mods:affiliation>Institute of Public Health, National Yang-Ming University, Taipei, Taiwan</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: homs@ibms.sinica.edu.tw</mods:affiliation></affiliation><affiliation><mods:affiliation>Reprints or correspondence: Dr. Mei-Shang Ho, IBMS, Academia Sinica, Taipei, 11529 Taiwan (homs@ibms.sinica.edu.tw).</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Clinical Infectious Diseases</title><title level="j" type="abbrev">Clinical Infectious Diseases</title><idno type="ISSN">1058-4838</idno><idno type="eISSN">1537-6591</idno><imprint><publisher>The University of Chicago Press</publisher><date type="published">2006</date><biblScope unit="vol">42</biblScope><biblScope unit="issue">11</biblScope><biblScope unit="page" from="1561">1561</biblScope><biblScope unit="page" to="1569">1569</biblScope></imprint><idno type="ISSN">1058-4838</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1058-4838</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">Background. A high initial or peak severe acute respiratory syndrome (SARS)—associated coronavirus (SARS-CoV) load in nasopharyngeal specimens was shown to be associated with a high mortality rate. Because all infected individuals were devoid of preeexisting protective immunity against SARS-CoV, the biological basis for the variable virus burdens in different patients remains elusive. Methods. The nationwide SARS database in Taiwan was analyzed, and genotyping of 281 single-nucleotide polymorphisms (SNPs) of 65 genes was performed for 94 patients with SARS, to identify SNPs for which distribution between patients with or without detectable nasopharyngeal shedding of SARS-CoV was biased. Results. Titers of SARS-CoV shed in nasopharyngeal specimens varied widely, ranging from nondetectable to 108 SARS-CoV RNA copies/mL, and they were correlated positively with a high mortality rate (P < .0001, by trend test) and with early death (i.e., death occurring within 2 weeks of the onset of illness) (P = .0015, by trend test). Virus shedding was found to be higher among male patients (P = .0014, by multivariate logistic regression) and among older patients (P = .015, by multivariate logistic regression). Detectable nasopharyngeal shedding of SARS-CoV was associated with polymorphic alleles of interleukins 18 (P = .014) and 1A (P = .031) and a member of NFκB complex (reticuloendotheliosis viral oncogene homolog B [RelB]) (P = .034), all of which are proinflammatory in nature, as well as the procoagulation molecule fibrinogen-like protein 2 (P = .008). Conclusion. The SARS-CoV load is a determinant of clinical outcomes of SARS, and it is associated with polymorphisms of genes involved in innate immunity, which might be regulated in an age- and sex-dependent manner. The findings of the present study provided leads to genes involved in the host response to SARS-CoV infection; if substantiated with functional studies, these findings may be applicable to other newly emerged respiratory viruses (e.g., the influenza pandemic strain).</div></front></TEI><istex><corpusName>oup</corpusName><keywords><teeft><json:string>sars</json:string><json:string>nasopharyngeal</json:string><json:string>coronavirus</json:string><json:string>severe acute respiratory syndrome</json:string><json:string>viral</json:string><json:string>virus load</json:string><json:string>fgl2</json:string><json:string>allele</json:string><json:string>polymorphism</json:string><json:string>nasopharyngeal specimen</json:string><json:string>immunol</json:string><json:string>multivariate</json:string><json:string>relb</json:string><json:string>june</json:string><json:string>snp</json:string><json:string>sarscov</json:string><json:string>database</json:string><json:string>datum</json:string><json:string>virus burden</json:string><json:string>allele frequency</json:string><json:string>trend test</json:string><json:string>clinical outcome</json:string><json:string>syndrome</json:string><json:string>undetectable</json:string><json:string>male patient</json:string><json:string>innate immunity</json:string><json:string>high mortality rate</json:string><json:string>detectable nasopharyngeal</json:string><json:string>fatal case</json:string><json:string>permutation test</json:string><json:string>multivariate logistic regression model</json:string><json:string>specimen collection</json:string><json:string>control patient</json:string><json:string>biological basis</json:string><json:string>undetectable level</json:string><json:string>nasopharyngeal virus load</json:string><json:string>adaptive immunity</json:string><json:string>exact test</json:string><json:string>clinical course</json:string><json:string>different patient</json:string><json:string>genetic study</json:string><json:string>acute phase</json:string><json:string>genetic polymorphism</json:string><json:string>severe acute respiratory coronavirus</json:string><json:string>older patient</json:string><json:string>academia sinica</json:string><json:string>virus</json:string><json:string>logistic</json:string><json:string>gene</json:string><json:string>clinical severity</json:string><json:string>reference group</json:string><json:string>datum analysis</json:string><json:string>univariate analysis</json:string><json:string>detectable sarscov</json:string><json:string>acute respiratory distress syndrome</json:string><json:string>disease control</json:string><json:string>cumulative logistic model</json:string><json:string>virus detection</json:string><json:string>viral load</json:string><json:string>detectable level</json:string><json:string>respiratory tract</json:string><json:string>functional study</json:string><json:string>host response</json:string><json:string>present study</json:string><json:string>nasopharyngeal virus</json:string><json:string>high initial</json:string><json:string>female patient</json:string><json:string>younger patient</json:string><json:string>detectable virus</json:string><json:string>reticuloendotheliosis viral oncogene homolog</json:string><json:string>sample collection</json:string><json:string>helper type</json:string><json:string>polymorphic allele</json:string><json:string>genotype distribution</json:string><json:string>multivariate logistic regression</json:string><json:string>multivariate analysis</json:string><json:string>clinical characteristic</json:string><json:string>early death</json:string><json:string>lung tissue</json:string><json:string>candidate gene</json:string><json:string>viral infection</json:string><json:string>broad sense</json:string><json:string>immune response</json:string><json:string>higher virus load</json:string><json:string>mouse uterus</json:string><json:string>biomedical science</json:string><json:string>higher mortality rate</json:string><json:string>other viral infection</json:string><json:string>viral hepatitis</json:string><json:string>nucleocapsid protein</json:string><json:string>virulent mouse hepatitis virus</json:string><json:string>unpublished datum</json:string><json:string>case patient</json:string><json:string>nationwide sars database</json:string><json:string>mortality rate</json:string><json:string>locus</json:string></teeft></keywords><author><json:item><name>Wei-Ju Chen</name><affiliations><json:string>Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan</json:string></affiliations></json:item><json:item><name>Jyh-Yuan Yang</name><affiliations><json:string>Center for Disease Control, Taipei, Taiwan</json:string></affiliations></json:item><json:item><name>Jih-Hui Lin</name><affiliations><json:string>Center for Disease Control, Taipei, Taiwan</json:string></affiliations></json:item><json:item><name>Cathy S. J. Fann</name><affiliations><json:string>Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan</json:string></affiliations></json:item><json:item><name>Valeriy Osyetrov</name><affiliations><json:string>Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan</json:string></affiliations></json:item><json:item><name>Chwan-Chuen King</name><affiliations><json:string>Graduate Institute of Epidemiology, National Taiwan University, Taipei, Taiwan</json:string></affiliations></json:item><json:item><name>Yi-Ming Arthur Chen</name><affiliations><json:string>Institute of Public Health, National Yang-Ming University, Taipei, Taiwan</json:string></affiliations></json:item><json:item><name>Hsiao-Ling Chang</name><affiliations><json:string>Center for Disease Control, Taipei, Taiwan</json:string></affiliations></json:item><json:item><name>Hung-Wei Kuo</name><affiliations><json:string>Center for Disease Control, Taipei, Taiwan</json:string></affiliations></json:item><json:item><name>Fong Liao</name><affiliations><json:string>Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan</json:string></affiliations></json:item><json:item><name>Mei-Shang Ho</name><affiliations><json:string>Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan</json:string><json:string>Graduate Institute of Epidemiology, National Taiwan University, Taipei, Taiwan</json:string><json:string>Institute of Public Health, National Yang-Ming University, Taipei, Taiwan</json:string><json:string>E-mail: homs@ibms.sinica.edu.tw</json:string><json:string>Reprints or correspondence: Dr. Mei-Shang Ho, IBMS, Academia Sinica, Taipei, 11529 Taiwan (homs@ibms.sinica.edu.tw).</json:string></affiliations></json:item></author><arkIstex>ark:/67375/HXZ-HB5XDM1W-T</arkIstex><language><json:string>unknown</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><abstract>Background. A high initial or peak severe acute respiratory syndrome (SARS)—associated coronavirus (SARS-CoV) load in nasopharyngeal specimens was shown to be associated with a high mortality rate. Because all infected individuals were devoid of preeexisting protective immunity against SARS-CoV, the biological basis for the variable virus burdens in different patients remains elusive. Methods. The nationwide SARS database in Taiwan was analyzed, and genotyping of 281 single-nucleotide polymorphisms (SNPs) of 65 genes was performed for 94 patients with SARS, to identify SNPs for which distribution between patients with or without detectable nasopharyngeal shedding of SARS-CoV was biased. Results. Titers of SARS-CoV shed in nasopharyngeal specimens varied widely, ranging from nondetectable to 108 SARS-CoV RNA copies/mL, and they were correlated positively with a high mortality rate (P > .0001, by trend test) and with early death (i.e., death occurring within 2 weeks of the onset of illness) (P = .0015, by trend test). Virus shedding was found to be higher among male patients (P = .0014, by multivariate logistic regression) and among older patients (P = .015, by multivariate logistic regression). Detectable nasopharyngeal shedding of SARS-CoV was associated with polymorphic alleles of interleukins 18 (P = .014) and 1A (P = .031) and a member of NFκB complex (reticuloendotheliosis viral oncogene homolog B [RelB]) (P = .034), all of which are proinflammatory in nature, as well as the procoagulation molecule fibrinogen-like protein 2 (P = .008). Conclusion. The SARS-CoV load is a determinant of clinical outcomes of SARS, and it is associated with polymorphisms of genes involved in innate immunity, which might be regulated in an age- and sex-dependent manner. The findings of the present study provided leads to genes involved in the host response to SARS-CoV infection; if substantiated with functional studies, these findings may be applicable to other newly emerged respiratory viruses (e.g., the influenza pandemic strain).</abstract><qualityIndicators><score>8.667</score><pdfWordCount>5043</pdfWordCount><pdfCharCount>32111</pdfCharCount><pdfVersion>1.4</pdfVersion><pdfPageCount>9</pdfPageCount><pdfPageSize>612 x 792 pts (letter)</pdfPageSize><pdfWordsPerPage>560</pdfWordsPerPage><pdfText>true</pdfText><refBibsNative>true</refBibsNative><abstractWordCount>307</abstractWordCount><abstractCharCount>2050</abstractCharCount><keywordCount>0</keywordCount></qualityIndicators><title>Nasopharyngeal Shedding of Severe Acute Respiratory Syndrome—Associated Coronavirus Is Associated with Genetic Polymorphisms</title><pmid><json:string>16652313</json:string></pmid><genre><json:string>research-article</json:string></genre><host><title>Clinical Infectious Diseases</title><language><json:string>unknown</json:string></language><issn><json:string>1058-4838</json:string></issn><eissn><json:string>1537-6591</json:string></eissn><publisherId><json:string>cid</json:string></publisherId><volume>42</volume><issue>11</issue><pages><first>1561</first><last>1569</last></pages><genre><json:string>journal</json:string></genre></host><namedEntities><unitex><date><json:string>2006</json:string><json:string>2003</json:string><json:string>1562</json:string></date><geogName></geogName><orgName><json:string>Academia Sinica and Taiwan National Science Council</json:string><json:string>Table 1: the 64 candidate genes</json:string><json:string>Graduate Institute of Epidemiology, National Taiwan University</json:string><json:string>Taiwan National Genotyping Center</json:string><json:string>Japan SNP Database</json:string><json:string>Division of Surveillance</json:string><json:string>Medical Research Ethics Committee of the Institute of Biomedical Sciences</json:string><json:string>SNP Consortium, the National Center for Biotechnology Information</json:string><json:string>Taiwan Central Government</json:string><json:string>Taiwan Center for Disease Control</json:string><json:string>HUGO Gene Nomenclature Committee</json:string><json:string>Institute of Public Health, National Yang-Ming University, Taipei, Taiwan Background</json:string></orgName><orgName_funder></orgName_funder><orgName_provider></orgName_provider><persName><json:string>L. Huang</json:string><json:string>Hong Kong</json:string><json:string>Arthur Chen</json:string><json:string>Real Art</json:string><json:string>S. J. Fann</json:string><json:string>L. Liu</json:string><json:string>Y. Tsai</json:string><json:string>Taiwan</json:string><json:string>In</json:string><json:string>Y. Chao</json:string><json:string>T. Lu</json:string><json:string>Yu-Jen Liang</json:string><json:string>L. Chiang</json:string><json:string>L. Chao</json:string><json:string>Yuan Yang</json:string><json:string>Hui Lin</json:string><json:string>Figure</json:string><json:string>I.J. Su</json:string></persName><placeName><json:string>Taiwan</json:string><json:string>Helsinki</json:string><json:string>Taipei</json:string></placeName><ref_url></ref_url><ref_bibl><json:string>[14, 15]</json:string><json:string>[45]</json:string><json:string>[18]</json:string><json:string>[6]</json:string><json:string>[44]</json:string><json:string>[10, 11]</json:string><json:string>[39]</json:string><json:string>[21]</json:string><json:string>[38]</json:string><json:string>Chen et al.</json:string><json:string>[31]</json:string><json:string>Beagley et al. [36]</json:string><json:string>[26]</json:string><json:string>Morales-Montor et al. [37]</json:string><json:string>[30]</json:string><json:string>[25]</json:string><json:string>[20, 21]</json:string><json:string>[16, 17]</json:string><json:string>[2]</json:string><json:string>[46]</json:string><json:string>[19]</json:string></ref_bibl><bibl></bibl></unitex></namedEntities><ark><json:string>ark:/67375/HXZ-HB5XDM1W-T</json:string></ark><categories><wos><json:string>1 - science</json:string><json:string>2 - microbiology</json:string><json:string>2 - infectious diseases</json:string><json:string>2 - immunology</json:string></wos><scienceMetrix><json:string>1 - health sciences</json:string><json:string>2 - biomedical research</json:string><json:string>3 - microbiology</json:string></scienceMetrix><scopus><json:string>1 - Health Sciences</json:string><json:string>2 - Medicine</json:string><json:string>3 - Infectious Diseases</json:string><json:string>1 - Health Sciences</json:string><json:string>2 - Medicine</json:string><json:string>3 - Microbiology (medical)</json:string></scopus><inist><json:string>1 - sciences appliquees, technologies et medecines</json:string><json:string>2 - sciences biologiques et medicales</json:string><json:string>3 - sciences medicales</json:string></inist></categories><publicationDate>2006</publicationDate><copyrightDate>2006</copyrightDate><doi><json:string>10.1086/503843</json:string></doi><id>9C32D2577E261A285735FBF93EC3393DFED7E0BD</id><score>1</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/ark:/67375/HXZ-HB5XDM1W-T/fulltext.pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/ark:/67375/HXZ-HB5XDM1W-T/bundle.zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/ark:/67375/HXZ-HB5XDM1W-T/fulltext.tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main">Nasopharyngeal Shedding of Severe Acute Respiratory Syndrome—Associated Coronavirus Is Associated with Genetic Polymorphisms</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>The University of Chicago Press</publisher><availability><licence>© 2006 by the Infectious Diseases Society of America</licence></availability><date type="Copyright" when="2006">2006</date><date type="published">2006</date></publicationStmt><notesStmt><note type="content-type" source="research-article" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</note><note type="publication-type" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note></notesStmt><sourceDesc><biblStruct type="article"><analytic><title level="a" type="main">Nasopharyngeal Shedding of Severe Acute Respiratory Syndrome—Associated Coronavirus Is Associated with Genetic Polymorphisms</title><author xml:id="author-0000"><persName><surname>Chen</surname><forename type="first">Wei-Ju</forename></persName><affiliation><orgName type="institution">Institute of Biomedical Science, Academia Sinica</orgName><address><addrLine>Taipei, Taiwan</addrLine></address></affiliation></author><author xml:id="author-0001"><persName><surname>Yang</surname><forename type="first">Jyh-Yuan</forename></persName><affiliation><orgName type="institution">Center for Disease Control</orgName><address><addrLine>Taipei, Taiwan</addrLine></address></affiliation></author><author xml:id="author-0002"><persName><surname>Lin</surname><forename type="first">Jih-Hui</forename></persName><affiliation><orgName type="institution">Center for Disease Control</orgName><address><addrLine>Taipei, Taiwan</addrLine></address></affiliation></author><author xml:id="author-0003"><persName><surname>Fann</surname><forename type="first">Cathy S. J.</forename></persName><affiliation><orgName type="institution">Institute of Biomedical Science, Academia Sinica</orgName><address><addrLine>Taipei, Taiwan</addrLine></address></affiliation></author><author xml:id="author-0004"><persName><surname>Osyetrov</surname><forename type="first">Valeriy</forename></persName><affiliation><orgName type="institution">Institute of Biomedical Science, Academia Sinica</orgName><address><addrLine>Taipei, Taiwan</addrLine></address></affiliation></author><author xml:id="author-0005"><persName><surname>King</surname><forename type="first">Chwan-Chuen</forename></persName><affiliation><orgName type="institution">Graduate Institute of Epidemiology, National Taiwan University</orgName><address><addrLine>Taipei, Taiwan</addrLine></address></affiliation></author><author xml:id="author-0006"><persName><surname>Chen</surname><forename type="first">Yi-Ming Arthur</forename></persName><affiliation><orgName type="institution">Institute of Public Health, National Yang-Ming University</orgName><address><addrLine>Taipei, Taiwan</addrLine></address></affiliation></author><author xml:id="author-0007"><persName><surname>Chang</surname><forename type="first">Hsiao-Ling</forename></persName><affiliation><orgName type="institution">Center for Disease Control</orgName><address><addrLine>Taipei, Taiwan</addrLine></address></affiliation></author><author xml:id="author-0008"><persName><surname>Kuo</surname><forename type="first">Hung-Wei</forename></persName><affiliation><orgName type="institution">Center for Disease Control</orgName><address><addrLine>Taipei, Taiwan</addrLine></address></affiliation></author><author xml:id="author-0009"><persName><surname>Liao</surname><forename type="first">Fong</forename></persName><affiliation><orgName type="institution">Institute of Biomedical Science, Academia Sinica</orgName><address><addrLine>Taipei, Taiwan</addrLine></address></affiliation></author><author xml:id="author-0010" role="corresp"><persName><surname>Ho</surname><forename type="first">Mei-Shang</forename></persName><affiliation><orgName type="institution">Institute of Biomedical Science, Academia Sinica</orgName><address><addrLine>Taipei, Taiwan</addrLine></address></affiliation><affiliation><orgName type="institution">Graduate Institute of Epidemiology, National Taiwan University</orgName><address><addrLine>Taipei, Taiwan</addrLine></address></affiliation><affiliation><orgName type="institution">Institute of Public Health, National Yang-Ming University</orgName><address><addrLine>Taipei, Taiwan</addrLine></address></affiliation></author><idno type="istex">9C32D2577E261A285735FBF93EC3393DFED7E0BD</idno><idno type="ark">ark:/67375/HXZ-HB5XDM1W-T</idno><idno type="DOI">10.1086/503843</idno></analytic><monogr><title level="j" type="main">Clinical Infectious Diseases</title><title level="j" type="abbrev">Clinical Infectious Diseases</title><idno type="hwp">cid</idno><idno type="publisher-id">cid</idno><idno type="pISSN">1058-4838</idno><idno type="eISSN">1537-6591</idno><imprint><publisher>The University of Chicago Press</publisher><date type="published">2006</date><biblScope unit="vol">42</biblScope><biblScope unit="issue">11</biblScope><biblScope unit="page" from="1561">1561</biblScope><biblScope unit="page" to="1569">1569</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><encodingDesc><schemaRef type="ODD" url="https://xml-schema.delivery.istex.fr/tei-istex.odd"></schemaRef><appInfo><application ident="pub2tei" version="1.0.41" when="2020-04-06"><label>pub2TEI-ISTEX</label><desc>A set of style sheets for converting XML documents encoded in various scientific publisher formats into a common TEI format.
