Vitamin D Receptor Polymorphisms and Susceptibility to Tuberculosis in West Africa: A Case-Control and Family Study
Identifieur interne : 003132 ( Istex/Corpus ); précédent : 003131; suivant : 003133Vitamin D Receptor Polymorphisms and Susceptibility to Tuberculosis in West Africa: A Case-Control and Family Study
Auteurs : Liza Bornman ; Sarah J. Campbell ; Katherine Fielding ; Boubacar Bah ; Jackson Sillah ; Per Gustafson ; Kebba Manneh ; Ida Lisse ; Angela Allen ; Giorgio Sirugo ; Aissatou Sylla ; Peter Aaby ; Keith P. W. J. Mcadam ; Oumou Bah Sow ; Steve Bennett ; Christian Lienhardt ; Adrian V. S. HillSource :
- Journal of Infectious Diseases [ 0022-1899 ] ; 2004-11-01.
Abstract
Vitamin D receptor (VDR) gene polymorphisms have been implicated in susceptibility to tuberculosis (TB), but reports have been inconsistent. We genotyped the VDR single-nucleotide polymorphisms (SNPs) FokI, BsmI, ApaI, and TaqI in 1139 case patients and control subjects and 382 families from The Gambia, Guinea, and Guinea-Bissau. The transmission-disequilibrium test on family data showed a significant global association of TB with SNP combinations FokI-BsmI-ApaI-TaqI and FokI-ApaI that were driven by the increased transmission to affected offspring of the FokI F and ApaI A alleles in combination. The ApaI A allele was also transmitted to affected offspring significantly more often than expected. Case-control analysis showed no statistically significant association between TB and VDR variants. BsmI, ApaI, and TaqI showed strong linkage disequilibrium. The significance of the family-based associations found between TB and FokI-BsmI-ApaI-TaqI and the FA haplotype supports a role for VDR haplotypes, rather than individual genotypes, in susceptibility to TB.
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DOI: 10.1086/424462
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Campbell</name><affiliation><mods:affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford</mods:affiliation></affiliation></author><author><name sortKey="Fielding, Katherine" sort="Fielding, Katherine" uniqKey="Fielding K" first="Katherine" last="Fielding">Katherine Fielding</name><affiliation><mods:affiliation>London School of Hygiene and Tropical Medicine, London, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Bah, Boubacar" sort="Bah, Boubacar" uniqKey="Bah B" first="Boubacar" last="Bah">Boubacar Bah</name><affiliation><mods:affiliation>Programme National de Lutte Anti-Tuberculeuse, Conakry, République de Guinée;</mods:affiliation></affiliation></author><author><name sortKey="Sillah, Jackson" sort="Sillah, Jackson" uniqKey="Sillah J" first="Jackson" last="Sillah">Jackson Sillah</name><affiliation><mods:affiliation>Medical Research Council Laboratories, Fajara</mods:affiliation></affiliation></author><author><name sortKey="Gustafson, Per" sort="Gustafson, Per" uniqKey="Gustafson P" first="Per" last="Gustafson">Per Gustafson</name><affiliation><mods:affiliation>Projecto de Saude de Bandim, Danish Epidemiology Science Centre,Bissau Guinea-Bissau</mods:affiliation></affiliation></author><author><name sortKey="Manneh, Kebba" sort="Manneh, Kebba" uniqKey="Manneh K" first="Kebba" last="Manneh">Kebba Manneh</name><affiliation><mods:affiliation>National TB/Leprosy Control Programme, Banjul, The Gambia</mods:affiliation></affiliation></author><author><name sortKey="Lisse, Ida" sort="Lisse, Ida" uniqKey="Lisse I" first="Ida" last="Lisse">Ida Lisse</name><affiliation><mods:affiliation>Projecto de Saude de Bandim, Danish Epidemiology Science Centre,Bissau Guinea-Bissau</mods:affiliation></affiliation></author><author><name sortKey="Allen, Angela" sort="Allen, Angela" uniqKey="Allen A" first="Angela" last="Allen">Angela Allen</name><affiliation><mods:affiliation>Medical Research Council Laboratories, Fajara</mods:affiliation></affiliation></author><author><name sortKey="Sirugo, Giorgio" sort="Sirugo, Giorgio" uniqKey="Sirugo G" first="Giorgio" last="Sirugo">Giorgio Sirugo</name><affiliation><mods:affiliation>Medical Research Council Laboratories, Fajara</mods:affiliation></affiliation></author><author><name sortKey="Sylla, Aissatou" sort="Sylla, Aissatou" uniqKey="Sylla A" first="Aissatou" last="Sylla">Aissatou Sylla</name><affiliation><mods:affiliation>Programme National de Lutte Anti-Tuberculeuse, Conakry, République de Guinée;</mods:affiliation></affiliation></author><author><name sortKey="Aaby, Peter" sort="Aaby, Peter" uniqKey="Aaby P" first="Peter" last="Aaby">Peter Aaby</name><affiliation><mods:affiliation>Projecto de Saude de Bandim, Danish Epidemiology Science Centre,Bissau Guinea-Bissau</mods:affiliation></affiliation></author><author><name sortKey="Mcadam, Keith P W J" sort="Mcadam, Keith P W J" uniqKey="Mcadam K" first="Keith P. W. J." last="Mcadam">Keith P. W. J. Mcadam</name><affiliation><mods:affiliation>London School of Hygiene and Tropical Medicine, London, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Sow, Oumou Bah" sort="Sow, Oumou Bah" uniqKey="Sow O" first="Oumou Bah" last="Sow">Oumou Bah Sow</name><affiliation><mods:affiliation>Programme National de Lutte Anti-Tuberculeuse, Conakry, République de Guinée;</mods:affiliation></affiliation></author><author><name sortKey="Bennett, Steve" sort="Bennett, Steve" uniqKey="Bennett S" first="Steve" last="Bennett">Steve Bennett</name><affiliation><mods:affiliation>London School of Hygiene and Tropical Medicine, London, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Lienhardt, Christian" sort="Lienhardt, Christian" uniqKey="Lienhardt C" first="Christian" last="Lienhardt">Christian Lienhardt</name><affiliation><mods:affiliation>Medical Research Council Laboratories, Fajara</mods:affiliation></affiliation><affiliation><mods:affiliation>Institute de Recherche pour le Développement, Hann, Dakar, Senegal</mods:affiliation></affiliation></author><author><name sortKey="Hill, Adrian V S" sort="Hill, Adrian V S" uniqKey="Hill A" first="Adrian V. S." last="Hill">Adrian V. S. Hill</name><affiliation><mods:affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Journal of Infectious Diseases</title><title level="j" type="abbrev">J Infect Dis.</title><idno type="ISSN">0022-1899</idno><idno type="eISSN">1537-6613</idno><imprint><publisher>The University of Chicago Press</publisher><date type="published" when="2004-11-01">2004-11-01</date><biblScope unit="volume">190</biblScope><biblScope unit="issue">9</biblScope><biblScope unit="page" from="1631">1631</biblScope><biblScope unit="page" to="1641">1641</biblScope></imprint><idno type="ISSN">0022-1899</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-1899</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">Vitamin D receptor (VDR) gene polymorphisms have been implicated in susceptibility to tuberculosis (TB), but reports have been inconsistent. We genotyped the VDR single-nucleotide polymorphisms (SNPs) FokI, BsmI, ApaI, and TaqI in 1139 case patients and control subjects and 382 families from The Gambia, Guinea, and Guinea-Bissau. The transmission-disequilibrium test on family data showed a significant global association of TB with SNP combinations FokI-BsmI-ApaI-TaqI and FokI-ApaI that were driven by the increased transmission to affected offspring of the FokI F and ApaI A alleles in combination. The ApaI A allele was also transmitted to affected offspring significantly more often than expected. Case-control analysis showed no statistically significant association between TB and VDR variants. BsmI, ApaI, and TaqI showed strong linkage disequilibrium. The significance of the family-based associations found between TB and FokI-BsmI-ApaI-TaqI and the FA haplotype supports a role for VDR haplotypes, rather than individual genotypes, in susceptibility to TB.