Independent and population-specific association of risk variants at the IRGM locus with Crohn's disease
Identifieur interne : 001312 ( Istex/Corpus ); précédent : 001311; suivant : 001313Independent and population-specific association of risk variants at the IRGM locus with Crohn's disease
Auteurs : Natalie J. Prescott ; Katherine M. Dominy ; Michiaki Kubo ; Cathryn M. Lewis ; Sheila A. Fisher ; Richard Redon ; Ni Huang ; Barbara E. Stranger ; Katarzyna Blaszczyk ; Barry Hudspith ; Gareth Parkes ; Naoya Hosono ; Keiko Yamazaki ; Clive M. Onnie ; Alastair Forbes ; Emmanouil T. Dermitzakis ; Yusuke Nakamura ; John C. Mansfield ; Jeremy Sanderson ; Matthew E. Hurles ; Roland G. Roberts ; Christopher G. MathewSource :
- Human Molecular Genetics [ 0964-6906 ] ; 2010-05-01.
Abstract
DNA polymorphisms in a region on chromosome 5q33.1 which contains two genes, immunity related GTPase related family, M (IRGM) and zinc finger protein 300 (ZNF300), are associated with Crohn's disease (CD). The deleted allele of a 20 kb copy number variation (CNV) upstream of IRGM was recently shown to be in strong linkage disequilibrium (LD) with the CD-associated single nucleotide polymorphisms and is itself associated with CD (P < 0.01). The deletion was correlated with increased or reduced expression of IRGM in transformed cells in a cell line-dependent manner, and has been proposed as a likely causal variant. We report here that small insertion/deletion polymorphisms in the promoter and 5 untranslated region of IRGM are, together with the CNV, strongly associated with CD (P 1.37 105 to 1.40 109), and that the CNV and the 5-untranslated region variant 308(GTTT)5 contribute independently to CD susceptibility (P 2.6 107 and P 2 105, respectively). We also show that the CD risk haplotype is associated with a significant decrease in IRGM expression (P < 1012) in untransformed lymphocytes from CD patients. Further analysis of these variants in a Japanese CD casecontrol sample and of IRGM expression in HapMap populations revealed that neither the IRGM insertion/deletion polymorphisms nor the CNV was associated with CD or with altered IRGM expression in the Asian population. This suggests that the involvement of the IRGM risk haplotype in the pathogenesis of CD requires genegene or geneenvironment interactions which are absent in Asian populations, or that none of the variants analysed are causal, and that the true causal variants arose after the EuropeanAsian split.
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DOI: 10.1093/hmg/ddq041
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Onnie</name><affiliation><mods:affiliation>Department of Gastroenterology, Whittington Hospital NHS Trust, London NW11 6BJ, UK,</mods:affiliation></affiliation></author><author><name sortKey="Forbes, Alastair" sort="Forbes, Alastair" uniqKey="Forbes A" first="Alastair" last="Forbes">Alastair Forbes</name><affiliation><mods:affiliation>Institute for Digestive Diseases, University College London Hospitals Trust, London NW1 2BU, UK,</mods:affiliation></affiliation></author><author><name sortKey="Dermitzakis, Emmanouil T" sort="Dermitzakis, Emmanouil T" uniqKey="Dermitzakis E" first="Emmanouil T." last="Dermitzakis">Emmanouil T. Dermitzakis</name><affiliation><mods:affiliation>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK,</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland</mods:affiliation></affiliation></author><author><name sortKey="Nakamura, Yusuke" sort="Nakamura, Yusuke" uniqKey="Nakamura Y" first="Yusuke" last="Nakamura">Yusuke Nakamura</name><affiliation><mods:affiliation>Laboratory of Molecular Medicine, Human Genome Centre, Institute of Medical Science, University of Tokyo, Tokyo 108, Japan</mods:affiliation></affiliation></author><author><name sortKey="Mansfield, John C" sort="Mansfield, John C" uniqKey="Mansfield J" first="John C." last="Mansfield">John C. Mansfield</name><affiliation><mods:affiliation>Department of Gastroenterology and Hepatology, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK</mods:affiliation></affiliation></author><author><name sortKey="Sanderson, Jeremy" sort="Sanderson, Jeremy" uniqKey="Sanderson J" first="Jeremy" last="Sanderson">Jeremy Sanderson</name><affiliation><mods:affiliation>Department of Gastroenterology, Guy's & St Thomas' NHS Foundation Trust, St Thomas' Hospital, London SE1 7EH, UK,</mods:affiliation></affiliation></author><author><name sortKey="Hurles, Matthew E" sort="Hurles, Matthew E" uniqKey="Hurles M" first="Matthew E." last="Hurles">Matthew E. Hurles</name><affiliation><mods:affiliation>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK,</mods:affiliation></affiliation></author><author><name sortKey="Roberts, Roland G" sort="Roberts, Roland G" uniqKey="Roberts R" first="Roland G." last="Roberts">Roland G. Roberts</name><affiliation><mods:affiliation>Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK,</mods:affiliation></affiliation></author><author><name sortKey="Mathew, Christopher G" sort="Mathew, Christopher G" uniqKey="Mathew C" first="Christopher G." last="Mathew">Christopher G. Mathew</name><affiliation><mods:affiliation>Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK,</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:230F05CDCBA08463E824A0B74D02D69FB5D50AC0</idno><date when="2010" year="2010">2010</date><idno type="doi">10.1093/hmg/ddq041</idno><idno type="url">https://api.istex.fr/document/230F05CDCBA08463E824A0B74D02D69FB5D50AC0/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">001312</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">Independent and population-specific association of risk variants at the IRGM locus with Crohn's disease</title><author><name sortKey="Prescott, Natalie J" sort="Prescott, Natalie J" uniqKey="Prescott N" first="Natalie J." last="Prescott">Natalie J. Prescott</name><affiliation><mods:affiliation>Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK,</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: natalie.prescott@genetics.kcl.ac.uk</mods:affiliation></affiliation></author><author><name sortKey="Dominy, Katherine M" sort="Dominy, Katherine M" uniqKey="Dominy K" first="Katherine M." last="Dominy">Katherine M. Dominy</name><affiliation><mods:affiliation>Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK,</mods:affiliation></affiliation></author><author><name sortKey="Kubo, Michiaki" sort="Kubo, Michiaki" uniqKey="Kubo M" first="Michiaki" last="Kubo">Michiaki Kubo</name><affiliation><mods:affiliation>Laboratory for Genotyping Development, Center of Genomic Medicine, RIKEN Yokohama Institute, Yokohama City, Japan,</mods:affiliation></affiliation></author><author><name sortKey="Lewis, Cathryn M" sort="Lewis, Cathryn M" uniqKey="Lewis C" first="Cathryn M." last="Lewis">Cathryn M. Lewis</name><affiliation><mods:affiliation>Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK,</mods:affiliation></affiliation></author><author><name sortKey="Fisher, Sheila A" sort="Fisher, Sheila A" uniqKey="Fisher S" first="Sheila A." last="Fisher">Sheila A. Fisher</name><affiliation><mods:affiliation>Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK,</mods:affiliation></affiliation></author><author><name sortKey="Redon, Richard" sort="Redon, Richard" uniqKey="Redon R" first="Richard" last="Redon">Richard Redon</name><affiliation><mods:affiliation>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK,</mods:affiliation></affiliation></author><author><name sortKey="Huang, Ni" sort="Huang, Ni" uniqKey="Huang N" first="Ni" last="Huang">Ni Huang</name><affiliation><mods:affiliation>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK,</mods:affiliation></affiliation></author><author><name sortKey="Stranger, Barbara E" sort="Stranger, Barbara E" uniqKey="Stranger B" first="Barbara E." last="Stranger">Barbara E. Stranger</name><affiliation><mods:affiliation>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK,</mods:affiliation></affiliation><affiliation><mods:affiliation>Division of Genetics, Harvard Medical School/Brigham and Women's Hospital, Boston MA, USA and</mods:affiliation></affiliation></author><author><name sortKey="Blaszczyk, Katarzyna" sort="Blaszczyk, Katarzyna" uniqKey="Blaszczyk K" first="Katarzyna" last="Blaszczyk">Katarzyna Blaszczyk</name><affiliation><mods:affiliation>Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK,</mods:affiliation></affiliation></author><author><name sortKey="Hudspith, Barry" sort="Hudspith, Barry" uniqKey="Hudspith B" first="Barry" last="Hudspith">Barry Hudspith</name><affiliation><mods:affiliation>Nutritional Sciences Division, King's College London, Waterloo Campus, London SE1 9NH, UK,</mods:affiliation></affiliation></author><author><name sortKey="Parkes, Gareth" sort="Parkes, Gareth" uniqKey="Parkes G" first="Gareth" last="Parkes">Gareth Parkes</name><affiliation><mods:affiliation>Department of Gastroenterology, Guy's & St Thomas' NHS Foundation Trust, St Thomas' Hospital, London SE1 7EH, UK,</mods:affiliation></affiliation></author><author><name sortKey="Hosono, Naoya" sort="Hosono, Naoya" uniqKey="Hosono N" first="Naoya" last="Hosono">Naoya Hosono</name><affiliation><mods:affiliation>Laboratory for Genotyping Development, Center of Genomic Medicine, RIKEN Yokohama Institute, Yokohama City, Japan,</mods:affiliation></affiliation></author><author><name sortKey="Yamazaki, Keiko" sort="Yamazaki, Keiko" uniqKey="Yamazaki K" first="Keiko" last="Yamazaki">Keiko Yamazaki</name><affiliation><mods:affiliation>Laboratory for Genotyping Development, Center of Genomic Medicine, RIKEN Yokohama Institute, Yokohama City, Japan,</mods:affiliation></affiliation></author><author><name sortKey="Onnie, Clive M" sort="Onnie, Clive M" uniqKey="Onnie C" first="Clive M." last="Onnie">Clive M. Onnie</name><affiliation><mods:affiliation>Department of Gastroenterology, Whittington Hospital NHS Trust, London NW11 6BJ, UK,</mods:affiliation></affiliation></author><author><name sortKey="Forbes, Alastair" sort="Forbes, Alastair" uniqKey="Forbes A" first="Alastair" last="Forbes">Alastair Forbes</name><affiliation><mods:affiliation>Institute for Digestive Diseases, University College London Hospitals Trust, London NW1 2BU, UK,</mods:affiliation></affiliation></author><author><name sortKey="Dermitzakis, Emmanouil T" sort="Dermitzakis, Emmanouil T" uniqKey="Dermitzakis E" first="Emmanouil T." last="Dermitzakis">Emmanouil T. Dermitzakis</name><affiliation><mods:affiliation>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK,</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland</mods:affiliation></affiliation></author><author><name sortKey="Nakamura, Yusuke" sort="Nakamura, Yusuke" uniqKey="Nakamura Y" first="Yusuke" last="Nakamura">Yusuke Nakamura</name><affiliation><mods:affiliation>Laboratory of Molecular Medicine, Human Genome Centre, Institute of Medical Science, University of Tokyo, Tokyo 108, Japan</mods:affiliation></affiliation></author><author><name sortKey="Mansfield, John C" sort="Mansfield, John C" uniqKey="Mansfield J" first="John C." last="Mansfield">John C. Mansfield</name><affiliation><mods:affiliation>Department of Gastroenterology and Hepatology, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK</mods:affiliation></affiliation></author><author><name sortKey="Sanderson, Jeremy" sort="Sanderson, Jeremy" uniqKey="Sanderson J" first="Jeremy" last="Sanderson">Jeremy Sanderson</name><affiliation><mods:affiliation>Department of Gastroenterology, Guy's & St Thomas' NHS Foundation Trust, St Thomas' Hospital, London SE1 7EH, UK,</mods:affiliation></affiliation></author><author><name sortKey="Hurles, Matthew E" sort="Hurles, Matthew E" uniqKey="Hurles M" first="Matthew E." last="Hurles">Matthew E. Hurles</name><affiliation><mods:affiliation>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK,</mods:affiliation></affiliation></author><author><name sortKey="Roberts, Roland G" sort="Roberts, Roland G" uniqKey="Roberts