<ref target="http://www.tei-c.org/">We use TEI</ref></desc></application></appInfo></encodingDesc><profileDesc><abstract><p><hi rend="bold"><hi rend="italic">Background</hi></hi>. A high initial or peak severe acute respiratory syndrome (SARS)—associated coronavirus (SARS-CoV) load in nasopharyngeal specimens was shown to be associated with a high mortality rate. Because all infected individuals were devoid of preeexisting protective immunity against SARS-CoV, the biological basis for the variable virus burdens in different patients remains elusive.</p><p><hi rend="bold"><hi rend="italic">Methods</hi></hi>. The nationwide SARS database in Taiwan was analyzed, and genotyping of 281 single-nucleotide polymorphisms (SNPs) of 65 genes was performed for 94 patients with SARS, to identify SNPs for which distribution between patients with or without detectable nasopharyngeal shedding of SARS-CoV was biased.</p><p><hi rend="bold"><hi rend="italic">Results</hi></hi>. Titers of SARS-CoV shed in nasopharyngeal specimens varied widely, ranging from nondetectable to 10<hi rend="superscript">8</hi> SARS-CoV RNA copies/mL, and they were correlated positively with a high mortality rate (<hi rend="italic">P</hi> < .0001, by trend test) and with early death (i.e., death occurring within 2 weeks of the onset of illness) (<hi rend="italic">P</hi> = .0015, by trend test). Virus shedding was found to be higher among male patients (<hi rend="italic">P</hi> = .0014, by multivariate logistic regression) and among older patients (<hi rend="italic">P</hi> = .015, by multivariate logistic regression). Detectable nasopharyngeal shedding of SARS-CoV was associated with polymorphic alleles of interleukins 18 (<hi rend="italic">P</hi> = .014) and 1A (<hi rend="italic">P</hi> = .031) and a member of NFκB complex (reticuloendotheliosis viral oncogene homolog B [<hi rend="italic">RelB</hi>]) (<hi rend="italic">P</hi> = .034), all of which are proinflammatory in nature, as well as the procoagulation molecule fibrinogen-like protein 2 (<hi rend="italic">P</hi> = .008).</p><p><hi rend="bold"><hi rend="italic">Conclusion</hi></hi>. The SARS-CoV load is a determinant of clinical outcomes of SARS, and it is associated with polymorphisms of genes involved in innate immunity, which might be regulated in an age- and sex-dependent manner. The findings of the present study provided leads to genes involved in the host response to SARS-CoV infection; if substantiated with functional studies, these findings may be applicable to other newly emerged respiratory viruses (e.g., the influenza pandemic strain).</p></abstract><textClass ana="subject"><keywords scheme="heading"><term>Articles and Commentaries</term></keywords></textClass><langUsage><language ident="EN"></language></langUsage></profileDesc><revisionDesc><change when="2020-04-06" who="#istex" xml:id="pub2tei">formatting</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/ark:/67375/HXZ-HB5XDM1W-T/fulltext.txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup, element #text not found" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article">
<front>
<journal-meta>
<journal-id journal-id-type="hwp">cid</journal-id>
<journal-id journal-id-type="publisher-id">cid</journal-id>
<journal-title>Clinical Infectious Diseases</journal-title>
<abbrev-journal-title>Clinical Infectious Diseases</abbrev-journal-title>
<issn pub-type="ppub">1058-4838</issn>
<issn pub-type="epub">1537-6591</issn>
<publisher>
<publisher-name>The University of Chicago Press</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.1086/503843</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Articles and Commentaries</subject>
<subj-group subj-group-type="heading">
<subject>Major Articles</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Nasopharyngeal Shedding of Severe Acute Respiratory Syndrome—Associated Coronavirus Is Associated with Genetic Polymorphisms</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author">
<name>
<surname>Chen</surname>
<given-names>Wei-Ju</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Yang</surname>
<given-names>Jyh-Yuan</given-names>
</name>
<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Lin</surname>
<given-names>Jih-Hui</given-names>
</name>
<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Fann</surname>
<given-names>Cathy S. J.</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Osyetrov</surname>
<given-names>Valeriy</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>King</surname>
<given-names>Chwan-Chuen</given-names>
</name>
<xref rid="aff3" ref-type="aff">3</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Chen</surname>
<given-names>Yi-Ming Arthur</given-names>
</name>
<xref rid="aff4" ref-type="aff">4</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Chang</surname>
<given-names>Hsiao-Ling</given-names>
</name>
<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Kuo</surname>
<given-names>Hung-Wei</given-names>
</name>
<xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Liao</surname>
<given-names>Fong</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref>
</contrib>
<contrib contrib-type="author" corresp="yes">
<name>
<surname>Ho</surname>
<given-names>Mei-Shang</given-names>
</name>
<xref rid="aff1" ref-type="aff">1</xref><xref rid="aff3" ref-type="aff">3</xref><xref rid="aff4" ref-type="aff">4</xref><xref rid="cor1" ref-type="corresp"></xref>
</contrib>
<aff id="aff1"><label>1</label><institution>Institute of Biomedical Science, Academia Sinica</institution>, <addr-line>Taipei, Taiwan</addr-line></aff>
<aff id="aff2"><label>2</label><institution>Center for Disease Control</institution>, <addr-line>Taipei, Taiwan</addr-line></aff>
<aff id="aff3"><label>3</label><institution>Graduate Institute of Epidemiology, National Taiwan University</institution>, <addr-line>Taipei, Taiwan</addr-line></aff>
<aff id="aff4"><label>1</label><institution>Institute of Public Health, National Yang-Ming University</institution>, <addr-line>Taipei, Taiwan</addr-line></aff>
</contrib-group>
<author-notes>
<corresp id="cor1">Reprints or correspondence: Dr. Mei-Shang Ho, IBMS, Academia Sinica, Taipei, 11529 Taiwan (<email>homs@ibms.sinica.edu.tw</email>).</corresp>
</author-notes>
<pub-date pub-type="ppub">
<day>1</day>
<month>6</month>
<year>2006</year>
</pub-date>
<volume>42</volume>
<issue>11</issue>
<fpage>1561</fpage>
<lpage>1569</lpage>
<history>
<date date-type="received">
<day>5</day>
<month>12</month>
<year>2005</year>
</date>
<date date-type="accepted">
<day>1</day>
<month>2</month>
<year>2006</year>
</date>
</history>
<copyright-statement>© 2006 by the Infectious Diseases Society of America</copyright-statement>
<copyright-year>2006</copyright-year>
<abstract>
<p><bold><italic>Background</italic></bold>. A high initial or peak severe acute respiratory syndrome (SARS)—associated coronavirus (SARS-CoV) load in nasopharyngeal specimens was shown to be associated with a high mortality rate. Because all infected individuals were devoid of preeexisting protective immunity against SARS-CoV, the biological basis for the variable virus burdens in different patients remains elusive.</p>
<p><bold><italic>Methods</italic></bold>. The nationwide SARS database in Taiwan was analyzed, and genotyping of 281 single-nucleotide polymorphisms (SNPs) of 65 genes was performed for 94 patients with SARS, to identify SNPs for which distribution between patients with or without detectable nasopharyngeal shedding of SARS-CoV was biased.</p>
<p><bold><italic>Results</italic></bold>. Titers of SARS-CoV shed in nasopharyngeal specimens varied widely, ranging from nondetectable to 10<sup>8</sup> SARS-CoV RNA copies/mL, and they were correlated positively with a high mortality rate (<italic>P</italic> < .0001, by trend test) and with early death (i.e., death occurring within 2 weeks of the onset of illness) (<italic>P</italic> = .0015, by trend test). Virus shedding was found to be higher among male patients (<italic>P</italic> = .0014, by multivariate logistic regression) and among older patients (<italic>P</italic> = .015, by multivariate logistic regression). Detectable nasopharyngeal shedding of SARS-CoV was associated with polymorphic alleles of interleukins 18 (<italic>P</italic> = .014) and 1A (<italic>P</italic> = .031) and a member of NFκB complex (reticuloendotheliosis viral oncogene homolog B [<italic>RelB</italic>]) (<italic>P</italic> = .034), all of which are proinflammatory in nature, as well as the procoagulation molecule fibrinogen-like protein 2 (<italic>P</italic> = .008).</p>
<p><bold><italic>Conclusion</italic></bold>. The SARS-CoV load is a determinant of clinical outcomes of SARS, and it is associated with polymorphisms of genes involved in innate immunity, which might be regulated in an age- and sex-dependent manner. The findings of the present study provided leads to genes involved in the host response to SARS-CoV infection; if substantiated with functional studies, these findings may be applicable to other newly emerged respiratory viruses (e.g., the influenza pandemic strain).</p>
</abstract>
</article-meta>
</front>
<body>
<p>Severe acute respiratory syndrome (SARS) is a recently identified infectious disease caused by a novel coronavirus, SARS-CoV, that causes significant mortality, especially among elderly patients and patients with comorbid factors [<xref rid="ref1" ref-type="bibr">1</xref>–<xref rid="ref4" ref-type="bibr">4</xref>]. The clinical course of SARS consists of initial onset of fever, followed by the development of respiratory symptoms that may progress to acute respiratory distress syndrome in some patients [<xref rid="ref2" ref-type="bibr">2</xref>, <xref rid="ref5" ref-type="bibr">5</xref>] but may be quite self-limiting in others. Serial chest radiographs of patients with SARS have disclosed distinct patterns of disease progression [<xref rid="ref6" ref-type="bibr">6</xref>] and have suggested prolonged recovery in correlation with the clinical severity of the disease. These findings, in conjunction with those of clinical studies of cytokines during the acute phase of SARS [<xref rid="ref7" ref-type="bibr">7</xref>–<xref rid="ref9" ref-type="bibr">9</xref>], have suggested that the development of acute respiratory distress syndrome in patients with SARS is due to an immunopathological response related to strong activation of T helper type 1 cell—mediated immunity and a hyperinnate inflammatory response, rather than to uncontrolled virus growth [<xref rid="ref2" ref-type="bibr">2</xref>].</p>
<p>However, a high initial or peak nasopharyngeal virus load is associated with a high mortality rate [<xref rid="ref10" ref-type="bibr">10</xref>, <xref rid="ref11" ref-type="bibr">11</xref>], and a high serum virus load correlates with an increased risk for admission to an intensive care unit [<xref rid="ref12" ref-type="bibr">12</xref>], highlighting the importance of virus burden to the clinical outcome. High SARS-CoV titers have also been recovered from saliva samples and mouth wash specimens, raising the possibility that the virus also replicates in the upper airway [<xref rid="ref13" ref-type="bibr">13</xref>]. Autopsy findings for patients with SARS who died within 2 weeks after the onset of illness showed that the presence of SARS-CoV was widespread in a number of tissues and organs [<xref rid="ref14" ref-type="bibr">14</xref>, <xref rid="ref15" ref-type="bibr">15</xref>], and that, in some surviving patients, the virus remained for prolonged periods (up to 80 days) [<xref rid="ref16" ref-type="bibr">16</xref>, <xref rid="ref17" ref-type="bibr">17</xref>]. Detection of virus in airway aspirates, serum samples, or fecal specimens beyond the 10th day of illness suggested continuing, unabated viral replication and indicated a poor prognosis [<xref rid="ref18" ref-type="bibr">18</xref>]. In a small study of a series of postmortem lung tissues, detection of a high virus load in lung tissue was associated with a survival time of <21 days [<xref rid="ref19" ref-type="bibr">19</xref>].</p>
<p>Given the assumption that all patients had neither preexisting protective immunity against SARS-CoV nor access to antiviral drugs, which can effectively alter the level of virus shedding, the biological basis for the differences in the virus burden in different patients is intriguing and has not yet been elucidated. In this report, the virus load of patients with confirmed SARS-CoV infection at the time of admission to the hospital was analyzed in relation to sex, age, and the genetic polymorphism of genes involved in proinflammation and innate immunity responses.</p>
<sec sec-type="material|methods" id="sec1">
<title>Material and Methods</title>
<p><bold><italic>The database</italic></bold>. The nationwide SARS database in Taiwan includes all laboratory-confirmed cases of SARS reported from March through June 2003. The details of data compilation have been described elsewhere [<xref rid="ref20" ref-type="bibr">20</xref>, <xref rid="ref21" ref-type="bibr">21</xref>]. Our analysis focused on the initial nasopharyngeal SARS-CoV load at the time of admission to the hospital and included 154 patients whose virus loads were quantified using a commercially available RT-PCR assay (Artus Real Art HPA-Coronavirus; Artus), as well as 111 patients who had successive negative results of testing of nasopharyngeal samples and for whom diagnoses of SARS were based on a positive finding of seroconversion of SARS-neutralizing antibody.</p>
<p><bold><italic>The genetic study</italic></bold>. The genetic study was designed to compare the genetic background of patients who had SARS with or without detectable nasopharyngeal SARS-CoV. All surviving patients with SARS were followed up, and 108 genetically unrelated patients with laboratory-confirmed SARS consented to participate in this study. A reference group of 94 Taiwanese subjects was selected, on the basis of an age- and sex-stratified random sampling scheme, from a biobank compiled as part of a nationwide population study that enrolled 3312 Han Chinese descendants residing in Taiwan [<xref rid="ref22" ref-type="bibr">22</xref>]. The study protocol, including an informed consent statement that conforms to the fifth edition of the Helsinki Declaration, was approved by the Medical Research Ethics Committee of the Institute of Biomedical Sciences (Taipei, Taiwan) (application #AS-IBMS-MREC-92-11).</p>
<p><bold><italic>Genes and single-nucleotide polymorphism (SNP) selection</italic></bold>. We focused on genes whose products are either known to or have been predicted to interact with SARS-CoV in antiviral responses, inflammation, or immunostimulation (<xref ref-type="fig" rid="tab1">table 1</xref>) [<xref rid="ref23" ref-type="bibr">23</xref>]. SNPs of these genes were identified in 5 databases: the SNP Consortium, the National Center for Biotechnology Information, GeneSNPs Public Internet Resource, GeneCards, and the Japan SNP Database. A total of 281 SNPs in 65 genes (<xref ref-type="fig" rid="tab1">table 1</xref>) were studied, with 127 (45.2%) of these 281 SNPs showing no variants (<1%) according to the results of a test run of 94 DNAs selected from the reference Han population (power, >80%) [<xref rid="ref25" ref-type="bibr">25</xref>].</p>
<p><bold><italic>SNP genotyping</italic></bold>. Genotyping was performed using either (1) the Sequenom MassArray MALDI-TOF system (Sequenom) at the Taiwan National Genotyping Center core facility, by use of primers for SNP typing that were designed using Spectro-Designer software (Sequenom), or (2) the ABI 7000 system (Applied Biosystems), if the Sequenom system could not design the primers. For quality control, genotyping of up to 20% of the samples was repeated; any discrepancy was verified by sequence analysis, and the error rate was <1%.</p>