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Liza Bornman</name><affiliations><json:string>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford</json:string><json:string>Biochemistry Division, Department of Chemistry and Biochemistry, Rand Afrikaans University, Auckland Park, South Africa</json:string><json:string>E-mail: lbo@na.rau.ac.za</json:string></affiliations></json:item><json:item><name>Sarah J. Campbell</name><affiliations><json:string>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford</json:string></affiliations></json:item><json:item><name>Katherine Fielding</name><affiliations><json:string>London School of Hygiene and Tropical Medicine, London, United Kingdom</json:string></affiliations></json:item><json:item><name>Boubacar Bah</name><affiliations><json:string>Programme National de Lutte Anti-Tuberculeuse, Conakry, République de Guinée;</json:string></affiliations></json:item><json:item><name>Jackson Sillah</name><affiliations><json:string>Medical Research Council Laboratories, Fajara</json:string></affiliations></json:item><json:item><name>Per Gustafson</name><affiliations><json:string>Projecto de Saude de Bandim, Danish Epidemiology Science Centre,Bissau Guinea-Bissau</json:string></affiliations></json:item><json:item><name>Kebba Manneh</name><affiliations><json:string>National TB/Leprosy Control Programme, Banjul, The Gambia</json:string></affiliations></json:item><json:item><name>Ida Lisse</name><affiliations><json:string>Projecto de Saude de Bandim, Danish Epidemiology Science Centre,Bissau Guinea-Bissau</json:string></affiliations></json:item><json:item><name>Angela Allen</name><affiliations><json:string>Medical Research Council Laboratories, Fajara</json:string></affiliations></json:item><json:item><name>Giorgio Sirugo</name><affiliations><json:string>Medical Research Council Laboratories, Fajara</json:string></affiliations></json:item><json:item><name>Aissatou Sylla</name><affiliations><json:string>Programme National de Lutte Anti-Tuberculeuse, Conakry, République de Guinée;</json:string></affiliations></json:item><json:item><name>Peter Aaby</name><affiliations><json:string>Projecto de Saude de Bandim, Danish Epidemiology Science Centre,Bissau Guinea-Bissau</json:string></affiliations></json:item><json:item><name>Keith P. W. J. McAdam</name><affiliations><json:string>London School of Hygiene and Tropical Medicine, London, United Kingdom</json:string></affiliations></json:item><json:item><name>Oumou Bah Sow</name><affiliations><json:string>Programme National de Lutte Anti-Tuberculeuse, Conakry, République de Guinée;</json:string></affiliations></json:item><json:item><name>Steve Bennett</name><affiliations><json:string>London School of Hygiene and Tropical Medicine, London, United Kingdom</json:string></affiliations></json:item><json:item><name>Christian Lienhardt</name><affiliations><json:string>Medical Research Council Laboratories, Fajara</json:string><json:string>Institute de Recherche pour le Développement, Hann, Dakar, Senegal</json:string></affiliations></json:item><json:item><name>Adrian V. S. Hill</name><affiliations><json:string>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford</json:string></affiliations></json:item></author><language><json:string>unknown</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><abstract>Vitamin D receptor (VDR) gene polymorphisms have been implicated in susceptibility to tuberculosis (TB), but reports have been inconsistent. We genotyped the VDR single-nucleotide polymorphisms (SNPs) FokI, BsmI, ApaI, and TaqI in 1139 case patients and control subjects and 382 families from The Gambia, Guinea, and Guinea-Bissau. The transmission-disequilibrium test on family data showed a significant global association of TB with SNP combinations FokI-BsmI-ApaI-TaqI and FokI-ApaI that were driven by the increased transmission to affected offspring of the FokI F and ApaI A alleles in combination. The ApaI A allele was also transmitted to affected offspring significantly more often than expected. Case-control analysis showed no statistically significant association between TB and VDR variants. BsmI, ApaI, and TaqI showed strong linkage disequilibrium. The significance of the family-based associations found between TB and FokI-BsmI-ApaI-TaqI and the FA haplotype supports a role for VDR haplotypes, rather than individual genotypes, in susceptibility to TB.</abstract><qualityIndicators><score>8.8</score><pdfVersion>1.3</pdfVersion><pdfPageSize>612 x 792 pts (letter)</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>0</keywordCount><abstractCharCount>1069</abstractCharCount><pdfWordCount>6019</pdfWordCount><pdfCharCount>39633</pdfCharCount><pdfPageCount>11</pdfPageCount><abstractWordCount>150</abstractWordCount></qualityIndicators><title>Vitamin D Receptor Polymorphisms and Susceptibility to Tuberculosis in West Africa: A Case-Control and Family Study</title><genre><json:string>research-article</json:string></genre><host><title>Journal of Infectious 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type="first">Liza</forename><surname>Bornman</surname></persName><email>lbo@na.rau.ac.za</email><email>lbo@na.rau.ac.za</email><affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford</affiliation><affiliation>Biochemistry Division, Department of Chemistry and Biochemistry, Rand Afrikaans University, Auckland Park, South Africa</affiliation><affiliation>Reprints or correspondence: Dr. Liza Bornman, Biochemistry Div., Dept. of Chemistry and Biochemistry, Rand Afrikaans University, PO Box 524, Auckland Park 2006, South Africa</affiliation></author><author xml:id="author-0001"><persName><forename type="first">Sarah J.</forename><surname>Campbell</surname></persName><affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford</affiliation></author><author xml:id="author-0002"><persName><forename type="first">Katherine</forename><surname>Fielding</surname></persName><affiliation>London School of Hygiene and Tropical Medicine, London, United 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type="first">Ida</forename><surname>Lisse</surname></persName><affiliation>Projecto de Saude de Bandim, Danish Epidemiology Science Centre,Bissau Guinea-Bissau</affiliation></author><author xml:id="author-0008"><persName><forename type="first">Angela</forename><surname>Allen</surname></persName><affiliation>Medical Research Council Laboratories, Fajara</affiliation></author><author xml:id="author-0009"><persName><forename type="first">Giorgio</forename><surname>Sirugo</surname></persName><affiliation>Medical Research Council Laboratories, Fajara</affiliation></author><author xml:id="author-0010"><persName><forename type="first">Aissatou</forename><surname>Sylla</surname></persName><affiliation>Programme National de Lutte Anti-Tuberculeuse, Conakry, République de Guinée;</affiliation></author><author xml:id="author-0011"><persName><forename type="first">Peter</forename><surname>Aaby</surname></persName><affiliation>Projecto de Saude de Bandim, Danish Epidemiology Science Centre,Bissau Guinea-Bissau</affiliation></author><author xml:id="author-0012"><persName><forename type="first">Keith P. W. J.</forename><surname>McAdam</surname></persName><affiliation>London School of Hygiene and Tropical Medicine, London, United Kingdom</affiliation></author><author xml:id="author-0013"><persName><forename type="first">Oumou Bah</forename><surname>Sow</surname></persName><affiliation>Programme National de Lutte Anti-Tuberculeuse, Conakry, République de Guinée;</affiliation></author><author xml:id="author-0014"><persName><forename type="first">Steve</forename><surname>Bennett</surname></persName><affiliation>London School of Hygiene and Tropical Medicine, London, United Kingdom</affiliation></author><author xml:id="author-0015"><persName><forename type="first">Christian</forename><surname>Lienhardt</surname></persName><affiliation>Medical Research Council Laboratories, Fajara</affiliation><affiliation>Institute de Recherche pour le Développement, Hann, Dakar, Senegal</affiliation></author><author xml:id="author-0016"><persName><forename type="first">Adrian V. S.</forename><surname>Hill</surname></persName><affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford</affiliation></author><idno type="istex">959F417CD61462667173508CF79AD562587B4AD5</idno><idno type="ark">ark:/67375/HXZ-VDK87M1P-T</idno><idno type="DOI">10.1086/424462</idno></analytic><monogr><title level="j">Journal of Infectious Diseases</title><title level="j" type="abbrev">J Infect Dis.</title><idno type="pISSN">0022-1899</idno><idno type="eISSN">1537-6613</idno><idno type="publisher-id">jid</idno><idno type="PublisherID-hwp">jinfdis</idno><imprint><publisher>The University of Chicago Press</publisher><date type="published" when="2004-11-01"></date><biblScope unit="volume">190</biblScope><biblScope unit="issue">9</biblScope><biblScope unit="page" from="1631">1631</biblScope><biblScope unit="page" to="1641">1641</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2004</date></creation><abstract><p>Vitamin D receptor (VDR) gene polymorphisms have been implicated in susceptibility to tuberculosis (TB), but reports have been inconsistent. We genotyped the VDR single-nucleotide polymorphisms (SNPs) FokI, BsmI, ApaI, and TaqI in 1139 case patients and control subjects and 382 families from The Gambia, Guinea, and Guinea-Bissau. The transmission-disequilibrium test on family data showed a significant global association of TB with SNP combinations FokI-BsmI-ApaI-TaqI and FokI-ApaI that were driven by the increased transmission to affected offspring of the FokI F and ApaI A alleles in combination. The ApaI A allele was also transmitted to affected offspring significantly more often than expected. Case-control analysis showed no statistically significant association between TB and VDR variants. BsmI, ApaI, and TaqI showed strong linkage disequilibrium. The significance of the family-based associations found between TB and FokI-BsmI-ApaI-TaqI and the FA haplotype supports a role for VDR haplotypes, rather than individual genotypes, in susceptibility to TB.</p></abstract></profileDesc><revisionDesc><change when="2004-11-01">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/959F417CD61462667173508CF79AD562587B4AD5/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">jinfdis</journal-id>