R" first="Roland G." last="Roberts">Roland G. Roberts</name><affiliation><mods:affiliation>Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK,</mods:affiliation></affiliation></author><author><name sortKey="Mathew, Christopher G" sort="Mathew, Christopher G" uniqKey="Mathew C" first="Christopher G." last="Mathew">Christopher G. Mathew</name><affiliation><mods:affiliation>Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK,</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Human Molecular Genetics</title><idno type="ISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2010-05-01">2010-05-01</date><biblScope unit="volume">19</biblScope><biblScope unit="issue">9</biblScope><biblScope unit="page" from="1828">1828</biblScope><biblScope unit="page" to="1839">1839</biblScope></imprint><idno type="ISSN">0964-6906</idno></series><idno type="istex">230F05CDCBA08463E824A0B74D02D69FB5D50AC0</idno><idno type="DOI">10.1093/hmg/ddq041</idno><idno type="ArticleID">ddq041</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0964-6906</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">DNA polymorphisms in a region on chromosome 5q33.1 which contains two genes, immunity related GTPase related family, M (IRGM) and zinc finger protein 300 (ZNF300), are associated with Crohn's disease (CD). The deleted allele of a 20 kb copy number variation (CNV) upstream of IRGM was recently shown to be in strong linkage disequilibrium (LD) with the CD-associated single nucleotide polymorphisms and is itself associated with CD (P < 0.01). The deletion was correlated with increased or reduced expression of IRGM in transformed cells in a cell line-dependent manner, and has been proposed as a likely causal variant. We report here that small insertion/deletion polymorphisms in the promoter and 5 untranslated region of IRGM are, together with the CNV, strongly associated with CD (P 1.37 105 to 1.40 109), and that the CNV and the 5-untranslated region variant 308(GTTT)5 contribute independently to CD susceptibility (P 2.6 107 and P 2 105, respectively). We also show that the CD risk haplotype is associated with a significant decrease in IRGM expression (P < 1012) in untransformed lymphocytes from CD patients. Further analysis of these variants in a Japanese CD casecontrol sample and of IRGM expression in HapMap populations revealed that neither the IRGM insertion/deletion polymorphisms nor the CNV was associated with CD or with altered IRGM expression in the Asian population. This suggests that the involvement of the IRGM risk haplotype in the pathogenesis of CD requires genegene or geneenvironment interactions which are absent in Asian populations, or that none of the variants analysed are causal, and that the true causal variants arose after the EuropeanAsian split.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Natalie J. Prescott</name><affiliations><json:string>Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK,</json:string><json:string>E-mail: natalie.prescott@genetics.kcl.ac.uk</json:string></affiliations></json:item><json:item><name>Katherine M. Dominy</name><affiliations><json:string>Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK,</json:string></affiliations></json:item><json:item><name>Michiaki Kubo</name><affiliations><json:string>Laboratory for Genotyping Development, Center of Genomic Medicine, RIKEN Yokohama Institute, Yokohama City, Japan,</json:string></affiliations></json:item><json:item><name>Cathryn M. Lewis</name><affiliations><json:string>Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK,</json:string></affiliations></json:item><json:item><name>Sheila A. Fisher</name><affiliations><json:string>Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK,</json:string></affiliations></json:item><json:item><name>Richard Redon</name><affiliations><json:string>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK,</json:string></affiliations></json:item><json:item><name>Ni Huang</name><affiliations><json:string>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK,</json:string></affiliations></json:item><json:item><name>Barbara E. Stranger</name><affiliations><json:string>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK,</json:string><json:string>Division of Genetics, Harvard Medical School/Brigham and Women's Hospital, Boston MA, USA and</json:string></affiliations></json:item><json:item><name>Katarzyna Blaszczyk</name><affiliations><json:string>Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK,</json:string></affiliations></json:item><json:item><name>Barry Hudspith</name><affiliations><json:string>Nutritional Sciences Division, King's College London, Waterloo Campus, London SE1 9NH, UK,</json:string></affiliations></json:item><json:item><name>Gareth Parkes</name><affiliations><json:string>Department of Gastroenterology, Guy's & St Thomas' NHS Foundation Trust, St Thomas' Hospital, London SE1 7EH, UK,</json:string></affiliations></json:item><json:item><name>Naoya Hosono</name><affiliations><json:string>Laboratory for Genotyping Development, Center of Genomic Medicine, RIKEN Yokohama Institute, Yokohama City, Japan,</json:string></affiliations></json:item><json:item><name>Keiko Yamazaki</name><affiliations><json:string>Laboratory for Genotyping Development, Center of Genomic Medicine, RIKEN Yokohama Institute, Yokohama City, Japan,</json:string></affiliations></json:item><json:item><name>Clive M. Onnie</name><affiliations><json:string>Department of Gastroenterology, Whittington Hospital NHS Trust, London NW11 6BJ, UK,</json:string></affiliations></json:item><json:item><name>Alastair Forbes</name><affiliations><json:string>Institute for Digestive Diseases, University College London Hospitals Trust, London NW1 2BU, UK,</json:string></affiliations></json:item><json:item><name>Emmanouil T. Dermitzakis</name><affiliations><json:string>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK,</json:string><json:string>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland</json:string></affiliations></json:item><json:item><name>Yusuke