<p><bold><italic>Statistical analysis</italic></bold>. Data analysis was performed, unless stated otherwise, by use of SAS, version 8, or SAS/Genetics (SAS Institute). Hardy-Weinberg equilibrium was tested for each SNP result of the Han reference population, and the genotyping assay was repeated or another method was used for testing if the results violated Hardy-Weinberg equilibrium. Haplotypes for all SNPs of each gene were predicted using the Phase 2.0.2 program [<xref rid="ref26" ref-type="bibr">26</xref>]. For each SNP, univariate analysis was performed by comparing the frequencies of alleles and genotypes between patients with or without detectable SARS-CoV in nasopharyngeal specimens. Tests for models of dominant/recessive or codominant traits were performed to identify the susceptible genotypes of the SNP. The empirical <italic>P</italic> value was calculated using the permutation test of 10,000 rounds for each SNP for which an association with the virus load was demonstrated. Tests of significance that were performed included the χ<sup>2</sup> test, the Cochran-Armitage trend test, Fisher's exact test, and the exact Mantel-Haenszel test. The continuous variables (i.e., age and virus load) were compared using the Wilcoxon rank sum test, to analyze factors that could have potentially affected the virus load, including demographic characteristics, the source of infection, and the duration of illness. Associations between nasopharyngeal SARS-CoV shedding and multiple variables were analyzed simultaneously in a cumulative logistic model. Interactions between genes were tested in a cumulative logistic model for virus detection.</p>
</sec>
<sec sec-type="results" id="sec2">
<title>Results</title>
<p><bold><italic>Nasopharyngeal SARS-CoV load</italic></bold>. The virus load in the respiratory tract at the time of admission to the hospital or diagnosis of SARS ranged widely (from undetectable to 10<sup>8</sup> SARS-CoV RNA copies/mL) (<xref rid="fig1" ref-type="fig">figure 1</xref>). Although a longitudinal study of patients with SARS indicated that the nasopharyngeal virus load increased between the fifth and the 10th days of illness and decreased by the 15th day of illness [<xref rid="ref2" ref-type="bibr">2</xref>], the virus loads at the time of admission of all patients with SARS in our data set did not reflect this trend of a rise and fall occurring during the first 2 weeks of the clinical course of SARS. Rather, on any given day within the first week of the clinical course of SARS, the nasopharyngeal virus load in different patients ranged widely. Overall, 111 (41.9%) of 265 patients with SARS had an undetectable level of nasopharyngeal virus shedding, and this lack of detection of virus did not correlate with the time of specimen collection, because successive samples were obtained from these patients, and the test results for these specimens remained negative.</p>
<p><bold><italic>Factors influencing the level of virus shedding</italic></bold>. Among patients with SARS, undetectable levels of nasopharyngeal SARS-CoV shedding were found more often among female patients (50.0%) than among male patients (27.4%), and they were also found more often among younger patients (53.1% of patients <30 years of age) than among older patients (37.7% of patients ⩾30 years of age) (<xref ref-type="fig" rid="tab2">table 2</xref> and <xref rid="fig2" ref-type="fig">figure 2</xref>). When only the virus titer of patients with detectable virus shedding was the focus of investigation, female patients consistently shed lower titers of virus than did male patients (<italic>P</italic> = .045, by the multivariate logistic regression model). Furthermore, in a multivariate cumulative logistic regression model in which (1) the date of sample collection was controlled, and (2) any underlying diseases and the source of infection (identifiable or not) were considered simultaneously, female sex (<italic>P</italic> = .001) and younger age (<italic>P</italic> = .005) were independently associated with a lower virus load, whereas having an underlying disease or a known source of infection did not influence virus shedding. Because the lack of virus detection may be the result of lower levels of virus shedding occurring at the time of sample collection during the early (<5 days of illness) or later (>15 days of illness) clinical phase of disease [<xref rid="ref2" ref-type="bibr">2</xref>], the multivariate model confirmed that nasopharyngeal specimens in which levels of virus shedding were undetectable were collected at the same time relative to disease onset as were specimens in which virus levels were detectable; lack of detection of virus did not correlate with early sample collection.</p>
<p><bold><italic>Clinical significance of virus shedding</italic></bold>. We further analyzed the mortality rate relative to the levels of virus shedding, to validate the biological significance of detection of virus in nasopharyngeal specimens (<xref ref-type="fig" rid="tab2">table 2</xref>). The mortality rate was 46.2% among patients with >10<sup>5</sup> SARS-CoV RNA copies/mL detected in nasopharyngeal specimens, whereas the mortality rate was only 9.9% among patients with undetectable levels of virus in nasopharyngeal specimens. Furthermore, the duration of survival for the patients whose cases of SARS were fatal was significantly shortened (to <2 weeks), with increasing levels of virus shedding occurring during the acute phase of the disease (<xref ref-type="fig" rid="tab3">table 3</xref>). of the patients with fatal cases of SARS who had >10<sup>5</sup> SARS-CoV RNA copies/mL detected in nasopharyngeal specimens, 77.8% died within the first 2 weeks of SARS illness, whereas, of the patients with fatal cases of SARS who did not have virus detected in nasopharyngeal specimens, only 18% died within the first 2 weeks of illness (<italic>P</italic> = .001, by Cochran-Armitage trend test).</p>
<p><bold><italic>Polymorphic genes associated with the detection of SARS-CoV in nasopharyngeal specimens</italic></bold>. With mortality data validating the biological significance of undetectable nasopharyngeal virus shedding, we then compared the genotype distribution of SNPs between the 2 groups of patients with detectable or undetectable virus shedding (<xref ref-type="fig" rid="tab4">table 4</xref> and <xref rid="fig3" ref-type="fig">figure 3</xref>). of the 281 SNPs tested, 4 SNPs of 4 genes showed a significant association with virus load. IL-18 <italic>(IL18)</italic> of -607T (rs1946518) in the promoter, IL-1A <italic>(IL1A)</italic> of -889T (rs1800587) upstream from the ATG, <italic>RelB</italic> (reticuloendotheliosis viral oncogene homolog B) in intron 5 at +23962T (rs2288918) from the ATG, and the fibrinogen-like protein 2 <italic>(FGL2)</italic> of +158A (rs2075761) (resulting in an amino acid substitution from glycine to glutamic acid) were overrepresented in patients with detectable levels of SARS-CoV. For the genotype distribution of each SNP, empirical <italic>P</italic> values were calculated using permutation tests of 10,000 rounds and confirmed the statistical significance of <italic>P</italic> < .05 (<xref ref-type="fig" rid="tab4">table 4</xref>).</p>
<p>Analysis performed by further stratification of these 4 genes did not suggest any interactions between these genes that contributed to the level of virus shedding. Multivariate analysis confirmed that all loci were independently associated with virus load (<xref ref-type="fig" rid="tab4">table 4</xref>). Furthermore, the homozygous individuals possessing 2 alleles of -607T <italic>IL18</italic> had increased risk of virus shedding, compared with the heterozygous individuals possessing only 1 allele when genotypes of the other 3 alleles were controlled. A total of 13 SNPs in the 4 genes were typed, and polymorphisms were found at 2 of 6 <italic>IL18</italic> loci (-607 and -137), at 1 of 2 <italic>RelB</italic> loci, at 1 <italic>IL1A</italic> locus, and at 3 of 4 <italic>FGL2</italic> loci (-1285, -656, and +158). The haplotypes were analyzed for <italic>IL18</italic> and <italic>FLG2;</italic> only a single locus of <italic>IL18</italic> (-607) and <italic>FGL2</italic> (+158) showed an association with virus load. We compared both the allelic and genotypic distributions of these 4 loci between the 94 patients with SARS and the 94 healthy Taiwanese in the reference group, and we found no statistical difference (<xref ref-type="fig" rid="tab4">table 4</xref>).</p>
</sec>
<sec sec-type="discussion" id="sec3">
<title>Discussion</title>
<p>The clinical significance of the virus burden is intuitive, but it has been difficult to directly demonstrate. In the present report, we showed the dramatic interindividual difference in virus burden and the direct correlation of such virus burden with clinical outcomes. Our analysis further indicated that a high SARS-CoV load is associated with early death, in addition to a high mortality rate, as previously reported elsewhere [<xref rid="ref10" ref-type="bibr">10</xref>–<xref rid="ref12" ref-type="bibr">12</xref>]. Therefore, our results suggest that (1) the level of nasopharyngeal virus shedding during the acute phase of SARS (<2 weeks of illness) can be monitored as an index for therapeutic and clinical progress, and (2) identification of genes associated with virus load can potentially provide leads to pathways involved in virus clearance during the early phase of infection. To the best of our knowledge, this is the first study to probe into the factors influencing the SARS-CoV load.</p>
<p>The exploratory nature of this genetic study necessitated the screening of a large number of SNPs; applying the conventional Bonferroni correction for multiple tests (<italic>n</italic> = 281) would not be most appropriate. However, the internal validity of results based on a small sample size in an epidemic setting was further substantiated by the results of permutation tests. On the basis of a preset level of statistical significance, 4 SNPs were singled out for further analysis and discussion. An additional 10 SNPs of 6 genes, which showed differences of >10% in the allele frequency between patients with or without detectable SARS-CoV but for which the differences did not reach the level considered to be significant (<xref rid="fig3" ref-type="fig">figure 3</xref>), were also highlighted and should be investigated if the opportunity arises. These candidate genes were selected on the basis of the biological plausibility of innate immune responses to viral infections in a broad sense, rather than specific to SARS-CoV; thus, similar considerations may be pertinent and applicable to a potential influenza pandemic in which no individuals have preexisting immunity and in which the effects of the innate immunity of the hosts would be most conspicuous.</p>
<p>Three of the 4 SNPs <italic>(IL18, IL1A</italic>, and <italic>RelB)</italic> belong to proinflammatory genes. Both <italic>IL18</italic> and <italic>IL1</italic> signal through pathways involving the transcription factor <italic>NFκB</italic> [<xref rid="ref27" ref-type="bibr">27</xref>–<xref rid="ref29" ref-type="bibr">29</xref>], to which several proinflammation pathways converge and <italic>RelB</italic> is a subunit. <italic>RelB</italic> belongs to the <italic>Rel</italic> proteins that are evolutionarily conserved mediators of immune responses and are especially important to cytokine expression and the differentiation and survival of cells in the immune system [<xref rid="ref30" ref-type="bibr">30</xref>]; <italic>RelB</italic> mutant mice display a severe and fatal multiorgan inflammation. The induction of <italic>NFκB</italic>, to which <italic>RelB</italic> is a subunit, is reduced in T lymphocytes from old mice [<xref rid="ref31" ref-type="bibr">31</xref>] and is a potential mechanism to explain the senescence of immunity. Whether the genetic variant of <italic>RelB</italic>, which is associated with higher virus load, represents a suppressed or an overly reactive function of <italic>RelB</italic> (i.e., inflammation signaling) remains elusive.</p>
<p><italic>IL18</italic>, which is a member of the <italic>IL1</italic> family and also is a pleiotropic proinflammatory cytokine in activating natural killer cells and enhancing the T helper type 1 cell immune response, is constitutively expressed in the lung [<xref rid="ref32" ref-type="bibr">32</xref>]. <italic>IL18</italic> knockout mice were shown to clear influenza virus more effectively [<xref rid="ref33" ref-type="bibr">33</xref>], and the polymorphic alleles of <italic>IL1A</italic> (-889) have been reported to predict control of plasma viremia in patients with HIV-1 infection who are undergoing antiretroviral therapy [<xref rid="ref34" ref-type="bibr">34</xref>], suggesting that both <italic>IL18</italic> and <italic>IL1A</italic> participate in the clearance of viral infection in a broad sense. Estrogen has been shown to reduce <italic>IL18</italic> mRNA levels in the mouse uterus [<xref rid="ref35" ref-type="bibr">35</xref>], suggesting that regulation of <italic>IL18</italic> expression could be sex dependent. The outcomes of infection or the level of response to vaccination has been noted to demonstrate sex differences (see Beagley et al. [<xref rid="ref36" ref-type="bibr">36</xref>] and Morales-Montor et al. [<xref rid="ref37" ref-type="bibr">37</xref>] for reviews); the innate and adaptive immunity may be regulated through sex hormones [<xref rid="ref38" ref-type="bibr">38</xref>]. A higher mortality rate among male patients with SARS was suggested in an analysis of the Hong Kong and Taiwan databases [<xref rid="ref39" ref-type="bibr">39</xref>]; it would be more informative if the analysis had included information on nasopharyngeal virus burden, which is currently a commonly used method of diagnosing SARS and other viral infections.</p>
<p>FGL2, an IFN-γ—inducible protein expressed by lymphocytes, macrophages, and endothelium, is a prothrombinase that has been reported to contribute to fibrin deposition during viral hepatitis, and its expression is associated with a number of pathological conditions [<xref rid="ref40" ref-type="bibr">40</xref>–<xref rid="ref42" ref-type="bibr">42</xref>]. The inclusion of <italic>FGL2</italic> in the present study was based on reports that <italic>FGL2</italic> expression could be induced by the nucleocapsid protein of virulent mouse hepatitis virus, also a coronavirus [<xref rid="ref43" ref-type="bibr">43</xref>]. The <italic>FGL2</italic> SNP at +158 also shows an association with the clinical severity of SARS (W.-Y. Tsai, C.S.J.F., W.-J.C., V.O., C.-C.K., Y.-M.A.C., Y.-T. Lu, C.-L. Liu, C.-L. Chao, H.-L.C., H.-W.K., B.-L. Chiang, F.L., I.-J. Su, and M.-S.H., unpublished data), and <italic>FGL2</italic> protein is highly expressed in the respiratory tract, according to the findings of immunohistochemical analysis (M.-L. Huang, L.-Y. Chao, and M.-S.H., unpublished data). Human <italic>FGL2</italic> mRNA was shown to be preferentially expressed in memory T lymphocytes (CD3<sup>+</sup>/CD45R0<sup>+</sup>) in one study [<xref rid="ref44" ref-type="bibr">44</xref>]. Patients with SARS who were of advanced age had a higher mortality rate [<xref rid="ref1" ref-type="bibr">1</xref>–<xref rid="ref4" ref-type="bibr">4</xref>] and higher virus loads than did younger patients in this study; how these observations are related to the preferential expression of <italic>FGL2</italic> in memory T lymphocytes remains to be investigated.</p>
<p>Most patients with the highest level of virus shedding (>10<sup>6</sup> SARS-CoV RNA copies/mL) were not included in our genetic analysis because of their early death. Therefore, it was not possible to conduct a multivariate analysis to simultaneously examine the effects of age, sex, and genetic polymorphism on death. The biological basis of the increased virus load in older patients remains elusive, be it the senescence of immunity (see Stout and Suttles [<xref rid="ref45" ref-type="bibr">45</xref>] for a review), which undermines the efficacy of both innate and adaptive immunity, or the enhanced virus infection, for which age is a confounder [<xref rid="ref21" ref-type="bibr">21</xref>].</p>