<journal-id journal-id-type="publisher-id">jid</journal-id>
<journal-title>Journal of Infectious Diseases</journal-title>
<abbrev-journal-title>J Infect Dis.</abbrev-journal-title>
<issn pub-type="ppub">0022-1899</issn>
<issn pub-type="epub">1537-6613</issn>
<publisher>
<publisher-name>The University of Chicago Press</publisher-name>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="doi">10.1086/424462</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Major Articles and Brief Reports</subject>
<subj-group subj-group-type="heading">
<subject>Bacteria</subject>
<subj-group subj-group-type="heading">
<subject>Major Articles</subject>
</subj-group>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Vitamin D Receptor Polymorphisms and Susceptibility to Tuberculosis in West Africa: A Case-Control and Family Study</article-title>
</title-group>
<contrib-group>
<contrib contrib-type="author" corresp="yes">
<name><surname>Bornman</surname><given-names>Liza</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="aff3" ref-type="aff">3</xref><xref rid="fna" ref-type="fn">a</xref><xref ref-type="corresp" rid="cor1"></xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Campbell</surname><given-names>Sarah J.</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="fna" ref-type="fn">a</xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Fielding</surname><given-names>Katherine</given-names></name><xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Bah</surname><given-names>Boubacar</given-names></name><xref rid="aff4" ref-type="aff">4</xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Sillah</surname><given-names>Jackson</given-names></name><xref rid="aff5" ref-type="aff">5</xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Gustafson</surname><given-names>Per</given-names></name><xref rid="aff7" ref-type="aff">7</xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Manneh</surname><given-names>Kebba</given-names></name><xref rid="aff6" ref-type="aff">6</xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Lisse</surname><given-names>Ida</given-names></name><xref rid="aff7" ref-type="aff">7</xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Allen</surname><given-names>Angela</given-names></name><xref rid="aff5" ref-type="aff">5</xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Sirugo</surname><given-names>Giorgio</given-names></name><xref rid="aff5" ref-type="aff">5</xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Sylla</surname><given-names>Aissatou</given-names></name><xref rid="aff4" ref-type="aff">4</xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Aaby</surname><given-names>Peter</given-names></name><xref rid="aff7" ref-type="aff">7</xref>
</contrib>
<contrib contrib-type="author">
<name><surname>McAdam</surname><given-names>Keith P. W. J.</given-names></name><xref rid="aff2" ref-type="aff">2</xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Sow</surname><given-names>Oumou Bah</given-names></name><xref rid="aff4" ref-type="aff">4</xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Bennett</surname><given-names>Steve</given-names></name><xref rid="aff2" ref-type="aff">2</xref><xref rid="fnb" ref-type="fn">b</xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Lienhardt</surname><given-names>Christian</given-names></name><xref rid="aff5" ref-type="aff">5</xref><xref rid="aff8" ref-type="aff">8</xref>
</contrib>
<contrib contrib-type="author">
<name><surname>Hill</surname><given-names>Adrian V. S.</given-names></name><xref rid="aff1" ref-type="aff">1</xref>
</contrib>
<aff id="aff1"><label>1</label><institution>Wellcome Trust Centre for Human Genetics, University of Oxford</institution>, <addr-line>Oxford</addr-line></aff>
<aff id="aff2"><label>2</label><institution>London School of Hygiene and Tropical Medicine</institution>, <addr-line>London, United Kingdom</addr-line></aff>
<aff id="aff3"><label>3</label><institution>Biochemistry Division</institution>, <institution>Department of Chemistry and Biochemistry</institution>, <institution>Rand Afrikaans University</institution>, <addr-line>Auckland Park, South Africa</addr-line></aff>
<aff id="aff4"><label>4</label><institution>Programme National de Lutte Anti-Tuberculeuse</institution>, <addr-line>Conakry, République de Guinée;</addr-line></aff>
<aff id="aff5"><label>5</label><institution>Medical Research Council Laboratories</institution>, <addr-line>Fajara</addr-line></aff>
<aff id="aff6"><label>6</label><institution>National TB/Leprosy Control Programme</institution>, <addr-line>Banjul, The Gambia</addr-line></aff>
<aff id="aff7"><label>7</label><institution>Projecto de Saude de Bandim</institution>, <institution>Danish Epidemiology Science Centre</institution>,<addr-line>Bissau Guinea-Bissau</addr-line></aff>
<aff id="aff8"><label>8</label><institution>Institute de Recherche pour le Développement</institution>, <addr-line>Hann</addr-line>, <addr-line>Dakar</addr-line>, <addr-line>Senegal</addr-line></aff>
</contrib-group>
<author-notes>
<corresp id="cor1">Reprints or correspondence: Dr. Liza Bornman, <institution>Biochemistry Div.</institution>, <institution>Dept. of Chemistry and Biochemistry</institution>, <institution>Rand Afrikaans University</institution>, <addr-line>PO Box 524, Auckland Park 2006, South Africa</addr-line> (<email>lbo@na.rau.ac.za</email>).</corresp>
</author-notes>
<pub-date pub-type="ppub">
<day>1</day>
<month>11</month>
<year>2004</year>
</pub-date>
<volume>190</volume>
<issue>9</issue>
<fpage>1631</fpage>
<lpage>1641</lpage>
<history>
<date date-type="received">
<day>8</day>
<month>10</month>
<year>2003</year>
</date>
<date date-type="accepted">
<day>19</day>
<month>4</month>
<year>2004</year>
</date>
</history>
<copyright-statement>© 2004 by the Infectious Diseases Society of America</copyright-statement>
<copyright-year>2004</copyright-year>
<abstract>
<p>Vitamin D receptor (<italic>VDR</italic>) gene polymorphisms have been implicated in susceptibility to tuberculosis (TB), but reports have been inconsistent. We genotyped the <italic>VDR</italic> single-nucleotide polymorphisms (SNPs) <italic>FokI, BsmI, ApaI</italic>, and <italic>TaqI</italic> in 1139 case patients and control subjects and 382 families from The Gambia, Guinea, and Guinea-Bissau. The transmission-disequilibrium test on family data showed a significant global association of TB with SNP combinations <italic>FokI-BsmI-ApaI-TaqI</italic> and <italic>FokI-ApaI</italic> that were driven by the increased transmission to affected offspring of the <italic>FokI F</italic> and <italic>ApaI</italic> A alleles in combination. The ApaI A allele was also transmitted to affected offspring significantly more often than expected. Case-control analysis showed no statistically significant association between TB and VDR variants. <italic>BsmI, ApaI</italic>, and <italic>TaqI</italic> showed strong linkage disequilibrium. The significance of the family-based associations found between TB and <italic>FokI-BsmI-ApaI-TaqI</italic> and the FA haplotype supports a role for <italic>VDR</italic> haplotypes, rather than individual genotypes, in susceptibility to TB.</p>
</abstract>
</article-meta>
</front>
<body>
<p>An improved understanding of the pathogenesis of tuberculosis (TB) and effective treatment for it are significantly influenced by our ability to untie the effects of host genetic and environmental factors in response to TB. A recent innovative approach involved joint investigation of these factors in 3 West African countries by use of a combined study design [<xref ref-type="bibr" rid="bib1">1</xref>]. In an accompanying paper, Bennett et al. [<xref ref-type="bibr" rid="bib2">2</xref>] reviewed evidence that host genetic factors play a role in susceptibility to TB. The present article is a component of the multicenter study described above and reports the investigation of the effect of vitamin D receptor (<italic>VDR</italic>) gene polymorphisms, as a host genetic factor, on the development of TB.</p>