Nakamura</name><affiliations><json:string>Laboratory of Molecular Medicine, Human Genome Centre, Institute of Medical Science, University of Tokyo, Tokyo 108, Japan</json:string></affiliations></json:item><json:item><name>John C. Mansfield</name><affiliations><json:string>Department of Gastroenterology and Hepatology, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK</json:string></affiliations></json:item><json:item><name>Jeremy Sanderson</name><affiliations><json:string>Department of Gastroenterology, Guy's & St Thomas' NHS Foundation Trust, St Thomas' Hospital, London SE1 7EH, UK,</json:string></affiliations></json:item><json:item><name>Matthew E. Hurles</name><affiliations><json:string>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK,</json:string></affiliations></json:item><json:item><name>Roland G. Roberts</name><affiliations><json:string>Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK,</json:string></affiliations></json:item><json:item><name>Christopher G. Mathew</name><affiliations><json:string>Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK,</json:string></affiliations></json:item></author><articleId><json:string>ddq041</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><abstract>DNA polymorphisms in a region on chromosome 5q33.1 which contains two genes, immunity related GTPase related family, M (IRGM) and zinc finger protein 300 (ZNF300), are associated with Crohn's disease (CD). The deleted allele of a 20 kb copy number variation (CNV) upstream of IRGM was recently shown to be in strong linkage disequilibrium (LD) with the CD-associated single nucleotide polymorphisms and is itself associated with CD (P > 0.01). The deletion was correlated with increased or reduced expression of IRGM in transformed cells in a cell line-dependent manner, and has been proposed as a likely causal variant. We report here that small insertion/deletion polymorphisms in the promoter and 5 untranslated region of IRGM are, together with the CNV, strongly associated with CD (P 1.37 105 to 1.40 109), and that the CNV and the 5-untranslated region variant 308(GTTT)5 contribute independently to CD susceptibility (P 2.6 107 and P 2 105, respectively). We also show that the CD risk haplotype is associated with a significant decrease in IRGM expression (P > 1012) in untransformed lymphocytes from CD patients. Further analysis of these variants in a Japanese CD casecontrol sample and of IRGM expression in HapMap populations revealed that neither the IRGM insertion/deletion polymorphisms nor the CNV was associated with CD or with altered IRGM expression in the Asian population. This suggests that the involvement of the IRGM risk haplotype in the pathogenesis of CD requires genegene or geneenvironment interactions which are absent in Asian populations, or that none of the variants analysed are causal, and that the true causal variants arose after the EuropeanAsian split.</abstract><qualityIndicators><score>9</score><pdfVersion>1.5</pdfVersion><pdfPageSize>612 x 797.953 pts</pdfPageSize><refBibsNative>false</refBibsNative><keywordCount>0</keywordCount><abstractCharCount>1691</abstractCharCount><pdfWordCount>7958</pdfWordCount><pdfCharCount>47961</pdfCharCount><pdfPageCount>12</pdfPageCount><abstractWordCount>265</abstractWordCount></qualityIndicators><title>Independent and population-specific association of risk variants at the IRGM locus with Crohn's disease</title><genre><json:string>research-article</json:string></genre><host><volume>19</volume><publisherId><json:string>hmg</json:string></publisherId><pages><last>1839</last><first>1828</first></pages><issn><json:string>0964-6906</json:string></issn><issue>9</issue><genre><json:string>journal</json:string></genre><language><json:string>unknown</json:string></language><eissn><json:string>1460-2083</json:string></eissn><title>Human Molecular Genetics</title></host><categories><wos><json:string>BIOCHEMISTRY & MOLECULAR BIOLOGY</json:string><json:string>GENETICS & HEREDITY</json:string></wos></categories><publicationDate>2010</publicationDate><copyrightDate>2010</copyrightDate><doi><json:string>10.1093/hmg/ddq041</json:string></doi><id>230F05CDCBA08463E824A0B74D02D69FB5D50AC0</id><score>0.23349598</score><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/230F05CDCBA08463E824A0B74D02D69FB5D50AC0/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/230F05CDCBA08463E824A0B74D02D69FB5D50AC0/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/230F05CDCBA08463E824A0B74D02D69FB5D50AC0/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a">Independent and population-specific association of risk variants at the IRGM locus with Crohn's disease</title><respStmt><resp>Références bibliographiques récupérées via GROBID</resp><name resp="ISTEX-API">ISTEX-API (INIST-CNRS)</name></respStmt></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Oxford University Press</publisher><availability><p>The Author 2010. Published by Oxford University Press.</p></availability><date>2010-01-27</date></publicationStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">Independent and population-specific association of risk variants at the IRGM locus with Crohn's disease</title><author xml:id="author-1"><persName><forename type="first">Natalie J.</forename><surname>Prescott</surname></persName><email>natalie.prescott@genetics.kcl.ac.uk</email><affiliation>Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK,</affiliation></author><author xml:id="author-2"><persName><forename type="first">Katherine M.</forename><surname>Dominy</surname></persName><affiliation>Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK,</affiliation></author><author xml:id="author-3"><persName><forename type="first">Michiaki</forename><surname>Kubo</surname></persName><affiliation>Laboratory for Genotyping Development, Center of Genomic Medicine, RIKEN Yokohama Institute, Yokohama City, Japan,</affiliation></author><author xml:id="author-4"><persName><forename type="first">Cathryn M.