<p>Because the Han descendants, who constitute >98% of the population of Taiwan, are genetically homogenous, according to a recent study of the SNPs of the major histocompatibility complexes [<xref rid="ref46" ref-type="bibr">46</xref>], population stratification that confounds our results is not of major concern. Furthermore, this work constitutes a population-based study in that all surviving patients with SARS were solicited, and no selection bias was involved in the classification of participating patients with SARS into case and control groups that were based on results of tests to determine virus burden.</p>
<p>In conclusion, the SARS-CoV load during the initial phase of infection, which is crucial to the clinical outcome of patients with SARS, is shown, for what we believe is the first time, to be associated with polymorphisms of genes involved in innate immunity. These genes, although not claimed to be a comprehensive list, have exemplified potential pathways of innate immunity in response to SARS-CoV or, more broadly, to other viral infections. It is imperative to proceed with functional studies to test whether these genes are indeed functionally active in signaling pathways to the direct suppression of virus replication or to the clearance of virally infected cells. Understanding how the interplay between the virus load during the early stage (<2 weeks of illness) and the later stage (>2 weeks of illness) of host response might contribute to the clinical outcome of SARS should be helpful in the clinical management of patients with SARS.</p>
</sec>
</body>
<back>
<ack>
<title>Acknowledgments</title>
<p>We thank all the public health nurses who helped collect epidemiological data; the Division of Surveillance staff at the Taiwan Center for Disease Control who compiled the epidemiological database; and Yu-Jen Liang, who assisted in data analysis.</p>
<p><bold><italic>Financial support</italic></bold>. Academia Sinica and Taiwan National Science Council (institutional grant #NSC92-2751-B-001-019-Y).</p>
<p><bold><italic>Potential conflicts of interest</italic></bold>. M.S.H. serves, on behalf of the Development Fund of the Executive Yuan (of the Taiwan Central Government), as a board member of ADImmune. All other authors: no conflicts.</p>
</ack>
<ref-list>
<title>References</title>
<ref id="ref1">
<label>1</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Booth</surname>
<given-names>CM</given-names>
</name>
<name>
<surname>Matukas</surname>
<given-names>LM</given-names>
</name>
<name>
<surname>Tomlinson</surname>
<given-names>GA</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area</article-title>
<source>JAMA</source>
<year>2003</year>
<volume>289</volume>
<fpage>2801</fpage>
<lpage>9</lpage>
</nlm-citation>
</ref>
<ref id="ref2">
<label>2</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Peiris</surname>
<given-names>JS</given-names>
</name>
<name>
<surname>Chu</surname>
<given-names>CM</given-names>
</name>
<name>
<surname>Cheng</surname>
<given-names>VC</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study</article-title>
<source>Lancet</source>
<year>2003</year>
<volume>361</volume>
<fpage>1767</fpage>
<lpage>72</lpage>
</nlm-citation>
</ref>
<ref id="ref3">
<label>3</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Rainer</surname>
<given-names>TH</given-names>
</name>
<name>
<surname>Chan</surname>
<given-names>PK</given-names>
</name>
<name>
<surname>Ip</surname>
<given-names>M</given-names>
</name>
<etal></etal>
</person-group>
<article-title>The spectrum of severe acute respiratory syndrome-associated coronavirus infection</article-title>
<source>Ann Intern Med</source>
<year>2004</year>
<volume>140</volume>
<fpage>614</fpage>
<lpage>9</lpage>
</nlm-citation>
</ref>
<ref id="ref4">
<label>4</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Tsui</surname>
<given-names>PT</given-names>
</name>
<name>
<surname>Kwok</surname>
<given-names>ML</given-names>
</name>
<name>
<surname>Yuen</surname>
<given-names>H</given-names>
</name>
<name>
<surname>Lai</surname>
<given-names>ST</given-names>
</name>
</person-group>
<article-title>Severe acute respiratory syndrome: clinical outcome and prognostic correlates</article-title>
<source>Emerg Infect Dis</source>
<year>2003</year>
<volume>9</volume>
<fpage>1064</fpage>
<lpage>9</lpage>
</nlm-citation>
</ref>
<ref id="ref5">
<label>5</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Cheung</surname>
<given-names>OY</given-names>
</name>
<name>
<surname>Chan</surname>
<given-names>JW</given-names>
</name>
<name>
<surname>Ng</surname>
<given-names>CK</given-names>
</name>
<name>
<surname>Koo</surname>
<given-names>CK</given-names>
</name>
</person-group>
<article-title>The spectrum of pathological changes in severe acute respiratory syndrome (SARS)</article-title>
<source>Histopathology</source>
<year>2004</year>
<volume>45</volume>
<fpage>119</fpage>
<lpage>24</lpage>
</nlm-citation>
</ref>
<ref id="ref6">
<label>6</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Wong</surname>
<given-names>KT</given-names>
</name>
<name>
<surname>Antonio</surname>
<given-names>GE</given-names>
</name>
<name>
<surname>Hui</surname>
<given-names>DS</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Severe acute respiratory syndrome: radiographic appearances and pattern of progression in 138 patients</article-title>
<source>Radiology</source>
<year>2003</year>
<volume>228</volume>
<fpage>401</fpage>
<lpage>6</lpage>
</nlm-citation>
</ref>
<ref id="ref7">
<label>7</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Wong</surname>
<given-names>CK</given-names>
</name>
<name>
<surname>Lam</surname>
<given-names>CW</given-names>
</name>
<name>
<surname>Wu</surname>
<given-names>AK</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome</article-title>
<source>Clin Exp Immunol</source>
<year>2004</year>
<volume>136</volume>
<fpage>95</fpage>
<lpage>103</lpage>
</nlm-citation>
</ref>
<ref id="ref8">
<label>8</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Jiang</surname>
<given-names>Y</given-names>
</name>
<name>
<surname>Xu</surname>
<given-names>J</given-names>
</name>
<name>
<surname>Zhou</surname>
<given-names>C</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Characterization of cytokine/chemokine profiles of severe acute respiratory syndrome</article-title>
<source>Am J Respir Crit Care Med</source>
<year>2005</year>
<volume>171</volume>
<fpage>850</fpage>
<lpage>7</lpage>
</nlm-citation>
</ref>
<ref id="ref9">
<label>9</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Huang</surname>
<given-names>KJ</given-names>
</name>
<name>
<surname>Su</surname>
<given-names>IJ</given-names>
</name>
<name>
<surname>Theron</surname>
<given-names>M</given-names>
</name>
<etal></etal>
</person-group>
<article-title>An interferon-gamma-related cytokine storm in SARS patients</article-title>
<source>J Med Virol</source>
<year>2005</year>
<volume>75</volume>
<fpage>185</fpage>
<lpage>94</lpage>
</nlm-citation>
</ref>
<ref id="ref10">
<label>10</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Chu</surname>
<given-names>CM</given-names>
</name>
<name>
<surname>Poon</surname>
<given-names>LL</given-names>
</name>
<name>
<surname>Cheng</surname>
<given-names>VC</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Initial viral load and the outcomes of SARS</article-title>
<source>CMAJ</source>
<year>2004</year>
<volume>171</volume>
<fpage>1349</fpage>
<lpage>52</lpage>
</nlm-citation>
</ref>
<ref id="ref11">
<label>11</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Cheng</surname>
<given-names>VC</given-names>
</name>
<name>
<surname>Hung</surname>
<given-names>IF</given-names>
</name>
<name>
<surname>Tang</surname>
<given-names>BS</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Viral replication in the nasopharynx is associated with diarrhea in patients with severe acute respiratory syndrome</article-title>
<source>Clin Infect Dis</source>
<year>2004</year>
<volume>38</volume>
<fpage>467</fpage>
<lpage>75</lpage>
</nlm-citation>
</ref>
<ref id="ref12">
<label>12</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Ng</surname>
<given-names>EK</given-names>
</name>
<name>
<surname>Hui</surname>
<given-names>DS</given-names>
</name>
<name>
<surname>Chan</surname>
<given-names>KC</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Quantitative analysis and prognostic implication of SARS coronavirus RNA in the plasma and serum of patients with severe acute respiratory syndrome</article-title>
<source>Clin Chem</source>
<year>2003</year>
<volume>49</volume>
<fpage>1976</fpage>
<lpage>80</lpage>
</nlm-citation>
</ref>
<ref id="ref13">
<label>13</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Wang</surname>
<given-names>WK</given-names>
</name>
<name>
<surname>Chen</surname>
<given-names>SY</given-names>
</name>
<name>
<surname>Liu</surname>
<given-names>IJ</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Detection of SARS-associated coronavirus in throat wash and saliva in early diagnosis</article-title>
<source>Emerg Infect Dis</source>
<year>2004</year>
<volume>10</volume>
<fpage>1213</fpage>
<lpage>9</lpage>
</nlm-citation>
</ref>
<ref id="ref14">
<label>14</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Ding</surname>
<given-names>YQ</given-names>
</name>
<name>
<surname>Wang</surname>
<given-names>HJ</given-names>
</name>
<name>
<surname>Shen</surname>
<given-names>H</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Study on etiology and pathology of severe acute respiratory syndrome [in Chinese]</article-title>
<source>Zhonghua Bing Li Xue Za Zhi</source>
<year>2003</year>
<volume>32</volume>
<fpage>195</fpage>
<lpage>200</lpage>
</nlm-citation>
</ref>
<ref id="ref15">
<label>15</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Farcas</surname>
<given-names>GA</given-names>
</name>
<name>
<surname>Poutanen</surname>
<given-names>SM</given-names>
</name>
<name>
<surname>Mazzulli</surname>
<given-names>T</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Fatal severe acute respiratory syndrome is associated with multiorgan involvement by coronavirus</article-title>
<source>J Infect Dis</source>
<year>2005</year>
<volume>191</volume>
<fpage>193</fpage>
<lpage>7</lpage>
</nlm-citation>
</ref>
<ref id="ref16">
<label>16</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Wang</surname>
<given-names>CH</given-names>
</name>
<name>
<surname>Liu</surname>
<given-names>CY</given-names>
</name>
<name>
<surname>Wan</surname>
<given-names>YL</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Persistence of lung inflammation and lung cytokines with high-resolution CT abnormalities during recovery from SARS</article-title>
<source>Respir Res</source>
<year>2005</year>
<volume>6</volume>
<fpage>42</fpage>
<lpage>0</lpage>
</nlm-citation>
</ref>
<ref id="ref17">
<label>17</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Chu</surname>
<given-names>CM</given-names>
</name>
<name>
<surname>Leung</surname>
<given-names>WS</given-names>
</name>
<name>
<surname>Cheng</surname>
<given-names>VC</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Duration of RT-PCR positivity in severe acute respiratory syndrome</article-title>
<source>Eur Respir J</source>
<year>2005</year>
<volume>25</volume>
<fpage>12</fpage>
<lpage>4</lpage>
</nlm-citation>
</ref>
<ref id="ref18">
<label>18</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Hung</surname>
<given-names>IF</given-names>
</name>
<name>
<surname>Cheng</surname>
<given-names>VC</given-names>
</name>
<name>
<surname>Wu</surname>
<given-names>AK</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Viral loads in clinical specimens and SARS manifestations</article-title>
<source>Emerg Infect Dis</source>
<year>2004</year>
<volume>10</volume>
<fpage>1550</fpage>
<lpage>7</lpage>
</nlm-citation>
</ref>
<ref id="ref19">
<label>19</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Mazzulli</surname>
<given-names>T</given-names>
</name>
<name>
<surname>Farcas</surname>
<given-names>GA</given-names>
</name>
<name>
<surname>Poutanen</surname>
<given-names>SM</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Severe acute respiratory syndrome-associated coronavirus in lung tissue</article-title>
<source>Emerg Infect Dis</source>
<year>2004</year>
<volume>10</volume>
<fpage>20</fpage>
<lpage>4</lpage>
</nlm-citation>
</ref>
<ref id="ref20">
<label>20</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Wu</surname>
<given-names>HS</given-names>
</name>
<name>
<surname>Chiu</surname>
<given-names>SC</given-names>
</name>
<name>
<surname>Tseng</surname>
<given-names>TC</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Serologic and molecular biologic methods for SARS-associated coronavirus infection, Taiwan</article-title>
<source>Emerg Infect Dis</source>
<year>2004</year>
<volume>10</volume>
<fpage>304</fpage>
<lpage>10</lpage>
</nlm-citation>
</ref>
<ref id="ref21">
<label>21</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Ho</surname>
<given-names>M-S</given-names>
</name>
<name>
<surname>Chen</surname>
<given-names>W-J</given-names>
</name>
<name>
<surname>Chen</surname>
<given-names>H-Y</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Neutralizing antibody response and SARS severity</article-title>
<source>Emerg Infect Dis</source>
<year>2005</year>
<volume>11</volume>
<fpage>1730</fpage>
<lpage>7</lpage>
</nlm-citation>
</ref>
<ref id="ref22">
<label>22</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Pan</surname>
<given-names>WH</given-names>
</name>
<name>
<surname>Fann</surname>
<given-names>CSJ</given-names>
</name>
<name>
<surname>Wu</surname>
<given-names>JY</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Han Chinese cell and genome bank in Taiwan: purpose, design and ethical considerations</article-title>
<source>Hum Hered</source>
<year>2006</year>
<volume>61</volume>
<fpage>27</fpage>
<lpage>30</lpage>
</nlm-citation>
</ref>
<ref id="ref23">
<label>23</label>
<nlm-citation citation-type="book">
<person-group person-group-type="author">
<name>
<surname>Chen</surname>
<given-names>WJ</given-names>
</name>
<name>
<surname>Fann</surname>
<given-names>CSJ</given-names>
</name>
<name>
<surname>Osyetrov</surname>
<given-names>V</given-names>
</name>
<name>
<surname>Ho</surname>
<given-names>MS</given-names>
</name>
</person-group>
<collab>Table 1: the 64 candidate genes</collab>
<comment>Available at: <ext-link ext-link-type="uri" xlink:href="http://www.ibms.sinica.edu.tw/html/pi/msho_download/Table%201_SARS%20&%20SNP_950127.pdf.">http://www.ibms.sinica.edu.tw/html/pi/msho_download/Table%201_SARS%20&%20SNP_950127.pdf.</ext-link> Accessed 27 January 2006</comment>
</nlm-citation>
</ref>
<ref id="ref24">
<label>24</label>
<nlm-citation citation-type="book">
<person-group person-group-type="author">
<collab>HUGO Gene Nomenclature Committee</collab>
</person-group>
<source>Searchgenes</source>
<comment>Available at: <ext-link ext-link-type="uri" xlink:href="http://www.gene.ucl.ac.uk/cgi-bin/nomenclature/searchgenes.pl.">http://www.gene.ucl.ac.uk/cgi-bin/nomenclature/searchgenes.pl.</ext-link> Accessed 31 November 2005</comment>
</nlm-citation>
</ref>
<ref id="ref25">
<label>25</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Ott</surname>
<given-names>J</given-names>
</name>
</person-group>
<article-title>Strategies for characterizing highly polymorphic markers in human gene mapping</article-title>
<source>Am J Hum Genet</source>
<year>1992</year>
<volume>51</volume>
<fpage>283</fpage>
<lpage>90</lpage>
</nlm-citation>
</ref>
<ref id="ref26">
<label>26</label>
<nlm-citation citation-type="book">
<person-group person-group-type="author">
<name>
<surname>Stephens</surname>
<given-names>M</given-names>
</name>
<etal></etal>
</person-group>
<source>PHASEv2</source>
<comment>Available at: <ext-link ext-link-type="uri" xlink:href="http://depts.washington.edu/ventures/UW_Technology/Express_Licenses/PHASEv2.php.">http://depts.washington.edu/ventures/UW_Technology/Express_Licenses/PHASEv2.php.</ext-link> Accessed 31 January 2005</comment>