<p>The development of TB in humans is a 2-stage process through which a susceptible person exposed to an infectious case first becomes infected and, after an interval of years or decades, may later develop the disease [<xref ref-type="bibr" rid="bib3">3</xref>]. The large majority of individuals infected with <italic>Mycobacterium tuberculosis</italic> have no recognizable ill effects. In some individuals, however, the primary infection is not contained and goes on to cause substantial tissue damage and clinical disease, either locally or by hematogenous spread of bacilli from the initial lung site to other organs of the body. This primary disease is more likely to occur in children, some weeks or months after the primary infection, but also in HIV-infected individuals. In most infected individuals, however, tubercle bacilli remain dormant, and overt pulmonary TB disease usually arises many years after primary infection, either through the breakdown of a localized lesion in the lungs (endogenous reactivation) or through reinfection from exposure to infectious TB [<xref ref-type="bibr" rid="bib4">4</xref>]. The relative contribution of reactivation and reinfection is likely to depend on the epidemiological context, but it is generally accepted that, in populations at high risk for infection, reinfection might be a major contributor to the overall rate of TB in adults, whereas, in populations at low risk for infection, most cases of postprimary disease in adults probably result from reactivation [<xref ref-type="bibr" rid="bib4">4</xref>, <xref ref-type="bibr" rid="bib5">5</xref>].</p>
<p>Among persons who are exposed to persons with infectious TB, the risk of becoming infected is primarily determined by the combined action of the infectivity of the source case, the intensity of exposure of the susceptible person to that case, and his/her susceptibility to infection [<xref ref-type="bibr" rid="bib4">4</xref>]. Factors reported to influence the risk of infection include age, sex, crowding, socioeconomic conditions, urbanization, race/ethnic group, and HIV status [<xref ref-type="bibr" rid="bib6">6</xref>]. The risk of developing disease after infection is strongly dependent on age and time, but any condition that modifies the balance established in the body between the tubercle bacilli and host immune defenses can have an effect on the risk of developing disease. Thus, factors that have been shown to influence this balance include age, sex, HIV infection, immunosuppressive treatment, diabetes, malnutrition, alcoholism, and bacille Calmette-Guérin vaccination [<xref ref-type="bibr" rid="bib7">7</xref>]. In addition, there is increasing evidence that genetic factors, in part, determine differences in host susceptibility to infection with mycobacteria and that they might contribute to the pattern of clinical disease [<xref ref-type="bibr" rid="bib8">8</xref>].</p>
<p>Differential susceptibility to TB is most likely determined by several genes [<xref ref-type="bibr" rid="bib9">9</xref>, <xref ref-type="bibr" rid="bib10">10</xref>], because genomewide screening has identified no single, strongly linked marker [<xref ref-type="bibr" rid="bib11">11</xref>, <xref ref-type="bibr" rid="bib12">12</xref>]. In support of this, candidate gene-based case-control studies found several immunogenetic polymorphisms with a moderate effect on risk of clinical TB [<xref ref-type="bibr" rid="bib9">9</xref>, <xref ref-type="bibr" rid="bib10">10</xref>], including allelic variants of <italic>VDR</italic> [<xref ref-type="bibr" rid="bib13">13</xref>]. VDR is synthesized in monocytes and activated T and B lymphocytes [<xref ref-type="bibr" rid="bib14">14</xref>], whereas its ligand, the active metabolite of vitamin D (1,25 dihydroxy vitamin D [calcitriol]), is produced in the kidney and by activated monocytes and macrophages, in particular in granuloma [<xref ref-type="bibr" rid="bib15">15</xref>, <xref ref-type="bibr" rid="bib16">16</xref>]. Through its interaction with vitamin D, the retinoid X receptor (RXR), and the vitamin D response element (VDRE), VDR exerts several immunomodulatory effects [<xref ref-type="bibr" rid="bib14">14</xref>]. These include the activation of monocytes and cell-mediated immunity, modulation of the Th1-Th2 host immune response, suppression of lymphocyte proliferation, and restriction of <italic>M. tuberculosis</italic> survival in macrophages [<xref ref-type="bibr" rid="bib17">17</xref>–<xref ref-type="bibr" rid="bib19">19</xref>].</p>
<p>In 1999, Bellamy et al. [<xref ref-type="bibr" rid="bib13">13</xref>] reported that the tt genotype of <italic>VDR</italic>, which is often associated with lower bone mineral density, was found less frequently in patients with pulmonary TB in The Gambia. In the same population, tt was found to be negatively associated with persistent hepatitis B virus infection [<xref ref-type="bibr" rid="bib13">13</xref>]. A subsequent study found tt to be associated with tuberculoid leprosy and TT with lepromatous leprosy in India [<xref ref-type="bibr" rid="bib20">20</xref>], which implicates that allelic variants of <italic>VDR</italic> influence a Th1-Th2 shift in the host immune response that determines leprosy type. Since then, several case-control studies have reexamined the association of VDR polymorphisms with diseases of mycobacterial origin in different populations [<xref ref-type="bibr" rid="bib21">21</xref>–<xref ref-type="bibr" rid="bib26">26</xref>], but different risk alleles have been reported or no independent association was found (summarized in Discussion). Particular haplotypes of <italic>VDR</italic>, which harbors alleles that affect both mRNA expression (promoter and the 3′ untranslated region [UTR]) and protein function (coding region), were proposed to reflect functional effects more accurately [<xref ref-type="bibr" rid="bib27">27</xref>] and may associate more consistently with disease.</p>
<p>In the present study, it was proposed that <italic>VDR</italic> haplotypes, rather than individual alleles or genotypes, are responsible for associations between TB and <italic>VDR</italic> variants. The objective was to identify susceptibility haplotypes inWest African populations by use of a family-based approach, which is robust to population stratification, and to verify the role that variants play in VDR haplotypes that were previously associated with TB in case-control studies. We genotyped the <italic>VDR</italic> single-nucleotide polymorphisms (SNPs) <italic>FokI, BsmI, ApaI</italic>, and <italic>TaqI</italic> in 382 families and 1139 case-control subjects from 3 West African countries: The Gambia, Guinea, and Guinea-Bissau. Results from the family-based study support a role for <italic>VDR</italic> haplotypes in susceptibility to TB in West Africans.</p>
<sec>
<title>PATIENTS AND METHODS</title>
<p><italic><bold>Patients.</bold></italic> The study was conducted in 3 West African countries (The Gambia, Guinea, and Guinea-Bissau) according to a protocol described elsewhere [<xref ref-type="bibr" rid="bib1">1</xref>, <xref ref-type="bibr" rid="bib2">2</xref>]. The present study did not use samples previously collected, as documented by Bellamy et al. [<xref ref-type="bibr" rid="bib13">13</xref>]. Patients with newly detected TB who were >15 years old who had been living at the same address for >3 months were eligible for inclusion in the study. Pulmonary TB was confirmed by 2 consecutive sputum smears positive for acidfast bacilli and/or a positive sputum culture. Patients were fully clinically examined, and an anterioposterior chest radiograph was systematically obtained to characterize disease severity. Matched healthy community control subjects were recruited from the vicinity of the patient with TB, as described elsewhere [<xref ref-type="bibr" rid="bib1">1</xref>]. Where possible, the father, mother, and full siblings of the patient with TB were also recruited, and those patients with TB whose family members had been genotyped were included in an independent family-based association analysis (<italic>n</italic> = 382). Initially, 436 families were included in the study, for a total of 1413 individuals. Inheritance checking was continuously done by genotyping 4 microsatellites and >50 SNPs, including the <italic>VDR</italic> SNPs. Samples were removed from the transmission-disequilibrium test (TDT) analysis if genotypes showed noninheritance at >2 loci, as genotyped on separate occasions, and 94 individuals were excluded from the study. The remaining case patients (<italic>n</italic> = 417) and healthy control subjects (<italic>n</italic> = 722) formed the case-control study, which had 80% power to detect an association (at <italic>P</italic> = .05) for a genotype of 6%–88% frequency and an odds ratio (OR) of ⩾2 or 22%–70% frequency and an OR of ⩾1.5. <xref ref-type="fig" rid="F2">Table 1</xref> shows demographic and clinical data for both studies.</p>