</forename><surname>Lewis</surname></persName><affiliation>Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK,</affiliation></author><author xml:id="author-5"><persName><forename type="first">Sheila A.</forename><surname>Fisher</surname></persName><affiliation>Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK,</affiliation></author><author xml:id="author-6"><persName><forename type="first">Richard</forename><surname>Redon</surname></persName><affiliation>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK,</affiliation></author><author xml:id="author-7"><persName><forename type="first">Ni</forename><surname>Huang</surname></persName><affiliation>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK,</affiliation></author><author xml:id="author-8"><persName><forename type="first">Barbara E.</forename><surname>Stranger</surname></persName><affiliation>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK,</affiliation><affiliation>Division of Genetics, Harvard Medical School/Brigham and Women's Hospital, Boston MA, USA and</affiliation></author><author xml:id="author-9"><persName><forename type="first">Katarzyna</forename><surname>Blaszczyk</surname></persName><affiliation>Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK,</affiliation></author><author xml:id="author-10"><persName><forename type="first">Barry</forename><surname>Hudspith</surname></persName><affiliation>Nutritional Sciences Division, King's College London, Waterloo Campus, London SE1 9NH, UK,</affiliation></author><author xml:id="author-11"><persName><forename type="first">Gareth</forename><surname>Parkes</surname></persName><affiliation>Department of Gastroenterology, Guy's & St Thomas' NHS Foundation Trust, St Thomas' Hospital, London SE1 7EH, UK,</affiliation></author><author xml:id="author-12"><persName><forename type="first">Naoya</forename><surname>Hosono</surname></persName><affiliation>Laboratory for Genotyping Development, Center of Genomic Medicine, RIKEN Yokohama Institute, Yokohama City, Japan,</affiliation></author><author xml:id="author-13"><persName><forename type="first">Keiko</forename><surname>Yamazaki</surname></persName><affiliation>Laboratory for Genotyping Development, Center of Genomic Medicine, RIKEN Yokohama Institute, Yokohama City, Japan,</affiliation></author><author xml:id="author-14"><persName><forename type="first">Clive M.</forename><surname>Onnie</surname></persName><affiliation>Department of Gastroenterology, Whittington Hospital NHS Trust, London NW11 6BJ, UK,</affiliation></author><author xml:id="author-15"><persName><forename type="first">Alastair</forename><surname>Forbes</surname></persName><affiliation>Institute for Digestive Diseases, University College London Hospitals Trust, London NW1 2BU, UK,</affiliation></author><author xml:id="author-16"><persName><forename type="first">Emmanouil T.</forename><surname>Dermitzakis</surname></persName><affiliation>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK,</affiliation><affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland</affiliation></author><author xml:id="author-17"><persName><forename type="first">Yusuke</forename><surname>Nakamura</surname></persName><affiliation>Laboratory of Molecular Medicine, Human Genome Centre, Institute of Medical Science, University of Tokyo, Tokyo 108, Japan</affiliation></author><author xml:id="author-18"><persName><forename type="first">John C.</forename><surname>Mansfield</surname></persName><affiliation>Department of Gastroenterology and Hepatology, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK</affiliation></author><author xml:id="author-19"><persName><forename type="first">Jeremy</forename><surname>Sanderson</surname></persName><affiliation>Department of Gastroenterology, Guy's & St Thomas' NHS Foundation Trust, St Thomas' Hospital, London SE1 7EH, UK,</affiliation></author><author xml:id="author-20"><persName><forename type="first">Matthew E.</forename><surname>Hurles</surname></persName><affiliation>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK,</affiliation></author><author xml:id="author-21"><persName><forename type="first">Roland G.</forename><surname>Roberts</surname></persName><affiliation>Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK,</affiliation></author><author xml:id="author-22"><persName><forename type="first">Christopher G.</forename><surname>Mathew</surname></persName><affiliation>Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK,</affiliation></author></analytic><monogr><title level="j">Human Molecular Genetics</title><idno type="pISSN">0964-6906</idno><idno type="eISSN">1460-2083</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2010-05-01"></date><biblScope unit="volume">19</biblScope><biblScope unit="issue">9</biblScope><biblScope unit="page" from="1828">1828</biblScope><biblScope unit="page" to="1839">1839</biblScope></imprint></monogr><idno type="istex">230F05CDCBA08463E824A0B74D02D69FB5D50AC0</idno><idno type="DOI">10.1093/hmg/ddq041</idno><idno type="ArticleID">ddq041</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2010-01-27</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>DNA polymorphisms in a region on chromosome 5q33.1 which contains two genes, immunity related GTPase related family, M (IRGM) and zinc finger protein 300 (ZNF300), are associated with Crohn's disease (CD). The deleted allele of a 20 kb copy number variation (CNV) upstream of IRGM was recently shown to be in strong linkage disequilibrium (LD) with the CD-associated single nucleotide polymorphisms and is itself associated with CD (P < 0.01). The deletion was correlated with increased or reduced expression of IRGM in transformed cells in a cell line-dependent manner, and has been proposed as a likely causal variant. We report here that small insertion/deletion polymorphisms in the promoter and 5 untranslated region