</nlm-citation>
</ref>
<ref id="ref27">
<label>27</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Weinstock</surname>
<given-names>JV</given-names>
</name>
<name>
<surname>Blum</surname>
<given-names>A</given-names>
</name>
<name>
<surname>Metwali</surname>
<given-names>A</given-names>
</name>
<name>
<surname>Elliott</surname>
<given-names>D</given-names>
</name>
<name>
<surname>Arsenescu</surname>
<given-names>R</given-names>
</name>
</person-group>
<article-title>IL-18 and IL-12 signal through the NF-κB pathway to induce NK-1R expression on T cells</article-title>
<source>J Immunol</source>
<year>2003</year>
<volume>170</volume>
<fpage>5003</fpage>
<lpage>7</lpage>
</nlm-citation>
</ref>
<ref id="ref28">
<label>28</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Sareneva</surname>
<given-names>T</given-names>
</name>
<name>
<surname>Julkunen</surname>
<given-names>I</given-names>
</name>
<name>
<surname>Matikainen</surname>
<given-names>S</given-names>
</name>
</person-group>
<article-title>IFN-alpha and IL-12 induce IL-18 receptor gene expression in human NK and T cells</article-title>
<source>J Immunol</source>
<year>2000</year>
<volume>165</volume>
<fpage>1933</fpage>
<lpage>8</lpage>
</nlm-citation>
</ref>
<ref id="ref29">
<label>29</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Wickremasinghe</surname>
<given-names>MI</given-names>
</name>
<name>
<surname>Thomas</surname>
<given-names>LH</given-names>
</name>
<name>
<surname>Friedland</surname>
<given-names>JS</given-names>
</name>
</person-group>
<article-title>Pulmonary epithelial cells are a source of IL-8 in the response to <italic>Mycobacterium tuberculosis:</italic> essential role of IL-1 from infected monocytes in a NF-κB-dependent network</article-title>
<source>J Immunol</source>
<year>1999</year>
<volume>163</volume>
<fpage>3936</fpage>
<lpage>47</lpage>
</nlm-citation>
</ref>
<ref id="ref30">
<label>30</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Ghosh</surname>
<given-names>S</given-names>
</name>
<name>
<surname>May</surname>
<given-names>MJ</given-names>
</name>
<name>
<surname>Kopp</surname>
<given-names>EB</given-names>
</name>
</person-group>
<article-title>NF-κB and Rel proteins: evolutionarily conserved mediators of immune responses</article-title>
<source>Annu Rev Immunol</source>
<year>1998</year>
<volume>16</volume>
<fpage>225</fpage>
<lpage>60</lpage>
</nlm-citation>
</ref>
<ref id="ref31">
<label>31</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Trebilcock</surname>
<given-names>GU</given-names>
</name>
<name>
<surname>Ponnappan</surname>
<given-names>U</given-names>
</name>
</person-group>
<article-title>Induction and regulation of NFκB during aging: role of protein kinases</article-title>
<source>Clin Immunol Immunopathol</source>
<year>1996</year>
<volume>79</volume>
<fpage>87</fpage>
<lpage>91</lpage>
</nlm-citation>
</ref>
<ref id="ref32">
<label>32</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Allan</surname>
<given-names>SM</given-names>
</name>
<name>
<surname>Tyrrell</surname>
<given-names>PJ</given-names>
</name>
<name>
<surname>Rothwell</surname>
<given-names>NJ</given-names>
</name>
</person-group>
<article-title>Interleukin-1 and neuronal injury</article-title>
<source>Nat Rev Immunol</source>
<year>2005</year>
<volume>5</volume>
<fpage>629</fpage>
<lpage>40</lpage>
</nlm-citation>
</ref>
<ref id="ref33">
<label>33</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Van Der Sluijs</surname>
<given-names>KF</given-names>
</name>
<name>
<surname>Van Elden</surname>
<given-names>LJ</given-names>
</name>
<name>
<surname>Arens</surname>
<given-names>R</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Enhanced viral clearance in interleukin-18 gene-deficient mice after pulmonary infection with influenza A virus</article-title>
<source>Immunology</source>
<year>2005</year>
<volume>114</volume>
<fpage>112</fpage>
<lpage>20</lpage>
</nlm-citation>
</ref>
<ref id="ref34">
<label>34</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Price</surname>
<given-names>P</given-names>
</name>
<name>
<surname>James</surname>
<given-names>I</given-names>
</name>
<name>
<surname>Fernandez</surname>
<given-names>S</given-names>
</name>
<name>
<surname>French</surname>
<given-names>MA</given-names>
</name>
</person-group>
<article-title>Alleles of the gene encoding IL-1α may predict control of plasma viraemia in HIV-1 patients on highly active antiretroviral therapy</article-title>
<source>AIDS</source>
<year>2004</year>
<volume>18</volume>
<fpage>1495</fpage>
<lpage>501</lpage>
</nlm-citation>
</ref>
<ref id="ref35">
<label>35</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Murakami</surname>
<given-names>Y</given-names>
</name>
<name>
<surname>Otsuki</surname>
<given-names>M</given-names>
</name>
<name>
<surname>Kusumoto</surname>
<given-names>K</given-names>
</name>
<name>
<surname>Takeuchi</surname>
<given-names>S</given-names>
</name>
<name>
<surname>Takahashi</surname>
<given-names>S</given-names>
</name>
</person-group>
<article-title>Estrogen inhibits interleukin-18 mRNA expression in the mouse uterus</article-title>
<source>J Reprod Dev</source>
<year>2005</year>
<volume>51</volume>
<fpage>639</fpage>
<lpage>47</lpage>
</nlm-citation>
</ref>
<ref id="ref36">
<label>36</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Beagley</surname>
<given-names>KW</given-names>
</name>
<name>
<surname>Gockel</surname>
<given-names>CM</given-names>
</name>
</person-group>
<article-title>Regulation of innate and adaptive immunity by the female sex hormones oestradiol and progesterone</article-title>
<source>FEMS Immunol Med Microbiol</source>
<year>2003</year>
<volume>38</volume>
<fpage>13</fpage>
<lpage>22</lpage>
</nlm-citation>
</ref>
<ref id="ref37">
<label>37</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Morales-Montor</surname>
<given-names>J</given-names>
</name>
<name>
<surname>Chavarria</surname>
<given-names>A</given-names>
</name>
<name>
<surname>De Leon</surname>
<given-names>MA</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Host gender in parasitic infections of mammals: an evaluation of the female host supremacy paradigm</article-title>
<source>J Parasitol</source>
<year>2004</year>
<volume>90</volume>
<fpage>531</fpage>
<lpage>46</lpage>
</nlm-citation>
</ref>
<ref id="ref38">
<label>38</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Mo</surname>
<given-names>R</given-names>
</name>
<name>
<surname>Chen</surname>
<given-names>J</given-names>
</name>
<name>
<surname>Grolleau-Julius</surname>
<given-names>A</given-names>
</name>
<name>
<surname>Murphy</surname>
<given-names>HS</given-names>
</name>
<name>
<surname>Richardson</surname>
<given-names>BC</given-names>
</name>
<name>
<surname>Yung</surname>
<given-names>RL</given-names>
</name>
</person-group>
<article-title>Estrogen regulates CCR gene expression and function in T lymphocytes</article-title>
<source>J Immunol</source>
<year>2005</year>
<volume>174</volume>
<fpage>6023</fpage>
<lpage>9</lpage>
</nlm-citation>
</ref>
<ref id="ref39">
<label>39</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Karlberg</surname>
<given-names>J</given-names>
</name>
<name>
<surname>Chong</surname>
<given-names>DS</given-names>
</name>
<name>
<surname>Lai</surname>
<given-names>WY</given-names>
</name>
</person-group>
<article-title>Do men have a higher case fatality rate of severe acute respiratory syndrome than women do?</article-title>
<source>Am J Epidemiol</source>
<year>2004</year>
<volume>159</volume>
<fpage>229</fpage>
<lpage>31</lpage>
</nlm-citation>
</ref>
<ref id="ref40">
<label>40</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Clark</surname>
<given-names>DA</given-names>
</name>
<name>
<surname>Foerster</surname>
<given-names>K</given-names>
</name>
<name>
<surname>Fung</surname>
<given-names>L</given-names>
</name>
<etal></etal>
</person-group>
<article-title>The fgl2 prothrombinase/fibroleukin gene is required for lipopolysaccharide-triggered abortions and for normal mouse reproduction</article-title>
<source>Mol Hum Reprod</source>
<year>2004</year>
<volume>10</volume>
<fpage>99</fpage>
<lpage>108</lpage>
</nlm-citation>
</ref>
<ref id="ref41">
<label>41</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Levy</surname>
<given-names>GA</given-names>
</name>
<name>
<surname>Liu</surname>
<given-names>M</given-names>
</name>
<name>
<surname>Ding</surname>
<given-names>J</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Molecular and functional analysis of the human prothrombinase gene <italic>(HFGL2)</italic> and its role in viral hepatitis</article-title>
<source>Am J Pathol</source>
<year>2000</year>
<volume>156</volume>
<fpage>1217</fpage>
<lpage>25</lpage>
</nlm-citation>
</ref>
<ref id="ref42">
<label>42</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Marsden</surname>
<given-names>PA</given-names>
</name>
<name>
<surname>Ning</surname>
<given-names>Q</given-names>
</name>
<name>
<surname>Fung</surname>
<given-names>LS</given-names>
</name>
<etal></etal>
</person-group>
<article-title>The Fgl2/fibroleukin prothrombinase contributes to immunologically mediated thrombosis in experimental and human viral hepatitis</article-title>
<source>J Clin Invest</source>
<year>2003</year>
<volume>112</volume>
<fpage>58</fpage>
<lpage>66</lpage>
</nlm-citation>
</ref>
<ref id="ref43">
<label>43</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Ning</surname>
<given-names>Q</given-names>
</name>
<name>
<surname>Lakatoo</surname>
<given-names>S</given-names>
</name>
<name>
<surname>Liu</surname>
<given-names>M</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Induction of prothrombinase <italic>fgl2</italic> by the nucleocapsid protein of virulent mouse hepatitis virus is dependent on host hepatic nuclear factor-4α</article-title>
<source>J Biol Chem</source>
<year>2003</year>
<volume>278</volume>
<fpage>15541</fpage>
<lpage>9</lpage>
</nlm-citation>
</ref>
<ref id="ref44">
<label>44</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Marazzi</surname>
<given-names>S</given-names>
</name>
<name>
<surname>Blum</surname>
<given-names>S</given-names>
</name>
<name>
<surname>Hartmann</surname>
<given-names>R</given-names>
</name>
<etal></etal>
</person-group>
<article-title>Characterization of human fibroleukin, a fibrinogen-like protein secreted by T lymphocytes</article-title>
<source>J Immunol</source>
<year>1998</year>
<volume>161</volume>
<fpage>138</fpage>
<lpage>47</lpage>
</nlm-citation>
</ref>
<ref id="ref45">
<label>45</label>
<nlm-citation citation-type="journal">
<person-group person-group-type="author">
<name>
<surname>Stout</surname>
<given-names>RD</given-names>
</name>
<name>
<surname>Suttles</surname>
<given-names>J</given-names>
</name>
</person-group>
<article-title>Immunosenescence and macrophage functional plasticity: dysregulation of macrophage function by age-associated microenvironmental changes</article-title>
<source>Immunol Rev</source>
<year>2005</year>
<volume>205</volume>
<fpage>60</fpage>
<lpage>71</lpage>
</nlm-citation>
</ref>
<ref id="ref46">
<label>46</label>
<nlm-citation citation-type="book">
<person-group person-group-type="author">
<name>
<surname>Yang</surname>
<given-names>HC</given-names>
</name>
<name>
<surname>Lin</surname>
<given-names>CH</given-names>
</name>
<name>
<surname>Hsu</surname>
<given-names>CL</given-names>
</name>
<etal></etal>
</person-group>
<article-title>A comparison of major histocompatibility complex SNPs in Han Chinese residing in Taiwan and Caucasians</article-title>
<source>J Biomed Sci</source>
<year>2006</year>
<comment>(in press)</comment>
</nlm-citation>
</ref>
</ref-list>
<sec sec-type="display-objects">
<title>Figures and Tables</title>
<fig position="anchor" id="fig1">
<label>Figure 1</label>
<caption>
<p>Scatter plot of titers of severe acute respiratory syndrome—associated coronavirus (SARS-CoV) in nasopharyngeal specimens from 154 patients vs. the day of specimen collection.</p>
</caption>
<graphic mimetype="image" xlink:href="42-11-1561-fig001.tif"></graphic>
</fig>
<fig position="anchor" id="fig2">
<label>Figure 2</label>
<caption>
<p>Rate of detection of shedding of severe acute respiratory syndrome—associated coronavirus (SARS-CoV) in nasopharyngeal specimens from 265 patients, as determined by RT-PCR, according to sex and age.</p>
</caption>
<graphic mimetype="image" xlink:href="42-11-1561-fig002.tif"></graphic>
</fig>
<fig position="anchor" id="fig3">
<label>Figure 3</label>
<caption>
<p>Power plotted against the allele frequency of each single-nucleotide polymorphism. Power is calculated based on the allele frequencies and the sample size of patients with severe acute respiratory syndrome (SARS) with (no. of case patients, 49) or without (no. of control patients, 45) detectable virus shedding. The curved lines denote the zones of differences between the allele frequencies of the case patients and control patients. Each black dot (·) denotes one single-nucleotide polymorphism plotted according to the allele frequency of the control patients with SARS without detectable SARS-associated coronavirus.</p>
</caption>
<graphic mimetype="image" xlink:href="42-11-1561-fig003.tif"></graphic>
</fig>
<fig position="anchor" id="tab1">
<label>Table 1</label>
<caption>
<p>Genes studied.</p>
</caption>
<graphic mimetype="image" xlink:href="42-11-1561-tbl001.tif"></graphic>
</fig>
<fig position="anchor" id="tab2">
<label>Table 2</label>
<caption>
<p>Distribution of 265 patients with severe acute respiratory syndrome (SARS), according to nasopharyngeal (NP) SARS-associated coronavirus (SARS-CoV) load at the time of admission, by demographic and clinical characteristics.</p>
</caption>
<graphic mimetype="image" xlink:href="42-11-1561-tbl002.tif"></graphic>
</fig>
<fig position="anchor" id="tab3">
<label>Table 3</label>
<caption>
<p>Nasopharyngeal severe acute respiratory syndrome (SARS)—associated coronavirus (SARS-CoV) load and length of survival for 71 patients with fatal cases of SARS.</p>
</caption>
<graphic mimetype="image" xlink:href="42-11-1561-tbl003.tif"></graphic>
</fig>
<fig position="anchor" id="tab4">
<label>Table 4</label>
<caption>
<p>Genetic polymorphisms and nasopharyngeal virus loads of 94 patients with severe acute respiratory syndrome (SARS).</p>
</caption>
<graphic mimetype="image" xlink:href="42-11-1561-tbl004.tif"></graphic>
</fig>
</sec>
</back>