<p>DNA was extracted from venous blood by use of the Nucleon BACC2 DNA extraction kit (Nucleon Bioscience) and standard phenol-chloroform procedures. After samples were transported to the University of Oxford, DNA concentrations were determined by use of the PicoGreen kit (Molecular Probes), and working stocks of DNA samples at 10 μg/mL were prepared. Informed consent was obtained from patients or their parents or guardians. Ethical approval was provided by the joint Gambian Government/Medical Research Council Ethical Committee, Ministry of Public Health (MINSAP, Guinea-Bissau), and National Ethics committee, Ministry of Health, Conakry, République de Guinée. Human-experimentation guidelines of these ministries were followed.</p>
<p><italic><bold>Genotyping.</bold></italic> The human <italic>VDR</italic> is located on 12q12–14 and contains 16 exons that encode the 5′ UTR (exons IA-IG), the DNA-binding domain (exons II and III), and the overlapping ligand-binding and heterodimerization domains (exons VI-IX) [<xref ref-type="bibr" rid="bib28">28</xref>, <xref ref-type="bibr" rid="bib29">29</xref>]. VDR contains >25 known polymorphisms, whereas >100 are expected on the basis of the observed genomewide frequency of SNPs [<xref ref-type="bibr" rid="bib27">27</xref>]. The most commonly studied variants include a <italic>FokI</italic> restriction fragment-length polymorphism (RFLP) in exon II (alleles F/f or nucleotides C/T), <italic>BsmI</italic> (B/b or nucleotides T/C) and <italic>ApaI</italic> (A/a or nucleotides T/G) variants in intron VIII, and a <italic>TaqI</italic> (T/t or nucleotides T/C) variant in exon IX, with lowercase patient alleles indicating the presence of restriction sites. <italic>BsmI, ApaI</italic>, and <italic>TaqI</italic> are in strong linkage disequilibrium (LD) with a singlet (A) repeat in the 3′ UTR, which results in short (S) or long (L) alleles.DNAsamples were genotyped for the <italic>VDR</italic> SNPs <italic>FokI, BsmI, ApaI</italic>, and <italic>TaqI</italic>, because they were relatively informative and have been previously associated with mycobacterial infections [<xref ref-type="bibr" rid="bib13">13</xref>, <xref ref-type="bibr" rid="bib21">21</xref>–<xref ref-type="bibr" rid="bib26">26</xref>, <xref ref-type="bibr" rid="bib30">30</xref>]. All SNPs, with the exception of <italic>Fok1</italic>, were genotyped by use of the ligation detection reaction (LDR) [<xref ref-type="bibr" rid="bib31">31</xref>]. LDR products were analyzed by use of a capillary electrophoresis ABI 3700 machine and the Genotyper software package (Applied Biosystems). Fok1 was genotyped by use of allele-specific polymerase chain reaction (PCR) and control amplification of the third intron of HLA-DRB1, followed by resolution on agarose gels [<xref ref-type="bibr" rid="bib32">32</xref>]. Genotyping was verified and confirmed by sequencing of 96 samples. No discrepancies were found, and no samples were excluded. The sequences of primers used for LDR and allelespecific PCR are summarized in <xref ref-type="fig" rid="F3">table 2</xref>. PCRs of the region containing <italic>BsmI, ApaI</italic>, and <italic>TaqI</italic> was performed by use of 3 consecutive cycles with annealing temperatures of 71°C, 64°C, and 55°C repeated 5, 21, and 4 times each. PCR of the FokI RFLP was performed by use of 1 cycle with an annealing temperature of 58°C repeated 35 times. The LDR ligation temperature was 72°C for <italic>BsmI, ApaI</italic>, and <italic>TaqI</italic>.</p>
<p><italic><bold>Statistical analysis.</bold></italic> In the case-control study, testing for association at each polymorphism was initially performed by use of a 3 × 2 χ<sup>2</sup> test with 2 <italic>df</italic>. Both the case patients and the control subjects were also tested for Hardy-Weinberg equilibrium (HWE) by use of a 3 × 2 χ<sup>2</sup> test with 1 <italic>df</italic>. Because the aim of the study [<xref ref-type="bibr" rid="bib1">1</xref>, <xref ref-type="bibr" rid="bib2">2</xref>] was to identify both genetic and nongenetic risk factors for TB, the case patients and control subjects were only matched by age [<xref ref-type="bibr" rid="bib1">1</xref>]. There are therefore significant differences between case patients and control subjects for variables such as sex, country, ethnic group, and HIV status. To control for the potential confounding effects of age, sex, country, ethnic group, and HIV status, multivariate logistic regression was performed by use of STATA (version 7; Stata). Where these factors were not found to have a significant effect, they were dropped from the model. Family-based association was analyzed by the TDT [<xref ref-type="bibr" rid="bib33">33</xref>] by use of the <italic>Transmit program</italic> [<xref ref-type="bibr" rid="bib34">34</xref>]. The TDT is robust to ethnic stratification, whereas Transmit allows for missing parents and the analysis of multilocus haplotypes. Rare haplotypes with frequencies <2% were combined in the analysis. For LD analysis, maximum-likelihood estimates of pairwise LD were obtained by use of LDMAX within the GOLD package [<xref ref-type="bibr" rid="bib35">35</xref>]. All case patients and control subjects were included in this analysis. For the sake of simplicity and for all analyses, results for individual SNPs are shown first.</p>
</sec>
<sec>
<title>RESULTS</title>
<p><italic><bold>Case-control study.</bold></italic> χ<sup>2</sup> analysis of the genotype frequencies for <italic>VDR</italic> polymorphisms in case patients with TB and control subjects from The Gambia, Guinea, and Guinea-Bissau, alone or in combination, showed no significant association with TB (<xref ref-type="fig" rid="F4">table 3</xref>). To investigate possible associations between the severity of disease and <italic>VDR</italic> polymorphisms, analysis was restricted to case patients with severe TB (<italic>n</italic> = 125), defined as ⩾4 lung zones affected and the presence of cavitations on radiographs (<xref ref-type="fig" rid="F2">table 1</xref>, bottom left). Again, no significant association between any genotype and TB was observed (<xref ref-type="fig" rid="F5">table 4</xref>). In all instances (i.e., case patients, control subjects, and different population groups), SNP genotypes were in HWE, and no confounding effect of sex, age, country, ethnicity, or HIV status was detected (data not shown). The HIV-positivity rate in control subjects was 6.8%, and that in case patients was 12.5% (<xref ref-type="fig" rid="F2">table 1</xref>). Although the numbers were very small, subgroup analysis for HIV-positive patients was done by comparing HIVpositive patients with TB versus HIV-positive control subjects and HIV-positive patients with TB versus all control subjects, for each SNP (all 3 genotypes). All tests showed no association (results not shown).</p>
<p><italic><bold>Family-based study.</bold></italic> The TDT, performed by use of <italic>Transmit</italic>, revealed that the ApaI A allele was transmitted to affected offspring significantly more often than expected (χ<sup>2</sup> = 4.925 <italic>P</italic> = .0265, 1 <italic>df</italic>) and the a allele significantly less often than expected (<xref ref-type="fig" rid="F6">table 5</xref>). Observed transmissions of alleles for <italic>FokI, BsmI</italic>, or <italic>TaqI</italic> were not significantly different from expected values (<xref ref-type="fig" rid="F6">table 5</xref>). However, <italic>ApaI</italic> did not conform to HWE in parents (<italic>P</italic> = .038), whereas all other SNPs did in both case patients with TB and their parents. It is possible that this contributes to the association of <italic>ApaI</italic> in the families; however, the deviation from HWE was of borderline significance and was not seen in any other group tested for <italic>ApaI</italic>. In addition to this, the frequency of the <italic>ApaI</italic> AA genotype in the case patients with TB from the family study (159/329 [48.3%]) was higher than that in the control subjects from the case-control study (266/634 [42.0%]), which shows that the association seen here cannot be entirely explained by the slight deviation from HWE seen in the parents.</p>