of IRGM are, together with the CNV, strongly associated with CD (P 1.37 105 to 1.40 109), and that the CNV and the 5-untranslated region variant 308(GTTT)5 contribute independently to CD susceptibility (P 2.6 107 and P 2 105, respectively). We also show that the CD risk haplotype is associated with a significant decrease in IRGM expression (P < 1012) in untransformed lymphocytes from CD patients. Further analysis of these variants in a Japanese CD casecontrol sample and of IRGM expression in HapMap populations revealed that neither the IRGM insertion/deletion polymorphisms nor the CNV was associated with CD or with altered IRGM expression in the Asian population. This suggests that the involvement of the IRGM risk haplotype in the pathogenesis of CD requires genegene or geneenvironment interactions which are absent in Asian populations, or that none of the variants analysed are causal, and that the true causal variants arose after the EuropeanAsian split.</p></abstract></profileDesc><revisionDesc><change when="2010-01-27">Created</change><change when="2010-05-01">Published</change><change xml:id="refBibs-istex" who="#ISTEX-API" when="2016-10-14">References added</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/230F05CDCBA08463E824A0B74D02D69FB5D50AC0/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</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="publisher-id">hmg</journal-id><journal-id journal-id-type="hwp">hmg</journal-id><journal-title>Human Molecular Genetics</journal-title><issn pub-type="ppub">0964-6906</issn><issn pub-type="epub">1460-2083</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.1093/hmg/ddq041</article-id><article-id pub-id-type="publisher-id">ddq041</article-id><article-categories><subj-group subj-group-type="heading"><subject>ASSOCIATION STUDIES ARTICLES</subject></subj-group></article-categories><title-group><article-title>Independent and population-specific association of risk variants at the <italic>IRGM</italic> locus with Crohn's disease</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Prescott</surname><given-names>Natalie J.</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib><contrib contrib-type="author"><name><surname>Dominy</surname><given-names>Katherine M.</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Kubo</surname><given-names>Michiaki</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Lewis</surname><given-names>Cathryn M.</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Fisher</surname><given-names>Sheila A.</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Redon</surname><given-names>Richard</given-names></name><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Huang</surname><given-names>Ni</given-names></name><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Stranger</surname><given-names>Barbara E.</given-names></name><xref ref-type="aff" rid="af3">3</xref><xref ref-type="aff" rid="af10">10</xref></contrib><contrib contrib-type="author"><name><surname>Blaszczyk</surname><given-names>Katarzyna</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Hudspith</surname><given-names>Barry</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Parkes</surname><given-names>Gareth</given-names></name><xref ref-type="aff" rid="af5">5</xref></contrib><contrib contrib-type="author"><name><surname>Hosono</surname><given-names>Naoya</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Yamazaki</surname><given-names>Keiko</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Onnie</surname><given-names>Clive M.</given-names></name><xref ref-type="aff" rid="af6">6</xref></contrib><contrib contrib-type="author"><name><surname>Forbes</surname><given-names>Alastair</given-names></name><xref ref-type="aff" rid="af7">7</xref></contrib><contrib contrib-type="author"><name><surname>Dermitzakis</surname><given-names>Emmanouil T.</given-names></name><xref ref-type="aff" rid="af3">3</xref><xref ref-type="aff" rid="af11">11</xref></contrib><contrib contrib-type="author"><name><surname>Nakamura</surname><given-names>Yusuke</given-names></name><xref ref-type="aff" rid="af8">8</xref></contrib><contrib contrib-type="author"><name><surname>Mansfield</surname><given-names>John C.</given-names></name><xref ref-type="aff" rid="af9">9</xref></contrib><contrib contrib-type="author"><name><surname>Sanderson</surname><given-names>Jeremy</given-names></name><xref ref-type="aff" rid="af5">5</xref></contrib><contrib contrib-type="author"><name><surname>Hurles</surname><given-names>Matthew E.</given-names></name><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Roberts</surname><given-names>Roland G.</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib><contrib contrib-type="author"><name><surname>Mathew</surname><given-names>Christopher G.</given-names></name><xref ref-type="aff" rid="af1">1</xref></contrib></contrib-group><aff id="af1"><label>1</label><addr-line>Department of Medical and Molecular Genetics</addr-line>, <institution>King's College London School of Medicine, Guy's Hospital</institution>, <addr-line>London SE1 9RT</addr-line>, <country>UK</country>,</aff><aff id="af2"><label>2</label><addr-line>Laboratory for Genotyping Development</addr-line>, <institution>Center of Genomic Medicine, RIKEN Yokohama Institute</institution>, <addr-line>Yokohama City</addr-line>, <country>Japan</country>,</aff><aff id="af3"><label>3</label><institution>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton</institution>, <addr-line>Cambridge CB10 1SA</addr-line>, <country>UK</country>,</aff><aff id="af4"><label>4</label><addr-line>Nutritional Sciences Division</addr-line>, <institution>King's College London, Waterloo Campus</institution>, <addr-line>London SE1 9NH</addr-line>, <country>UK</country>,</aff><aff id="af5"><label>5</label><addr-line>Department of Gastroenterology</addr-line>, <institution>Guy's & St Thomas' NHS Foundation Trust, St Thomas' Hospital</institution>, <addr-line>London SE1 