</article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Nasopharyngeal Shedding of Severe Acute Respiratory Syndrome—Associated Coronavirus Is Associated with Genetic Polymorphisms</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Nasopharyngeal Shedding of Severe Acute Respiratory Syndrome—Associated Coronavirus Is Associated with Genetic Polymorphisms</title></titleInfo><name type="personal"><namePart type="given">Wei-Ju</namePart><namePart type="family">Chen</namePart><affiliation>Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jyh-Yuan</namePart><namePart type="family">Yang</namePart><affiliation>Center for Disease Control, Taipei, Taiwan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jih-Hui</namePart><namePart type="family">Lin</namePart><affiliation>Center for Disease Control, Taipei, Taiwan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Cathy S. J.</namePart><namePart type="family">Fann</namePart><affiliation>Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Valeriy</namePart><namePart type="family">Osyetrov</namePart><affiliation>Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Chwan-Chuen</namePart><namePart type="family">King</namePart><affiliation>Graduate Institute of Epidemiology, National Taiwan University, Taipei, Taiwan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Yi-Ming Arthur</namePart><namePart type="family">Chen</namePart><affiliation>Institute of Public Health, National Yang-Ming University, Taipei, Taiwan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Hsiao-Ling</namePart><namePart type="family">Chang</namePart><affiliation>Center for Disease Control, Taipei, Taiwan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Hung-Wei</namePart><namePart type="family">Kuo</namePart><affiliation>Center for Disease Control, Taipei, Taiwan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Fong</namePart><namePart type="family">Liao</namePart><affiliation>Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal" displayLabel="corresp"><namePart type="given">Mei-Shang</namePart><namePart type="family">Ho</namePart><affiliation>Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan</affiliation><affiliation>Graduate Institute of Epidemiology, National Taiwan University, Taipei, Taiwan</affiliation><affiliation>Institute of Public Health, National Yang-Ming University, Taipei, Taiwan</affiliation><affiliation>E-mail: homs@ibms.sinica.edu.tw</affiliation><affiliation>Reprints or correspondence: Dr. Mei-Shang Ho, IBMS, Academia Sinica, Taipei, 11529 Taiwan (homs@ibms.sinica.edu.tw).</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</genre><originInfo><publisher>The University of Chicago Press</publisher><dateIssued encoding="w3cdtf">2006-06-01</dateIssued><dateCreated encoding="w3cdtf">2006-02-01</dateCreated><copyrightDate encoding="w3cdtf">2006</copyrightDate></originInfo><abstract>Background. A high initial or peak severe acute respiratory syndrome (SARS)—associated coronavirus (SARS-CoV) load in nasopharyngeal specimens was shown to be associated with a high mortality rate. Because all infected individuals were devoid of preeexisting protective immunity against SARS-CoV, the biological basis for the variable virus burdens in different patients remains elusive. Methods. The nationwide SARS database in Taiwan was analyzed, and genotyping of 281 single-nucleotide polymorphisms (SNPs) of 65 genes was performed for 94 patients with SARS, to identify SNPs for which distribution between patients with or without detectable nasopharyngeal shedding of SARS-CoV was biased. Results. Titers of SARS-CoV shed in nasopharyngeal specimens varied widely, ranging from nondetectable to 108 SARS-CoV RNA copies/mL, and they were correlated positively with a high mortality rate (P < .0001, by trend test) and with early death (i.e., death occurring within 2 weeks of the onset of illness) (P = .0015, by trend test). Virus shedding was found to be higher among male patients (P = .0014, by multivariate logistic regression) and among older patients (P = .015, by multivariate logistic regression). Detectable nasopharyngeal shedding of SARS-CoV was associated with polymorphic alleles of interleukins 18 (P = .014) and 1A (P = .031) and a member of NFκB complex (reticuloendotheliosis viral oncogene homolog B [RelB]) (P = .034), all of which are proinflammatory in nature, as well as the procoagulation molecule fibrinogen-like protein 2 (P = .008). Conclusion. The SARS-CoV load is a determinant of clinical outcomes of SARS, and it is associated with polymorphisms of genes involved in innate immunity, which might be regulated in an age- and sex-dependent manner. The findings of the present study provided leads to genes involved in the host response to SARS-CoV infection; if substantiated with functional studies, these findings may be applicable to other newly emerged respiratory viruses (e.g., the influenza pandemic strain).</abstract><relatedItem type="host"><titleInfo><title>Clinical Infectious Diseases</title></titleInfo><titleInfo type="abbreviated"><title>Clinical Infectious Diseases</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><identifier type="ISSN">1058-4838</identifier><identifier type="eISSN">1537-6591</identifier><identifier type="PublisherID">cid</identifier><identifier type="PublisherID-hwp">cid</identifier><part><date>2006</date><detail type="volume"><caption>vol.</caption><number>42</number></detail><detail type="issue"><caption>no.</caption><number>11</number></detail><extent unit="pages"><start>1561</start><end>1569</end></extent></part></relatedItem><relatedItem type="references" displayLabel="b1"><titleInfo><title>Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area</title></titleInfo><name type="personal"><namePart type="given">CM</namePart><namePart type="family">Booth</namePart></name><name type="personal"><namePart type="given">LM</namePart><namePart type="family">Matukas</namePart></name><name type="personal"><namePart type="given">GA</namePart><namePart type="family">Tomlinson</namePart></name><genre>journal</genre><note>Booth CM Matukas LM Tomlinson GA Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area JAMA 2003 289 2801 9</note><relatedItem type="host"><titleInfo><title>JAMA</title></titleInfo><part><date>2003</date><detail type="volume"><caption>vol.</caption><number>289</number></detail><extent unit="pages"><start>2801</start><end>9</end><list>2801-9</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b2"><titleInfo><title>Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study</title></titleInfo><name type="personal"><namePart type="given">JS</namePart><namePart type="family">Peiris</namePart></name><name type="personal"><namePart type="given">CM</namePart><namePart type="family">Chu</namePart></name><name type="personal"><namePart type="given">VC</namePart><namePart type="family">Cheng</namePart></name><genre>journal</genre><note>Peiris JS Chu CM Cheng VC Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study Lancet 2003 361 1767 72</note><relatedItem type="host"><titleInfo><title>Lancet</title></titleInfo><part><date>2003</date><detail type="volume"><caption>vol.</caption><number>361</number></detail><extent unit="pages"><start>1767</start><end>72</end><list>1767-72</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b3"><titleInfo><title>The spectrum of severe acute respiratory syndrome-associated coronavirus infection</title></titleInfo><name type="personal"><namePart type="given">TH</namePart><namePart type="family">Rainer</namePart></name><name type="personal"><namePart type="given">PK</namePart><namePart type="family">Chan</namePart></name><name type="personal"><namePart type="given">M</namePart><namePart type="family">Ip</namePart></name><genre>journal</genre><note>Rainer TH Chan PK Ip M The spectrum of severe acute respiratory syndrome-associated coronavirus infection Ann Intern Med 2004 140 614 9</note><relatedItem type="host"><titleInfo><title>Ann Intern Med</title></titleInfo><part><date>2004</date><detail type="volume"><caption>vol.</caption><number>140</number></detail><extent unit="pages"><start>614</start><end>9</end><list>614-9</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b4"><titleInfo><title>Severe acute respiratory syndrome: clinical outcome and prognostic correlates</title></titleInfo><name type="personal"><namePart type="given">PT</namePart><namePart type="family">Tsui</namePart></name><name type="personal"><namePart type="given">ML</namePart><namePart type="family">Kwok</namePart></name><name type="personal"><namePart type="given">H</namePart><namePart type="family">Yuen</namePart></name><name type="personal"><namePart type="given">ST</namePart><namePart type="family">Lai</namePart></name><genre>journal</genre><note>Tsui PT Kwok ML Yuen H Lai ST Severe acute respiratory syndrome: clinical outcome and prognostic correlates Emerg Infect Dis 2003 9 1064 9</note><relatedItem type="host"><titleInfo><title>Emerg Infect Dis</title></titleInfo><part><date>2003</date><detail type="volume"><caption>vol.</caption><number>9</number></detail><extent unit="pages"><start>1064</start><end>9</end><list>1064-9</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b5"><titleInfo><title>The spectrum of pathological changes in severe acute respiratory syndrome (SARS)</title></titleInfo><name type="personal"><namePart type="given">OY</namePart><namePart type="family">Cheung</namePart></name><name type="personal"><namePart type="given">JW</namePart><namePart type="family">Chan</namePart></name><name type="personal"><namePart type="given">CK</namePart><namePart type="family">Ng</namePart></name><name type="personal"><namePart type="given">CK</namePart><namePart type="family">Koo</namePart></name><genre>journal</genre><note>Cheung OY Chan JW Ng CK Koo CK The spectrum of pathological changes in severe acute respiratory syndrome (SARS) Histopathology 2004 45 119 24</note><relatedItem type="host"><titleInfo><title>Histopathology</title></titleInfo><part><date>2004</date><detail type="volume"><caption>vol.</caption><number>45</number></detail><extent unit="pages"><start>119</start><end>24</end><list>119-24</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b6"><titleInfo><title>Severe acute respiratory syndrome: radiographic appearances and pattern of progression in 138 patients</title></titleInfo><name type="personal"><namePart type="given">KT</namePart><namePart type="family">Wong</namePart></name><name type="personal"><namePart type="given">GE</namePart><namePart type="family">Antonio</namePart></name><name type="personal"><namePart type="given">DS</namePart><namePart type="family">Hui</namePart></name><genre>journal</genre><note>Wong KT Antonio GE Hui DS Severe acute respiratory syndrome: radiographic appearances and pattern of progression in 138 patients Radiology 2003 228 401 6</note><relatedItem type="host"><titleInfo><title>Radiology</title></titleInfo><part><date>2003</date><detail type="volume"><caption>vol.</caption><number>228</number></detail><extent unit="pages"><start>401</start><end>6</end><list>401-6</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b7"><titleInfo><title>Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome</title></titleInfo><name type="personal"><namePart type="given">CK</namePart><namePart type="family">Wong</namePart></name><name type="personal"><namePart type="given">CW</namePart><namePart type="family">Lam</namePart></name><name type="personal"><namePart type="given">AK</namePart><namePart type="family">Wu</namePart></name><genre>journal</genre><note>Wong CK Lam CW Wu AK Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome Clin Exp Immunol 2004 136 95 103</note><relatedItem type="host"><titleInfo><title>Clin Exp Immunol</title></titleInfo><part><date>2004</date><detail type="volume"><caption>vol.</caption><number>136</number></detail><extent unit="pages"><start>95</start><end>103</end></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b8"><titleInfo><title>Characterization of cytokine/chemokine profiles of severe acute respiratory syndrome</title></titleInfo><name type="personal"><namePart type="given">Y</namePart><namePart type="family">Jiang</namePart></name><name type="personal"><namePart type="given">J</namePart><namePart type="family">Xu</namePart></name><name type="personal"><namePart type="given">C</namePart><namePart type="family">Zhou</namePart></name><genre>journal</genre><note>Jiang Y Xu J Zhou C Characterization of cytokine/chemokine profiles of severe acute respiratory syndrome Am J Respir Crit Care Med 2005 171 850 7</note><relatedItem type="host"><titleInfo><title>Am J Respir Crit Care Med</title></titleInfo><part><date>2005</date><detail type="volume"><caption>vol.</caption><number>171</number></detail><extent unit="pages"><start>850</start><end>7</end><list>850-7</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b9"><titleInfo><title>An interferon-gamma-related cytokine storm in SARS patients</title></titleInfo><name type="personal"><namePart type="given">KJ</namePart><namePart type="family">Huang</namePart></name><name type="personal"><namePart type="given">IJ</namePart><namePart type="family">Su</namePart></name><name type="personal"><namePart type="given">M</namePart><namePart type="family">Theron</namePart></name><genre>journal</genre><note>Huang KJ Su IJ Theron M An interferon-gamma-related cytokine storm in SARS patients J Med Virol 2005 75 185 94</note><relatedItem type="host"><titleInfo><title>J Med Virol</title></titleInfo><part><date>2005</date><detail type="volume"><caption>vol.</caption><number>75</number></detail><extent unit="pages"><start>185</start><end>94</end><list>185-94</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b10"><titleInfo><title>Initial viral load and the outcomes of SARS</title></titleInfo><name type="personal"><namePart type="given">CM</namePart><namePart type="family">Chu</namePart></name><name type="personal"><namePart type="given">LL</namePart><namePart type="family">Poon</namePart></name><name type="personal"><namePart type="given">VC</namePart><namePart type="family">Cheng</namePart></name><genre>journal</genre><note>Chu CM Poon LL Cheng VC Initial viral load and the outcomes of SARS CMAJ 2004 171 1349 52</note><relatedItem type="host"><titleInfo><title>CMAJ</title></titleInfo><part><date>2004</date><detail type="volume"><caption>vol.</caption><number>171</number></detail><extent unit="pages"><start>1349</start><end>52</end><list>1349-52</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b11"><titleInfo><title>Viral replication in the nasopharynx is associated with diarrhea in patients with severe acute respiratory syndrome</title></titleInfo><name type="personal"><namePart type="given">VC</namePart><namePart type="family">Cheng</namePart></name><name type="personal"><namePart type="given">IF</namePart><namePart type="family">Hung</namePart></name><name type="personal"><namePart type="given">BS</namePart><namePart type="family">Tang</namePart></name><genre>journal</genre><note>Cheng VC Hung IF Tang BS Viral replication in the nasopharynx is associated with diarrhea in patients with severe acute respiratory syndrome Clin Infect Dis 2004 38 467 75</note><relatedItem type="host"><titleInfo><title>Clin Infect Dis</title></titleInfo><part><date>2004</date><detail type="volume"><caption>vol.</caption><number>38</number></detail><extent unit="pages"><start>467</start><end>75</end><list>467-75</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b12"><titleInfo><title>Quantitative analysis and prognostic implication of SARS coronavirus RNA in the plasma and serum of patients with severe acute respiratory syndrome</title></titleInfo><name type="personal"><namePart type="given">EK</namePart><namePart type="family">Ng</namePart></name><name type="personal"><namePart type="given">DS</namePart><namePart type="family">Hui</namePart></name><name type="personal"><namePart type="given">KC</namePart><namePart type="family">Chan</namePart></name><genre>journal</genre><note>Ng EK Hui DS Chan KC Quantitative analysis and prognostic implication of SARS coronavirus RNA in the plasma and serum of patients with severe acute respiratory syndrome Clin Chem 2003 49 1976 80</note><relatedItem type="host"><titleInfo><title>Clin Chem</title></titleInfo><part><date>2003</date><detail type="volume"><caption>vol.</caption><number>49</number></detail><extent unit="pages"><start>1976</start><end>80</end><list>1976-80</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b13"><titleInfo><title>Detection of SARS-associated coronavirus in throat wash and saliva in early diagnosis</title></titleInfo><name type="personal"><namePart type="given">WK</namePart><namePart type="family">Wang</namePart></name><name type="personal"><namePart type="given">SY</namePart><namePart type="family">Chen</namePart></name><name type="personal"><namePart type="given">IJ</namePart><namePart type="family">Liu</namePart></name><genre>journal</genre><note>Wang WK Chen SY Liu IJ Detection of SARS-associated coronavirus in throat wash and saliva in early diagnosis Emerg Infect Dis 2004 10 1213 9</note><relatedItem type="host"><titleInfo><title>Emerg Infect Dis</title></titleInfo><part><date>2004</date><detail type="volume"><caption>vol.