<p>To investigate whether <italic>ApaI</italic> or a neighboring, untested polymorphism was causative, the transmission of haplotypes was also studied. Significant global association with TB was detected for the haplotypic combination of all 4 SNPs (<italic>FokI-BsmI-ApaI-TaqI</italic>, χ<sup>2</sup> = 22.113, <italic>P</italic> = .0085, 9 <italic>df</italic>; <xref ref-type="fig" rid="F6">table 5</xref>). However, no individual haplotype was significantly associated. <italic>TaqI</italic> does not contribute significantly to the observed effect—haplotypes produced by <italic>FokI, BsmI</italic>, and <italic>ApaI</italic> were also globally associated (χ<sup>2</sup> = 15.451, <italic>P</italic> = .0170, 6 <italic>df</italic>), primarily because of the in- x creased transmission of FBA and decreased transmission of Fba and fBA (<xref ref-type="fig" rid="F6">table 5</xref>). To further define the haplotypes that drive these associations, we examined combinations of 2 SNPs from this 3-SNP haplotype (i.e., <italic>FokI-ApaI, BsmI-ApaI</italic>, and <italic>FokI-BsmI</italic>). The strongest association was observed for <italic>FokI-ApaI</italic> haplotypes (global χ<sup>2</sup> = 12.33, <italic>P</italic> = .0063, 3 <italic>df</italic>), driven by increased transmission of the FA haplotype (χ<sup>2</sup> = 11.621 <italic>P</italic> = 0007, 1 <italic>df</italic>). Other associated haplotypes (<xref ref-type="fig" rid="F6">table 5</xref>) were FB (χ<sup>2</sup> = 4.355, <italic>P</italic> = .0369, 1 <italic>df</italic>), which was transmitted to affected offspring more often than expected, and Fa (χ<sup>2</sup> = 3.917 <italic>P</italic> = .0478, 1 <italic>df</italic>), Ba (χ<sup>2</sup> = 4.226, <italic>P</italic> = .0398, 1 <italic>df</italic>), and fB (χ<sup>2</sup> = 4.063, <italic>P</italic> = .0438, 1 <italic>df</italic>), which were transmitted to affected offspring significantly less often than expected. Because a <italic>TaqI</italic> protective association with the tt genotype was previously reported in The Gambia [<xref ref-type="bibr" rid="bib13">13</xref>], the ApaI-TaqI haplotype was also investigated; however, no significant association was found (<xref ref-type="fig" rid="F6">table 5</xref>).</p>
<p><italic><bold>LD analysis.</bold></italic> LD analysis of the 4 <italic>VDR</italic> SNPs studied was conducted in the case-control samples and illustrated in <xref ref-type="fig" rid="F1">figure 1</xref>. The three 3′ SNPs (<italic>BsmI-ApaI-TaqI</italic>) showed significant, strong LD with each other, as has been shown in previous studies [<xref ref-type="bibr" rid="bib36">36</xref>, <xref ref-type="bibr" rid="bib37">37</xref>], especially <italic>BsmI-ApaI</italic> and <italic>ApaI-TaqI</italic>. In contrast, <italic>FokI</italic> was in LD with only <italic>BsmI</italic>, significantly but less strong than the LD between <italic>BsmI-ApaI</italic> and <italic>ApaI-TaqI</italic>. The pattern of LD was the same in all 3 countries (data not shown).</p>
</sec>
<sec>
<title>DISCUSSION</title>
<p>In the family-based study, the TDT showed a global association of the SNP combinations <italic>FokI-BsmI-ApaI-TaqI</italic> and <italic>FokI-ApaI</italic> with TB that was more significant than that to any individual SNP. This supports the proposal that haplotypes more accurately and consistently reflect associations between TB and <italic>VDR</italic> variants than to individual polymorphisms. The role that <italic>VDR</italic> polymorphisms play in susceptibility to TB in West Africa was evaluated by use of both a case-control and a family-based approach. The case-control study results provide an estimate of the association between a certain gene or allele and a given disease but suffer from potential bias due to population admixture or stratification, as is likely to exist in ethnically mixed African populations. In contrast, being performed within families, the TDT is robust to population stratification and minimizes that bias, but it does not give an estimate of relative risk. The TDT allows accurate analysis of haplotypes, whereas computational methods to generate haplotypes from case-control studies are unreliable. Therefore, the combination of these 2 complementary approaches increases the reliability of the results collected within the study testing the association of genetic factors with susceptibility to TB.</p>
<p>In the case-control study, no significant association was found between alleles or genotypes of the <italic>VDR</italic> SNPs in any of the 3 countries or in the combined data (<xref ref-type="fig" rid="F4">table 3</xref>). This observation adds to the inconsistency in the literature concerning associations found between <italic>VDR</italic> polymorphisms and TB (summarized in <xref ref-type="fig" rid="F7">table 6</xref>). Several factors could influence the discrepancy of associations found between case-control studies of different or the same populations. First, the <italic>VDR</italic> is one of several polymorphic genes that have been implicated in human infectious diseases [<xref ref-type="bibr" rid="bib9">9</xref>, <xref ref-type="bibr" rid="bib10">10</xref>]. Given the small effect of <italic>VDR</italic> on TB, the statistical power is often too low to draw conclusions about the presence or absence of an effect. Second, many of the SNPs used in association studies are nonfunctional and are more likely markers of truly causative polymorphisms. When associated alleles are truly causative, the same-risk allele would consistently be associated [<xref ref-type="bibr" rid="bib27">27</xref>]. However, the association of nonfunctional variants depends on the patterns of LD across the relevant chromosomal region, which may differ between populations [<xref ref-type="bibr" rid="bib36">36</xref>] and contribute to heterogeneity among associations found [<xref ref-type="bibr" rid="bib27">27</xref>]. A high degree of genetic diversity is characteristic of African populations, giving rise to different patterns of LD and haplotype blocks [<xref ref-type="bibr" rid="bib38">38</xref>]. Data on the worldwide distribution of VDR alleles and genotypes further support ethnic variation in the distribution of VDR variants, in particular between European and black populations [<xref ref-type="bibr" rid="bib39">39</xref>]. This may explain the proposed ethnic-specific and unique candidate gene polymorphisms observed in certain populations [<xref ref-type="bibr" rid="bib25">25</xref>]. Third, the interaction between different genes and/or environmental factors plays a role in the action of VDR [<xref ref-type="bibr" rid="bib22">22</xref>, <xref ref-type="bibr" rid="bib40">40</xref>]. Gene-gene or gene-environment interactions most likely differ between populations. VDR is a "master" transcription factor that influences several endocrine pathways [<xref ref-type="bibr" rid="bib14">14</xref>]. Similar to the role of <italic>VDR</italic> variants in bone biology [<xref ref-type="bibr" rid="bib27">27</xref>], the association between VDR polymorphisms and TB is most likely confounded by numerous potential gene-gene and/or gene-environment interactions.</p>
<p>The significant underrepresentation of tt in case patients with TB in The Gambia reported by Bellamy et al. [<xref ref-type="bibr" rid="bib13">13</xref>] was not confirmed by the present case-control study. In the present study, particular care was taken in the characterization and recruitment of case patients with TB and the selection of control subjects. Only those with at least 2 positive sputum smears were included in the study, and, in The Gambia, >95% of these were culture confirmed. In the study by Bellamy et al. [<xref ref-type="bibr" rid="bib13">13</xref>], characterization of case patients with TB was less well defined, and the matching of control subjects was not as strict. Control subjects were male, whereas case patients were male and female—a potential confounder, because being female has been reported to be a protective factor against TB in Africa [<xref ref-type="bibr" rid="bib6">6</xref>]. Differences in the power of these 2 studies, together with undetected stratification in the population sampled and variations in the way case patients with TB were characterized, could have contributed to the inconsistent observation.</p>
<p>Studies of the genetic components involved in disease severity after virulent <italic>M. tuberculosis</italic> infection have been largely limited to animals [<xref ref-type="bibr" rid="bib41">41</xref>]. In our case-control study, we have illustrated an approach to investigate the possible involvement of VDR polymorphisms in TB disease severity. However, no significant association was observed between <italic>VDR</italic> polymorphisms and severe TB (<xref ref-type="fig" rid="F5">table 4</xref>).</p>