7EH</addr-line>, <country>UK</country>,</aff><aff id="af6"><label>6</label><addr-line>Department of Gastroenterology</addr-line>, <institution>Whittington Hospital NHS Trust</institution>, <addr-line>London NW11 6BJ</addr-line>, <country>UK</country>,</aff><aff id="af7"><label>7</label><institution>Institute for Digestive Diseases, University College London Hospitals Trust</institution>, <addr-line>London NW1 2BU</addr-line>, <country>UK</country>,</aff><aff id="af8"><label>8</label><institution>Laboratory of Molecular Medicine, Human Genome Centre, Institute of Medical Science, University of Tokyo</institution>, <addr-line>Tokyo 108</addr-line>, <country>Japan</country></aff><aff id="af9"><label>9</label><addr-line>Department of Gastroenterology and Hepatology</addr-line>, <institution>University of Newcastle upon Tyne, Royal Victoria Infirmary</institution>, <addr-line>Newcastle upon Tyne NE1 4LP</addr-line>, <country>UK</country></aff><aff id="af10"><label>10</label><addr-line>Division of Genetics, Harvard Medical School/Brigham and Women's Hospital, Boston MA</addr-line>, <country>USA</country> and</aff><aff id="af11"><label>11</label><addr-line>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva</addr-line>, <country>Switzerland</country></aff><author-notes><corresp id="cor1"><label>*</label>To whom correspondence should be addressed at: <addr-line>Department of Medical and Molecular Genetics</addr-line>, <institution>King's College London School of Medicine</institution>, <addr-line>7th Floor Tower Wing, Guy's Hospital, London SE1 9RT</addr-line>, <country>UK</country>. Tel: <phone>+44 2071883713</phone>; Fax: <fax>+44 2071882585</fax>; Email: <email>natalie.prescott@genetics.kcl.ac.uk</email></corresp></author-notes><pub-date pub-type="ppub"><day>1</day><month>5</month><year>2010</year></pub-date><pub-date pub-type="epub"><day>27</day><month>1</month><year>2010</year></pub-date><volume>19</volume><issue>9</issue><fpage>1828</fpage><lpage>1839</lpage><history><date date-type="received"><day>12</day><month>10</month><year>2009</year></date><date date-type="rev-recd"><day>12</day><month>1</month><year>2010</year></date><date date-type="accepted"><day>25</day><month>1</month><year>2010</year></date></history><permissions><copyright-statement>© The Author 2010. Published by Oxford University Press.</copyright-statement><copyright-year>2010</copyright-year><license license-type="creative-commons" xlink:href="http://creativecommons.org/licenses/by-nc/2.0/uk/"><p>This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.</p></license></permissions><abstract><p>DNA polymorphisms in a region on chromosome 5q33.1 which contains two genes, immunity related GTPase related family, M (<italic>IRGM</italic>) and zinc finger protein 300 (<italic>ZNF300</italic>), are associated with Crohn's disease (CD). The deleted allele of a 20 kb copy number variation (CNV) upstream of <italic>IRGM</italic> was recently shown to be in strong linkage disequilibrium (LD) with the CD-associated single nucleotide polymorphisms and is itself associated with CD (<italic>P</italic> < 0.01). The deletion was correlated with increased or reduced expression of <italic>IRGM</italic> in transformed cells in a cell line-dependent manner, and has been proposed as a likely causal variant. We report here that small insertion/deletion polymorphisms in the promoter and 5′ untranslated region of <italic>IRGM</italic> are, together with the CNV, strongly associated with CD (<italic>P</italic> = 1.37 × 10<sup>−5</sup> to 1.40 × 10<sup>−9</sup>), and that the CNV and the 5′-untranslated region variant −308(GTTT)<sub>5</sub> contribute independently to CD susceptibility (<italic>P</italic> = 2.6 × 10<sup>−7</sup> and <italic>P</italic> = 2 × 10<sup>−5</sup>, respectively). We also show that the CD risk haplotype is associated with a significant decrease in <italic>IRGM</italic> expression (<italic>P</italic> < 10<sup>−12</sup>) in untransformed lymphocytes from CD patients. Further analysis of these variants in a Japanese CD case–control sample and of <italic>IRGM</italic> expression in HapMap populations revealed that neither the <italic>IRGM</italic> insertion/deletion polymorphisms nor the CNV was associated with CD or with altered <italic>IRGM</italic> expression in the Asian population. This suggests that the involvement of the <italic>IRGM</italic> risk haplotype in the pathogenesis of CD requires gene–gene or gene–environment interactions which are absent in Asian populations, or that none of the variants analysed are causal, and that the true causal variants arose after the European–Asian split.</p></abstract></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Independent and population-specific association of risk variants at the IRGM locus with Crohn's disease</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Independent and population-specific association of risk variants at the IRGM locus with Crohn's disease</title></titleInfo><name type="personal"><namePart type="given">Natalie J.</namePart><namePart type="family">Prescott</namePart><affiliation>Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK,</affiliation><affiliation>E-mail: natalie.prescott@genetics.kcl.ac.uk</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Katherine M.</namePart><namePart type="family">Dominy</namePart><affiliation>Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Michiaki</namePart><namePart type="family">Kubo</namePart><affiliation>Laboratory for Genotyping Development, Center of Genomic Medicine, RIKEN Yokohama Institute, Yokohama City, Japan,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Cathryn M.</namePart><namePart type="family">Lewis</namePart><affiliation>Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Sheila A.</namePart><namePart type="family">Fisher</namePart><affiliation>Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Richard</namePart><namePart type="family">Redon</namePart><affiliation>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ni</namePart><namePart type="family">Huang</namePart><affiliation>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Barbara E.