</caption><number>10</number></detail><extent unit="pages"><start>1213</start><end>9</end><list>1213-9</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b14"><titleInfo><title>Study on etiology and pathology of severe acute respiratory syndrome [in Chinese]</title></titleInfo><name type="personal"><namePart type="given">YQ</namePart><namePart type="family">Ding</namePart></name><name type="personal"><namePart type="given">HJ</namePart><namePart type="family">Wang</namePart></name><name type="personal"><namePart type="given">H</namePart><namePart type="family">Shen</namePart></name><genre>journal</genre><note>Ding YQ Wang HJ Shen H Study on etiology and pathology of severe acute respiratory syndrome [in Chinese] Zhonghua Bing Li Xue Za Zhi 2003 32 195 200</note><relatedItem type="host"><titleInfo><title>Zhonghua Bing Li Xue Za Zhi</title></titleInfo><part><date>2003</date><detail type="volume"><caption>vol.</caption><number>32</number></detail><extent unit="pages"><start>195</start><end>200</end></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b15"><titleInfo><title>Fatal severe acute respiratory syndrome is associated with multiorgan involvement by coronavirus</title></titleInfo><name type="personal"><namePart type="given">GA</namePart><namePart type="family">Farcas</namePart></name><name type="personal"><namePart type="given">SM</namePart><namePart type="family">Poutanen</namePart></name><name type="personal"><namePart type="given">T</namePart><namePart type="family">Mazzulli</namePart></name><genre>journal</genre><note>Farcas GA Poutanen SM Mazzulli T Fatal severe acute respiratory syndrome is associated with multiorgan involvement by coronavirus J Infect Dis 2005 191 193 7</note><relatedItem type="host"><titleInfo><title>J Infect Dis</title></titleInfo><part><date>2005</date><detail type="volume"><caption>vol.</caption><number>191</number></detail><extent unit="pages"><start>193</start><end>7</end><list>193-7</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b16"><titleInfo><title>Persistence of lung inflammation and lung cytokines with high-resolution CT abnormalities during recovery from SARS</title></titleInfo><name type="personal"><namePart type="given">CH</namePart><namePart type="family">Wang</namePart></name><name type="personal"><namePart type="given">CY</namePart><namePart type="family">Liu</namePart></name><name type="personal"><namePart type="given">YL</namePart><namePart type="family">Wan</namePart></name><genre>journal</genre><note>Wang CH Liu CY Wan YL Persistence of lung inflammation and lung cytokines with high-resolution CT abnormalities during recovery from SARS Respir Res 2005 6 42 0</note><relatedItem type="host"><titleInfo><title>Respir Res</title></titleInfo><part><date>2005</date><detail type="volume"><caption>vol.</caption><number>6</number></detail><extent unit="pages"><start>42</start><end>0</end><list>42-0</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b17"><titleInfo><title>Duration of RT-PCR positivity in severe acute respiratory syndrome</title></titleInfo><name type="personal"><namePart type="given">CM</namePart><namePart type="family">Chu</namePart></name><name type="personal"><namePart type="given">WS</namePart><namePart type="family">Leung</namePart></name><name type="personal"><namePart type="given">VC</namePart><namePart type="family">Cheng</namePart></name><genre>journal</genre><note>Chu CM Leung WS Cheng VC Duration of RT-PCR positivity in severe acute respiratory syndrome Eur Respir J 2005 25 12 4</note><relatedItem type="host"><titleInfo><title>Eur Respir J</title></titleInfo><part><date>2005</date><detail type="volume"><caption>vol.</caption><number>25</number></detail><extent unit="pages"><start>12</start><end>4</end><list>12-4</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b18"><titleInfo><title>Viral loads in clinical specimens and SARS manifestations</title></titleInfo><name type="personal"><namePart type="given">IF</namePart><namePart type="family">Hung</namePart></name><name type="personal"><namePart type="given">VC</namePart><namePart type="family">Cheng</namePart></name><name type="personal"><namePart type="given">AK</namePart><namePart type="family">Wu</namePart></name><genre>journal</genre><note>Hung IF Cheng VC Wu AK Viral loads in clinical specimens and SARS manifestations Emerg Infect Dis 2004 10 1550 7</note><relatedItem type="host"><titleInfo><title>Emerg Infect Dis</title></titleInfo><part><date>2004</date><detail type="volume"><caption>vol.</caption><number>10</number></detail><extent unit="pages"><start>1550</start><end>7</end><list>1550-7</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b19"><titleInfo><title>Severe acute respiratory syndrome-associated coronavirus in lung tissue</title></titleInfo><name type="personal"><namePart type="given">T</namePart><namePart type="family">Mazzulli</namePart></name><name type="personal"><namePart type="given">GA</namePart><namePart type="family">Farcas</namePart></name><name type="personal"><namePart type="given">SM</namePart><namePart type="family">Poutanen</namePart></name><genre>journal</genre><note>Mazzulli T Farcas GA Poutanen SM Severe acute respiratory syndrome-associated coronavirus in lung tissue Emerg Infect Dis 2004 10 20 4</note><relatedItem type="host"><titleInfo><title>Emerg Infect Dis</title></titleInfo><part><date>2004</date><detail type="volume"><caption>vol.</caption><number>10</number></detail><extent unit="pages"><start>20</start><end>4</end><list>20-4</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b20"><titleInfo><title>Serologic and molecular biologic methods for SARS-associated coronavirus infection, Taiwan</title></titleInfo><name type="personal"><namePart type="given">HS</namePart><namePart type="family">Wu</namePart></name><name type="personal"><namePart type="given">SC</namePart><namePart type="family">Chiu</namePart></name><name type="personal"><namePart type="given">TC</namePart><namePart type="family">Tseng</namePart></name><genre>journal</genre><note>Wu HS Chiu SC Tseng TC Serologic and molecular biologic methods for SARS-associated coronavirus infection, Taiwan Emerg Infect Dis 2004 10 304 10</note><relatedItem type="host"><titleInfo><title>Emerg Infect Dis</title></titleInfo><part><date>2004</date><detail type="volume"><caption>vol.</caption><number>10</number></detail><extent unit="pages"><start>304</start><end>10</end><list>304-10</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b21"><titleInfo><title>Neutralizing antibody response and SARS severity</title></titleInfo><name type="personal"><namePart type="given">M-S</namePart><namePart type="family">Ho</namePart></name><name type="personal"><namePart type="given">W-J</namePart><namePart type="family">Chen</namePart></name><name type="personal"><namePart type="given">H-Y</namePart><namePart type="family">Chen</namePart></name><genre>journal</genre><note>Ho M-S Chen W-J Chen H-Y Neutralizing antibody response and SARS severity Emerg Infect Dis 2005 11 1730 7</note><relatedItem type="host"><titleInfo><title>Emerg Infect Dis</title></titleInfo><part><date>2005</date><detail type="volume"><caption>vol.</caption><number>11</number></detail><extent unit="pages"><start>1730</start><end>7</end><list>1730-7</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b22"><titleInfo><title>Han Chinese cell and genome bank in Taiwan: purpose, design and ethical considerations</title></titleInfo><name type="personal"><namePart type="given">WH</namePart><namePart type="family">Pan</namePart></name><name type="personal"><namePart type="given">CSJ</namePart><namePart type="family">Fann</namePart></name><name type="personal"><namePart type="given">JY</namePart><namePart type="family">Wu</namePart></name><genre>journal</genre><note>Pan WH Fann CSJ Wu JY Han Chinese cell and genome bank in Taiwan: purpose, design and ethical considerations Hum Hered 2006 61 27 30</note><relatedItem type="host"><titleInfo><title>Hum Hered</title></titleInfo><part><date>2006</date><detail type="volume"><caption>vol.</caption><number>61</number></detail><extent unit="pages"><start>27</start><end>30</end></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b23"><titleInfo><title>Chen WJ Fann CSJ Osyetrov V Ho MS Table 1: the 64 candidate genes Available at: http://www.ibms.sinica.edu.tw/html/pi/msho_download/Table%201_SARS%20&%20SNP_950127.pdf. Accessed 27 January 2006</title></titleInfo><name type="corporate"><namePart>Table 1: the 64 candidate genes</namePart></name><name type="personal"><namePart type="given">WJ</namePart><namePart type="family">Chen</namePart></name><name type="personal"><namePart type="given">CSJ</namePart><namePart type="family">Fann</namePart></name><name type="personal"><namePart type="given">V</namePart><namePart type="family">Osyetrov</namePart></name><name type="personal"><namePart type="given">MS</namePart><namePart type="family">Ho</namePart></name><genre>book</genre><note>Available at: http://www.ibms.sinica.edu.tw/html/pi/msho_download/Table%201_SARS%20&%20SNP_950127.pdf. Accessed 27 January 2006</note><note>Chen WJ Fann CSJ Osyetrov V Ho MS Table 1: the 64 candidate genes Available at: http://www.ibms.sinica.edu.tw/html/pi/msho_download/Table%201_SARS%20&%20SNP_950127.pdf. Accessed 27 January 2006</note></relatedItem><relatedItem type="references" displayLabel="b24"><titleInfo><title>Searchgenes</title></titleInfo><genre>book</genre><note>Available at: http://www.gene.ucl.ac.uk/cgi-bin/nomenclature/searchgenes.pl. Accessed 31 November 2005</note><note>HUGO Gene Nomenclature Committee Searchgenes Available at: http://www.gene.ucl.ac.uk/cgi-bin/nomenclature/searchgenes.pl. Accessed 31 November 2005</note></relatedItem><relatedItem type="references" displayLabel="b25"><titleInfo><title>Strategies for characterizing highly polymorphic markers in human gene mapping</title></titleInfo><name type="personal"><namePart type="given">J</namePart><namePart type="family">Ott</namePart></name><genre>journal</genre><note>Ott J Strategies for characterizing highly polymorphic markers in human gene mapping Am J Hum Genet 1992 51 283 90</note><relatedItem type="host"><titleInfo><title>Am J Hum Genet</title></titleInfo><part><date>1992</date><detail type="volume"><caption>vol.</caption><number>51</number></detail><extent unit="pages"><start>283</start><end>90</end><list>283-90</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b26"><titleInfo><title>PHASEv2</title></titleInfo><name type="personal"><namePart type="given">M</namePart><namePart type="family">Stephens</namePart></name><genre>book</genre><note>Available at: http://depts.washington.edu/ventures/UW_Technology/Express_Licenses/PHASEv2.php. Accessed 31 January 2005</note><note>Stephens M PHASEv2 Available at: http://depts.washington.edu/ventures/UW_Technology/Express_Licenses/PHASEv2.php. Accessed 31 January 2005</note></relatedItem><relatedItem type="references" displayLabel="b27"><titleInfo><title>IL-18 and IL-12 signal through the NF-κB pathway to induce NK-1R expression on T cells</title></titleInfo><name type="personal"><namePart type="given">JV</namePart><namePart type="family">Weinstock</namePart></name><name type="personal"><namePart type="given">A</namePart><namePart type="family">Blum</namePart></name><name type="personal"><namePart type="given">A</namePart><namePart type="family">Metwali</namePart></name><name type="personal"><namePart type="given">D</namePart><namePart type="family">Elliott</namePart></name><name type="personal"><namePart type="given">R</namePart><namePart type="family">Arsenescu</namePart></name><genre>journal</genre><note>Weinstock JV Blum A Metwali A Elliott D Arsenescu R IL-18 and IL-12 signal through the NF-κB pathway to induce NK-1R expression on T cells J Immunol 2003 170 5003 7</note><relatedItem type="host"><titleInfo><title>J Immunol</title></titleInfo><part><date>2003</date><detail type="volume"><caption>vol.</caption><number>170</number></detail><extent unit="pages"><start>5003</start><end>7</end><list>5003-7</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b28"><titleInfo><title>IFN-alpha and IL-12 induce IL-18 receptor gene expression in human NK and T cells</title></titleInfo><name type="personal"><namePart type="given">T</namePart><namePart type="family">Sareneva</namePart></name><name type="personal"><namePart type="given">I</namePart><namePart type="family">Julkunen</namePart></name><name type="personal"><namePart type="given">S</namePart><namePart type="family">Matikainen</namePart></name><genre>journal</genre><note>Sareneva T Julkunen I Matikainen S IFN-alpha and IL-12 induce IL-18 receptor gene expression in human NK and T cells J Immunol 2000 165 1933 8</note><relatedItem type="host"><titleInfo><title>J Immunol</title></titleInfo><part><date>2000</date><detail type="volume"><caption>vol.</caption><number>165</number></detail><extent unit="pages"><start>1933</start><end>8</end><list>1933-8</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b29"><titleInfo><title>Pulmonary epithelial cells are a source of IL-8 in the response to Mycobacterium tuberculosis: essential role of IL-1 from infected monocytes in a NF-κB-dependent network</title></titleInfo><name type="personal"><namePart type="given">MI</namePart><namePart type="family">Wickremasinghe</namePart></name><name type="personal"><namePart type="given">LH</namePart><namePart type="family">Thomas</namePart></name><name type="personal"><namePart type="given">JS</namePart><namePart type="family">Friedland</namePart></name><genre>journal</genre><note>Wickremasinghe MI Thomas LH Friedland JS Pulmonary epithelial cells are a source of IL-8 in the response to Mycobacterium tuberculosis: essential role of IL-1 from infected monocytes in a NF-κB-dependent network J Immunol 1999 163 3936 47</note><relatedItem type="host"><titleInfo><title>J Immunol</title></titleInfo><part><date>1999</date><detail type="volume"><caption>vol.</caption><number>163</number></detail><extent unit="pages"><start>3936</start><end>47</end><list>3936-47</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b30"><titleInfo><title>NF-κB and Rel proteins: evolutionarily conserved mediators of immune responses</title></titleInfo><name type="personal"><namePart type="given">S</namePart><namePart type="family">Ghosh</namePart></name><name type="personal"><namePart type="given">MJ</namePart><namePart type="family">May</namePart></name><name type="personal"><namePart type="given">EB</namePart><namePart type="family">Kopp</namePart></name><genre>journal</genre><note>Ghosh S May MJ Kopp EB NF-κB and Rel proteins: evolutionarily conserved mediators of immune responses Annu Rev Immunol 1998 16 225 60</note><relatedItem type="host"><titleInfo><title>Annu Rev Immunol</title></titleInfo><part><date>1998</date><detail type="volume"><caption>vol.</caption><number>16</number></detail><extent unit="pages"><start>225</start><end>60</end><list>225-60</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b31"><titleInfo><title>Induction and regulation of NFκB during aging: role of protein kinases</title></titleInfo><name type="personal"><namePart type="given">GU</namePart><namePart type="family">Trebilcock</namePart></name><name type="personal"><namePart type="given">U</namePart><namePart type="family">Ponnappan</namePart></name><genre>journal</genre><note>Trebilcock GU Ponnappan U Induction and regulation of NFκB during aging: role of protein kinases Clin Immunol Immunopathol 1996 79 87 91</note><relatedItem type="host"><titleInfo><title>Clin Immunol Immunopathol</title></titleInfo><part><date>1996</date><detail type="volume"><caption>vol.</caption><number>79</number></detail><extent unit="pages"><start>87</start><end>91</end></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b32"><titleInfo><title>Interleukin-1 and neuronal injury</title></titleInfo><name type="personal"><namePart type="given">SM</namePart><namePart type="family">Allan</namePart></name><name type="personal"><namePart type="given">PJ</namePart><namePart type="family">Tyrrell</namePart></name><name type="personal"><namePart type="given">NJ</namePart><namePart type="family">Rothwell</namePart></name><genre>journal</genre><note>Allan SM Tyrrell PJ Rothwell NJ Interleukin-1 and neuronal injury Nat Rev Immunol 2005 5 629 40</note><relatedItem type="host"><titleInfo><title>Nat Rev Immunol</title></titleInfo><part><date>2005</date><detail type="volume"><caption>vol.