<p>Family-based association tests such as the TDT are robust to population stratification but have rarely been used in studies of <italic>VDR</italic> polymorphisms. In the present study, family-based analysis showed that the <italic>ApaI</italic> A allele, alone and, more so in haplotype, with <italic>FokI</italic> F (FA), was most significantly associated with TB, driving the significant global associations observed for <italic>FokI-ApaI</italic> and possibly <italic>FokI-BsmI-ApaI-TaqI</italic> SNP combinations (<xref ref-type="fig" rid="F4">table 5</xref>). A similar, significant global association between TB and the <italic>FokI-BsmI-ApaI-TaqI</italic> SNP combination was observed in a small family-based association study of the Venda population of South Africa (authors' unpublished data). The Hardy-Weinberg disequilibrium of <italic>ApaI</italic> in parents may influence the significance of its observed association; however, considering that the frequency of the <italic>ApaI</italic> AA genotype in the case patients with TB from the family study (159/329 [48.3%]) was higher than that in the control subjects from the case-control study (266/634 [42.0%]) and that the haplotype associations are so strong, this disequilibrium is unlikely to fully explain the associations reported. Variation between results obtained for the case-control and family studies may also have been influenced by the factors described above for discrepancies between different case-control studies. In addition, the mean age of case patients in the family study was 29.1 years (SD, 10.6 years), compared with 34.7 years (SD, 12.6 years) in the casecontrol study, which may have further contributed to the inconsistency between results.</p>
<p>The <italic>ApaI</italic> SNP has no known functional significance, and its association with TB most likely involves a nearby causative polymorphism. The A allele frequency is, on average, 29% among Asians, 53% among whites, and 67% among African Americans [<xref ref-type="bibr" rid="bib39">39</xref>]. This higher frequency of "susceptible" variants among African populations may contribute to their increased susceptibility to TB. The more significant association found for the haplotype FA (χ<sup>2</sup> = 11.621, <italic>P</italic> = .0007, 1 <italic>df</italic>), compared with A alone (χ<sup>2</sup> = 4.925, <italic>P</italic> = .0265, 1 <italic>df</italic>), suggests the pres- x p4.925 Pp.0265 ence of an as-yet-untyped polymorphism that lies on this haplotype background and that is causative of the associations observed with this gene. The <italic>FokI</italic> RFLP, although not independently associated with TB, has functional consequences for the action of vitamin D; the F allele in combination with the L allele of the poly A microsatellite in exon IX (L/S) increases vitamin D-induced receptor function [<xref ref-type="bibr" rid="bib28">28</xref>] and may account for the most significant FA association. The FA haplotype, together with unidentified, associated functional alleles, may influence the function of C- and N-terminal VDR domains. Besides forming a heterodimer with RXR on directrepeat responsive elements, VDR possesses 2 interaction interfaces with the basal transcription factor, TFIIB—1 in the N-terminal DNA-binding region and the other in the C-terminalvitamin D-binding domain [<xref ref-type="bibr" rid="bib42">42</xref>]. The 2 biallelic variants of <italic>FokI</italic> SNP in exon 2 vary in protein sequence (f/M1 being 3 aa longer than F/M4) and influence this VDR-TFIIB interaction [<xref ref-type="bibr" rid="bib42">42</xref>]. The F/M4 protein represents a more transcriptionally active VDR isoform and is 1.5–2.5-fold more transcriptionally active than the f/M1 protein. It has been proposed that, in the tertiary structures of full-length VDR, the N- and C-terminal interaction regions combine to form a single docking scaffold for TFIIB [<xref ref-type="bibr" rid="bib42">42</xref>]. This ensures the efficient delivery of TFIIB to the transcriptional initiation complex and transcriptional activation of vitamin D-controlled genes through the VDRE present within their promoter region. If the 3′ region of VDR houses functional yet unidentified polymorphisms, which are in LD with <italic>BsmI, ApaI</italic>, and <italic>TaqI</italic> and encode an altered ligand-binding and heterodimerization domain, it could explain the significant association observed with the FA haplotype and 3′ polymorphisms reported here and in previous studies. The association of TB with the FA haplotype or previously described 3′ polymorphisms may be masked by environmental factors, such as the intake and light activation of vitamin D, making genotypic effects most apparent under conditions of vitamin D deficiency [<xref ref-type="bibr" rid="bib22">22</xref>, <xref ref-type="bibr" rid="bib40">40</xref>, <xref ref-type="bibr" rid="bib43">43</xref>].</p>
<p>All SNPs were in LD except for <italic>FokI-ApaI</italic> and <italic>FokI-TaqI</italic> (<xref ref-type="fig" rid="F1">figure 1</xref>). Although reports on the LD between FokI and the 3′ end are limited, the results that we obtained are in general agreement with reported LD patterns. LD among markers in the 3′ region in the present study is comparable with the strength of LD observed for African Americans, departing from the almost complete LD observed for whites [<xref ref-type="bibr" rid="bib36">36</xref>, <xref ref-type="bibr" rid="bib39">39</xref>].</p>
<p>The present study supports the proposed role for <italic>VDR</italic> haplotypes in susceptibility to TB, which suggests that previously associated nonfunctional alleles are most likely markers for asyet- unidentified disease susceptibility and resistance loci. An important aim in future research would be to identify more functional sequence variants in <italic>VDR</italic>, to define haplotype patterns in different populations, and to understand the functional consequences of haplotypes and their interaction with environmental factors that cause differential susceptibility to TB.</p>
</sec>
</body>
<back>
<ack>
<title>Acknowledgments</title>
<p>We are grateful to Angela Frodsham for fruitful discussions, to Simon Donkor and Sadio Diallo for their help with data management, and to John Murray for his valuable help in reading the radiographs.</p>
</ack>
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<sec>
<title>Figures and Tables</title>
<fig id="F1" position="float">
<label><bold>Figure 1.</bold></label>
<caption><p>A schematic diagram of the vitamin D receptor (<italic>VDR</italic>) gene, showing approximate positions and pairwise linkage disequilibrium (LD) between polymorphisms. Maximum-likelihood estimates of pairwise LD were obtained by use of LDMAX within the GOLD software package [<xref ref-type="bibr" rid="bib35">35</xref>]. No significant LD was detected between <italic>FokI</italic> and <italic>ApaI</italic> (D′ = 0.117; <italic>P</italic> = .12) or <italic>FokI</italic> and <italic>TaqI</italic> (D′ = 0.141; <italic>P</italic> = .080). The line weight of arrows connecting pairs of single-nucleotide polymorphisms reflects the strength in LD.</p></caption>
<graphic mimetype="image" xlink:href="190-9-1631-fig001.tif"></graphic>
</fig>
<fig id="F2" position="float">
<label>Table 1.</label>
<caption><p>Demographic and clinical details of participants in the case-control and family studies.</p></caption>
<graphic mimetype="image" xlink:href="190-9-1631-tab001.tif"></graphic>
</fig>
<fig id="F3" position="float">
<label>Table 2.</label>
<caption><p>The sequence of polymerase chain reaction (PCR) primers used for the analysis of single-nucleotide polymorphisms (SNPs) in the vitamin D receptor (<italic>VDR</italic>): <italic>BsmI, ApaI</italic>, and <italic>TaqI</italic> by ligation detection reaction and <italic>FokI</italic> by allele-specific PCR.</p></caption>
<graphic mimetype="image" xlink:href="190-9-1631-tab002.tif"></graphic>
</fig>
<fig id="F4" position="float">
<label>Table 3.</label>
<caption><p>Genotype frequencies for single-nucleotide polymorphisms (SNPs) in the vitamin D receptor (<italic>VDR</italic>) in all patients with tuberculosis (TB) and control subjects from The Gambia, Guinea, and Guinea-Bissau combined.</p></caption>
<graphic mimetype="image" xlink:href="190-9-1631-tab003.tif"></graphic>
</fig>
<fig id="F5" position="float">
<label>Table 4.</label>
<caption><p>Genotype frequencies for single-nucleotide polymorphisms (SNPs) in the vitamin D receptor (<italic>VDR</italic>) in patients with severe tuberculosis (TB) and control subjects from The Gambia, Guinea, and Guinea-Bissau, combined.</p></caption>
<graphic mimetype="image" xlink:href="190-9-1631-tab004.tif"></graphic>
</fig>
<fig id="F6" position="float">
<label>Table 5.</label>