</namePart><namePart type="family">Stranger</namePart><affiliation>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK,</affiliation><affiliation>Division of Genetics, Harvard Medical School/Brigham and Women's Hospital, Boston MA, USA and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Katarzyna</namePart><namePart type="family">Blaszczyk</namePart><affiliation>Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Barry</namePart><namePart type="family">Hudspith</namePart><affiliation>Nutritional Sciences Division, King's College London, Waterloo Campus, London SE1 9NH, UK,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Gareth</namePart><namePart type="family">Parkes</namePart><affiliation>Department of Gastroenterology, Guy's & St Thomas' NHS Foundation Trust, St Thomas' Hospital, London SE1 7EH, UK,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Naoya</namePart><namePart type="family">Hosono</namePart><affiliation>Laboratory for Genotyping Development, Center of Genomic Medicine, RIKEN Yokohama Institute, Yokohama City, Japan,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Keiko</namePart><namePart type="family">Yamazaki</namePart><affiliation>Laboratory for Genotyping Development, Center of Genomic Medicine, RIKEN Yokohama Institute, Yokohama City, Japan,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Clive M.</namePart><namePart type="family">Onnie</namePart><affiliation>Department of Gastroenterology, Whittington Hospital NHS Trust, London NW11 6BJ, UK,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Alastair</namePart><namePart type="family">Forbes</namePart><affiliation>Institute for Digestive Diseases, University College London Hospitals Trust, London NW1 2BU, UK,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Emmanouil T.</namePart><namePart type="family">Dermitzakis</namePart><affiliation>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK,</affiliation><affiliation>Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Yusuke</namePart><namePart type="family">Nakamura</namePart><affiliation>Laboratory of Molecular Medicine, Human Genome Centre, Institute of Medical Science, University of Tokyo, Tokyo 108, Japan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">John C.</namePart><namePart type="family">Mansfield</namePart><affiliation>Department of Gastroenterology and Hepatology, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jeremy</namePart><namePart type="family">Sanderson</namePart><affiliation>Department of Gastroenterology, Guy's & St Thomas' NHS Foundation Trust, St Thomas' Hospital, London SE1 7EH, UK,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Matthew E.</namePart><namePart type="family">Hurles</namePart><affiliation>Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Roland G.</namePart><namePart type="family">Roberts</namePart><affiliation>Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Christopher G.</namePart><namePart type="family">Mathew</namePart><affiliation>Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2010-05-01</dateIssued><dateCreated encoding="w3cdtf">2010-01-27</dateCreated><copyrightDate encoding="w3cdtf">2010</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>DNA polymorphisms in a region on chromosome 5q33.1 which contains two genes, immunity related GTPase related family, M (IRGM) and zinc finger protein 300 (ZNF300), are associated with Crohn's disease (CD). The deleted allele of a 20 kb copy number variation (CNV) upstream of IRGM was recently shown to be in strong linkage disequilibrium (LD) with the CD-associated single nucleotide polymorphisms and is itself associated with CD (P < 0.01). The deletion was correlated with increased or reduced expression of IRGM in transformed cells in a cell line-dependent manner, and has been proposed as a likely causal variant. We report here that small insertion/deletion polymorphisms in the promoter and 5 untranslated region of IRGM are, together with the CNV, strongly associated with CD (P 1.37 105 to 1.40 109), and that the CNV and the 5-untranslated region variant 308(GTTT)5 contribute independently to CD susceptibility (P 2.6 107 and P 2 105, respectively). We also show that the CD risk haplotype is associated with a significant decrease in IRGM expression (P < 1012) in untransformed lymphocytes from CD patients. Further analysis of these variants in a Japanese CD casecontrol sample and of IRGM expression in HapMap populations revealed that neither the IRGM insertion/deletion polymorphisms nor the CNV was associated with CD or with altered IRGM expression in the Asian population. This suggests that the involvement of the IRGM risk haplotype in the pathogenesis of CD requires genegene or geneenvironment interactions which are absent in Asian populations, or that none of the variants analysed are causal, and that the true causal variants arose after the EuropeanAsian split.</abstract><relatedItem type="host"><titleInfo><title>Human Molecular Genetics</title></titleInfo><genre type="journal">journal</genre><identifier type="ISSN">0964-6906</identifier><identifier type="eISSN">1460-2083</identifier><identifier type="PublisherID">hmg</identifier><identifier type="PublisherID-hwp">hmg</identifier><part><date>2010</date><detail type="volume"><caption>vol.</caption><number>19</number></detail><detail type="issue"><caption>no.</caption><number>9</number></detail><extent unit="pages"><start>1828</start><end>1839</end></extent></part></relatedItem><identifier type="istex">230F05CDCBA08463E824A0B74D02D69FB5D50AC0</identifier><identifier type="DOI">10.1093/hmg/ddq041</identifier><identifier type="ArticleID">ddq041</identifier><accessCondition type="use and reproduction" contentType="copyright">The Author 2010. 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