</caption><number>5</number></detail><extent unit="pages"><start>629</start><end>40</end><list>629-40</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b33"><titleInfo><title>Enhanced viral clearance in interleukin-18 gene-deficient mice after pulmonary infection with influenza A virus</title></titleInfo><name type="personal"><namePart type="given">KF</namePart><namePart type="family">Van Der Sluijs</namePart></name><name type="personal"><namePart type="given">LJ</namePart><namePart type="family">Van Elden</namePart></name><name type="personal"><namePart type="given">R</namePart><namePart type="family">Arens</namePart></name><genre>journal</genre><note>Van Der Sluijs KF Van Elden LJ Arens R Enhanced viral clearance in interleukin-18 gene-deficient mice after pulmonary infection with influenza A virus Immunology 2005 114 112 20</note><relatedItem type="host"><titleInfo><title>Immunology</title></titleInfo><part><date>2005</date><detail type="volume"><caption>vol.</caption><number>114</number></detail><extent unit="pages"><start>112</start><end>20</end><list>112-20</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b34"><titleInfo><title>Alleles of the gene encoding IL-1α may predict control of plasma viraemia in HIV-1 patients on highly active antiretroviral therapy</title></titleInfo><name type="personal"><namePart type="given">P</namePart><namePart type="family">Price</namePart></name><name type="personal"><namePart type="given">I</namePart><namePart type="family">James</namePart></name><name type="personal"><namePart type="given">S</namePart><namePart type="family">Fernandez</namePart></name><name type="personal"><namePart type="given">MA</namePart><namePart type="family">French</namePart></name><genre>journal</genre><note>Price P James I Fernandez S French MA Alleles of the gene encoding IL-1α may predict control of plasma viraemia in HIV-1 patients on highly active antiretroviral therapy AIDS 2004 18 1495 501</note><relatedItem type="host"><titleInfo><title>AIDS</title></titleInfo><part><date>2004</date><detail type="volume"><caption>vol.</caption><number>18</number></detail><extent unit="pages"><start>1495</start><end>501</end><list>1495-501</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b35"><titleInfo><title>Estrogen inhibits interleukin-18 mRNA expression in the mouse uterus</title></titleInfo><name type="personal"><namePart type="given">Y</namePart><namePart type="family">Murakami</namePart></name><name type="personal"><namePart type="given">M</namePart><namePart type="family">Otsuki</namePart></name><name type="personal"><namePart type="given">K</namePart><namePart type="family">Kusumoto</namePart></name><name type="personal"><namePart type="given">S</namePart><namePart type="family">Takeuchi</namePart></name><name type="personal"><namePart type="given">S</namePart><namePart type="family">Takahashi</namePart></name><genre>journal</genre><note>Murakami Y Otsuki M Kusumoto K Takeuchi S Takahashi S Estrogen inhibits interleukin-18 mRNA expression in the mouse uterus J Reprod Dev 2005 51 639 47</note><relatedItem type="host"><titleInfo><title>J Reprod Dev</title></titleInfo><part><date>2005</date><detail type="volume"><caption>vol.</caption><number>51</number></detail><extent unit="pages"><start>639</start><end>47</end><list>639-47</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b36"><titleInfo><title>Regulation of innate and adaptive immunity by the female sex hormones oestradiol and progesterone</title></titleInfo><name type="personal"><namePart type="given">KW</namePart><namePart type="family">Beagley</namePart></name><name type="personal"><namePart type="given">CM</namePart><namePart type="family">Gockel</namePart></name><genre>journal</genre><note>Beagley KW Gockel CM Regulation of innate and adaptive immunity by the female sex hormones oestradiol and progesterone FEMS Immunol Med Microbiol 2003 38 13 22</note><relatedItem type="host"><titleInfo><title>FEMS Immunol Med Microbiol</title></titleInfo><part><date>2003</date><detail type="volume"><caption>vol.</caption><number>38</number></detail><extent unit="pages"><start>13</start><end>22</end></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b37"><titleInfo><title>Host gender in parasitic infections of mammals: an evaluation of the female host supremacy paradigm</title></titleInfo><name type="personal"><namePart type="given">J</namePart><namePart type="family">Morales-Montor</namePart></name><name type="personal"><namePart type="given">A</namePart><namePart type="family">Chavarria</namePart></name><name type="personal"><namePart type="given">MA</namePart><namePart type="family">De Leon</namePart></name><genre>journal</genre><note>Morales-Montor J Chavarria A De Leon MA Host gender in parasitic infections of mammals: an evaluation of the female host supremacy paradigm J Parasitol 2004 90 531 46</note><relatedItem type="host"><titleInfo><title>J Parasitol</title></titleInfo><part><date>2004</date><detail type="volume"><caption>vol.</caption><number>90</number></detail><extent unit="pages"><start>531</start><end>46</end><list>531-46</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b38"><titleInfo><title>Estrogen regulates CCR gene expression and function in T lymphocytes</title></titleInfo><name type="personal"><namePart type="given">R</namePart><namePart type="family">Mo</namePart></name><name type="personal"><namePart type="given">J</namePart><namePart type="family">Chen</namePart></name><name type="personal"><namePart type="given">A</namePart><namePart type="family">Grolleau-Julius</namePart></name><name type="personal"><namePart type="given">HS</namePart><namePart type="family">Murphy</namePart></name><name type="personal"><namePart type="given">BC</namePart><namePart type="family">Richardson</namePart></name><name type="personal"><namePart type="given">RL</namePart><namePart type="family">Yung</namePart></name><genre>journal</genre><note>Mo R Chen J Grolleau-Julius A Murphy HS Richardson BC Yung RL Estrogen regulates CCR gene expression and function in T lymphocytes J Immunol 2005 174 6023 9</note><relatedItem type="host"><titleInfo><title>J Immunol</title></titleInfo><part><date>2005</date><detail type="volume"><caption>vol.</caption><number>174</number></detail><extent unit="pages"><start>6023</start><end>9</end><list>6023-9</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b39"><titleInfo><title>Do men have a higher case fatality rate of severe acute respiratory syndrome than women do?</title></titleInfo><name type="personal"><namePart type="given">J</namePart><namePart type="family">Karlberg</namePart></name><name type="personal"><namePart type="given">DS</namePart><namePart type="family">Chong</namePart></name><name type="personal"><namePart type="given">WY</namePart><namePart type="family">Lai</namePart></name><genre>journal</genre><note>Karlberg J Chong DS Lai WY Do men have a higher case fatality rate of severe acute respiratory syndrome than women do? Am J Epidemiol 2004 159 229 31</note><relatedItem type="host"><titleInfo><title>Am J Epidemiol</title></titleInfo><part><date>2004</date><detail type="volume"><caption>vol.</caption><number>159</number></detail><extent unit="pages"><start>229</start><end>31</end><list>229-31</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b40"><titleInfo><title>The fgl2 prothrombinase/fibroleukin gene is required for lipopolysaccharide-triggered abortions and for normal mouse reproduction</title></titleInfo><name type="personal"><namePart type="given">DA</namePart><namePart type="family">Clark</namePart></name><name type="personal"><namePart type="given">K</namePart><namePart type="family">Foerster</namePart></name><name type="personal"><namePart type="given">L</namePart><namePart type="family">Fung</namePart></name><genre>journal</genre><note>Clark DA Foerster K Fung L The fgl2 prothrombinase/fibroleukin gene is required for lipopolysaccharide-triggered abortions and for normal mouse reproduction Mol Hum Reprod 2004 10 99 108</note><relatedItem type="host"><titleInfo><title>Mol Hum Reprod</title></titleInfo><part><date>2004</date><detail type="volume"><caption>vol.</caption><number>10</number></detail><extent unit="pages"><start>99</start><end>108</end></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b41"><titleInfo><title>Molecular and functional analysis of the human prothrombinase gene (HFGL2) and its role in viral hepatitis</title></titleInfo><name type="personal"><namePart type="given">GA</namePart><namePart type="family">Levy</namePart></name><name type="personal"><namePart type="given">M</namePart><namePart type="family">Liu</namePart></name><name type="personal"><namePart type="given">J</namePart><namePart type="family">Ding</namePart></name><genre>journal</genre><note>Levy GA Liu M Ding J Molecular and functional analysis of the human prothrombinase gene (HFGL2) and its role in viral hepatitis Am J Pathol 2000 156 1217 25</note><relatedItem type="host"><titleInfo><title>Am J Pathol</title></titleInfo><part><date>2000</date><detail type="volume"><caption>vol.</caption><number>156</number></detail><extent unit="pages"><start>1217</start><end>25</end><list>1217-25</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b42"><titleInfo><title>The Fgl2/fibroleukin prothrombinase contributes to immunologically mediated thrombosis in experimental and human viral hepatitis</title></titleInfo><name type="personal"><namePart type="given">PA</namePart><namePart type="family">Marsden</namePart></name><name type="personal"><namePart type="given">Q</namePart><namePart type="family">Ning</namePart></name><name type="personal"><namePart type="given">LS</namePart><namePart type="family">Fung</namePart></name><genre>journal</genre><note>Marsden PA Ning Q Fung LS The Fgl2/fibroleukin prothrombinase contributes to immunologically mediated thrombosis in experimental and human viral hepatitis J Clin Invest 2003 112 58 66</note><relatedItem type="host"><titleInfo><title>J Clin Invest</title></titleInfo><part><date>2003</date><detail type="volume"><caption>vol.</caption><number>112</number></detail><extent unit="pages"><start>58</start><end>66</end></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b43"><titleInfo><title>Induction of prothrombinase fgl2 by the nucleocapsid protein of virulent mouse hepatitis virus is dependent on host hepatic nuclear factor-4α</title></titleInfo><name type="personal"><namePart type="given">Q</namePart><namePart type="family">Ning</namePart></name><name type="personal"><namePart type="given">S</namePart><namePart type="family">Lakatoo</namePart></name><name type="personal"><namePart type="given">M</namePart><namePart type="family">Liu</namePart></name><genre>journal</genre><note>Ning Q Lakatoo S Liu M Induction of prothrombinase fgl2 by the nucleocapsid protein of virulent mouse hepatitis virus is dependent on host hepatic nuclear factor-4α J Biol Chem 2003 278 15541 9</note><relatedItem type="host"><titleInfo><title>J Biol Chem</title></titleInfo><part><date>2003</date><detail type="volume"><caption>vol.</caption><number>278</number></detail><extent unit="pages"><start>15541</start><end>9</end><list>15541-9</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b44"><titleInfo><title>Characterization of human fibroleukin, a fibrinogen-like protein secreted by T lymphocytes</title></titleInfo><name type="personal"><namePart type="given">S</namePart><namePart type="family">Marazzi</namePart></name><name type="personal"><namePart type="given">S</namePart><namePart type="family">Blum</namePart></name><name type="personal"><namePart type="given">R</namePart><namePart type="family">Hartmann</namePart></name><genre>journal</genre><note>Marazzi S Blum S Hartmann R Characterization of human fibroleukin, a fibrinogen-like protein secreted by T lymphocytes J Immunol 1998 161 138 47</note><relatedItem type="host"><titleInfo><title>J Immunol</title></titleInfo><part><date>1998</date><detail type="volume"><caption>vol.</caption><number>161</number></detail><extent unit="pages"><start>138</start><end>47</end><list>138-47</list></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b45"><titleInfo><title>Immunosenescence and macrophage functional plasticity: dysregulation of macrophage function by age-associated microenvironmental changes</title></titleInfo><name type="personal"><namePart type="given">RD</namePart><namePart type="family">Stout</namePart></name><name type="personal"><namePart type="given">J</namePart><namePart type="family">Suttles</namePart></name><genre>journal</genre><note>Stout RD Suttles J Immunosenescence and macrophage functional plasticity: dysregulation of macrophage function by age-associated microenvironmental changes Immunol Rev 2005 205 60 71</note><relatedItem type="host"><titleInfo><title>Immunol Rev</title></titleInfo><part><date>2005</date><detail type="volume"><caption>vol.</caption><number>205</number></detail><extent unit="pages"><start>60</start><end>71</end></extent></part></relatedItem></relatedItem><relatedItem type="references" displayLabel="b46"><titleInfo><title>A comparison of major histocompatibility complex SNPs in Han Chinese residing in Taiwan and Caucasians</title></titleInfo><name type="personal"><namePart type="given">HC</namePart><namePart type="family">Yang</namePart></name><name type="personal"><namePart type="given">CH</namePart><namePart type="family">Lin</namePart></name><name type="personal"><namePart type="given">CL</namePart><namePart type="family">Hsu</namePart></name><genre>book</genre><note>(in press)</note><note>Yang HC Lin CH Hsu CL A comparison of major histocompatibility complex SNPs in Han Chinese residing in Taiwan and Caucasians J Biomed Sci 2006 (in press)</note><relatedItem type="host"><titleInfo><title>J Biomed Sci</title></titleInfo><part><date>2006</date></part></relatedItem></relatedItem><identifier type="istex">9C32D2577E261A285735FBF93EC3393DFED7E0BD</identifier><identifier type="ark">ark:/67375/HXZ-HB5XDM1W-T</identifier><identifier type="DOI">10.1086/503843</identifier><accessCondition type="use and reproduction" contentType="copyright">© 2006 by the Infectious Diseases Society of America</accessCondition><recordInfo><recordContentSource authority="ISTEX" authorityURI="https://loaded-corpus.data.istex.fr" valueURI="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-GTWS0RDP-M">oup</recordContentSource><recordOrigin>Converted from (version 1.2.10) to MODS version 3.6.</recordOrigin><recordCreationDate encoding="w3cdtf">2020-04-16</recordCreationDate></recordInfo></mods><json:item><extension>json</extension><original>false</original><mimetype>application/json</mimetype><uri>https://api.istex.fr/ark:/67375/HXZ-HB5XDM1W-T/record.json</uri></json:item></metadata><covers><json:item><extension>tiff</extension><original>true</original><mimetype>image/tiff</mimetype><uri>https://api.istex.fr/document/9C32D2577E261A285735FBF93EC3393DFED7E0BD/covers/tiff</uri></json:item><json:item><extension>html</extension><original>true</original><mimetype>text/html</mimetype><uri>https://api.istex.fr/ark:/67375/HXZ-HB5XDM1W-T/covers.html</uri></json:item></covers><annexes><json:item><extension>gif</extension><original>true</original><mimetype>image/gif</mimetype><uri>https://api.istex.fr/ark:/67375/HXZ-HB5XDM1W-T/annexes.gif</uri></json:item><json:item><extension>jpeg</extension><original>true</original><mimetype>image/jpeg</mimetype><uri>https://api.istex.fr/ark:/67375/HXZ-HB5XDM1W-T/annexes.jpeg</uri></json:item><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/ark:/67375/HXZ-HB5XDM1W-T/annexes.pdf</uri></json:item></annexes><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/SrasV1/Data/Istex/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000071 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Istex/Corpus/biblio.hfd -nk 000071 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Sante
|area= SrasV1
|flux= Istex
|étape= Corpus
|type= RBID
|clé= ISTEX:9C32D2577E261A285735FBF93EC3393DFED7E0BD
|texte= Nasopharyngeal Shedding of Severe Acute Respiratory Syndrome—Associated Coronavirus Is Associated with Genetic Polymorphisms
}}
| This area was generated with Dilib version V0.6.33. |  |