<caption><p>Results obtained for the transmission-disequilibrium test [<xref ref-type="bibr" rid="bib33">33</xref>] by use of <italic>Transmit</italic> [<xref ref-type="bibr" rid="bib34">34</xref>].</p></caption>
<graphic mimetype="image" xlink:href="190-9-1631-tab005.tif"></graphic>
</fig>
<fig id="F7" position="float">
<label>Table 6.</label>
<caption><p>A summary of the literature verifying the association between single-nucleotide polymorphisms (SNPs) in the vitamin D receptor (<italic>VDR</italic>) and tuberculosis (TB).</p></caption>
<graphic mimetype="image" xlink:href="190-9-1631-tab006.tif"></graphic>
</fig>
</sec>
<fn-group>
<fn fn-type="financial-disclosure">
<p>Financial support: European Union (contract IC18CT980375, coordinated by C.L., for methodology support and sample collection at the 3 sites); Commonwealth (fellowship to L.B.); Medical Research Council (MRC; grant G0000690 to G.S. for sample collection in The Gambia); National Research Foundation of South Africa (grant 2053199 to L.B.); Wellcome Trust (Prize Fellowship to S.J.C., Principal Research Fellowship to A.V.S.H.); MRC Tropical Epidemiology Group (support to S.B. and K.F.).</p>
</fn>
<fn id="fna">
<label>a</label>
<p>L.B. and S.J.C. contributed equally to this work.</p>
</fn>
<fn id="fnb">
<label>b</label>
<p>Died in March 2003.</p>
</fn>
</fn-group>
</back>
</article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Vitamin D Receptor Polymorphisms and Susceptibility to Tuberculosis in West Africa: A Case-Control and Family Study</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Vitamin D Receptor Polymorphisms and Susceptibility to Tuberculosis in West Africa: A Case-Control and Family Study</title></titleInfo><name type="personal" displayLabel="corresp"><namePart type="given">Liza</namePart><namePart type="family">Bornman</namePart><affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford</affiliation><affiliation>Biochemistry Division, Department of Chemistry and Biochemistry, Rand Afrikaans University, Auckland Park, South Africa</affiliation><affiliation>E-mail: lbo@na.rau.ac.za</affiliation><affiliation>Reprints or correspondence: Dr. Liza Bornman, Biochemistry Div., Dept. of Chemistry and Biochemistry, Rand Afrikaans University, PO Box 524, Auckland Park 2006, South Africa</affiliation><affiliation>E-mail: lbo@na.rau.ac.za</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Sarah J.</namePart><namePart type="family">Campbell</namePart><affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Katherine</namePart><namePart type="family">Fielding</namePart><affiliation>London School of Hygiene and Tropical Medicine, London, United Kingdom</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Boubacar</namePart><namePart type="family">Bah</namePart><affiliation>Programme National de Lutte Anti-Tuberculeuse, Conakry, République de Guinée;</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jackson</namePart><namePart type="family">Sillah</namePart><affiliation>Medical Research Council Laboratories, Fajara</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Per</namePart><namePart type="family">Gustafson</namePart><affiliation>Projecto de Saude de Bandim, Danish Epidemiology Science Centre,Bissau Guinea-Bissau</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kebba</namePart><namePart type="family">Manneh</namePart><affiliation>National TB/Leprosy Control Programme, Banjul, The Gambia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ida</namePart><namePart type="family">Lisse</namePart><affiliation>Projecto de Saude de Bandim, Danish Epidemiology Science Centre,Bissau Guinea-Bissau</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Angela</namePart><namePart type="family">Allen</namePart><affiliation>Medical Research Council Laboratories, Fajara</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Giorgio</namePart><namePart type="family">Sirugo</namePart><affiliation>Medical Research Council Laboratories, Fajara</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Aissatou</namePart><namePart type="family">Sylla</namePart><affiliation>Programme National de Lutte Anti-Tuberculeuse, Conakry, République de Guinée;</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Peter</namePart><namePart type="family">Aaby</namePart><affiliation>Projecto de Saude de Bandim, Danish Epidemiology Science Centre,Bissau Guinea-Bissau</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Keith P. W. J.</namePart><namePart type="family">McAdam</namePart><affiliation>London School of Hygiene and Tropical Medicine, London, United Kingdom</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Oumou Bah</namePart><namePart type="family">Sow</namePart><affiliation>Programme National de Lutte Anti-Tuberculeuse, Conakry, République de Guinée;</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Steve</namePart><namePart type="family">Bennett</namePart><affiliation>London School of Hygiene and Tropical Medicine, London, United Kingdom</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Christian</namePart><namePart type="family">Lienhardt</namePart><affiliation>Medical Research Council Laboratories, Fajara</affiliation><affiliation>Institute de Recherche pour le Développement, Hann, Dakar, Senegal</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Adrian V. S.</namePart><namePart type="family">Hill</namePart><affiliation>Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford</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">2004-11-01</dateIssued><copyrightDate encoding="w3cdtf">2004</copyrightDate></originInfo><abstract>Vitamin D receptor (VDR) gene polymorphisms have been implicated in susceptibility to tuberculosis (TB), but reports have been inconsistent. We genotyped the VDR single-nucleotide polymorphisms (SNPs) FokI, BsmI, ApaI, and TaqI in 1139 case patients and control subjects and 382 families from The Gambia, Guinea, and Guinea-Bissau. The transmission-disequilibrium test on family data showed a significant global association of TB with SNP combinations FokI-BsmI-ApaI-TaqI and FokI-ApaI that were driven by the increased transmission to affected offspring of the FokI F and ApaI A alleles in combination. The ApaI A allele was also transmitted to affected offspring significantly more often than expected. Case-control analysis showed no statistically significant association between TB and VDR variants. BsmI, ApaI, and TaqI showed strong linkage disequilibrium. The significance of the family-based associations found between TB and FokI-BsmI-ApaI-TaqI and the FA haplotype supports a role for VDR haplotypes, rather than individual genotypes, in susceptibility to TB.</abstract><relatedItem type="host"><titleInfo><title>Journal of Infectious Diseases</title></titleInfo><titleInfo type="abbreviated"><title>J Infect Dis.</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">0022-1899</identifier><identifier type="eISSN">1537-6613</identifier><identifier type="PublisherID">jid</identifier><identifier type="PublisherID-hwp">jinfdis</identifier><part><date>2004</date><detail type="volume"><caption>vol.</caption><number>190</number></detail><detail type="issue"><caption>no.</caption><number>9</number></detail><extent unit="pages"><start>1631</start><end>1641</end></extent></part></relatedItem><identifier type="istex">959F417CD61462667173508CF79AD562587B4AD5</identifier><identifier type="DOI">10.1086/424462</identifier><accessCondition type="use and reproduction" contentType="copyright">© 2004 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>© 2004 by the Infectious Diseases Society of America</recordOrigin></recordInfo></mods><json:item><extension>json</extension><original>false</original><mimetype>application/json</mimetype><uri>https://api.istex.fr/document/959F417CD61462667173508CF79AD562587B4AD5/metadata/json</uri></json:item></metadata><covers><json:item><extension>tiff</extension><original>true</original><mimetype>image/tiff</mimetype><uri>https://api.istex.fr/document/959F417CD61462667173508CF79AD562587B4AD5/covers/tiff</uri></json:item><json:item><extension>html</extension><original>true</original><mimetype>text/html</mimetype><uri>https://api.istex.fr/document/959F417CD61462667173508CF79AD562587B4AD5/covers/html</uri></json:item></covers><annexes><json:item><extension>jpeg</extension><original>true</original><mimetype>image/jpeg</mimetype><uri>https://api.istex.fr/document/959F417CD61462667173508CF79AD562587B4AD5/annexes/jpeg</uri></json:item><json:item><extension>gif</extension><original>true</original><mimetype>image/gif</mimetype><uri>https://api.istex.fr/document/959F417CD61462667173508CF79AD562587B4AD5/annexes/gif</uri></json:item></annexes><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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