Independent and population-specific association of risk variants at the IRGM locus with Crohn's disease
| Autor: | Katarzyna Blaszczyk, Naoya Hosono, Ni Huang, Matthew E. Hurles, Christopher G. Mathew, Alastair Forbes, Yusuke Nakamura, Sheila A. Fisher, Cathryn M. Lewis, Clive M. Onnie, Barbara E. Stranger, Michiaki Kubo, Richard Redon, Keiko Yamazaki, Emmanouil T. Dermitzakis, Jeremy D. Sanderson, Gareth Parkes, John C. Mansfield, Katherine M. Dominy, Roland G. Roberts, Barry N. Hudspith, Natalie J. Prescott |
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| Rok vydání: | 2010 |
| Předmět: |
Untranslated region
Linkage disequilibrium DNA Copy Number Variations Genotype Molecular Sequence Data Locus (genetics) Single-nucleotide polymorphism Biology White People 03 medical and health sciences 0302 clinical medicine Asian People Crohn Disease INDEL Mutation GTP-Binding Proteins Genetics Humans Genetic Predisposition to Disease Copy-number variation Allele Promoter Regions Genetic Molecular Biology Genetics (clinical) DNA Primers Oligonucleotide Array Sequence Analysis 030304 developmental biology ddc:616 0303 health sciences Base Sequence Reverse Transcriptase Polymerase Chain Reaction Association Studies Articles Haplotype Genetic Variation Sequence Analysis DNA General Medicine United Kingdom Logistic Models Haplotypes IRGM 030211 gastroenterology & hepatology |
| Zdroj: | Human Molecular Genetics, Vol. 19, No 9 (2010) pp. 1828-1839 Human Molecular Genetics |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddq041 |
| Popis: | 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 x 10(-5) to 1.40 x 10(-9)), and that the CNV and the 5'-untranslated region variant -308(GTTT)(5) contribute independently to CD susceptibility (P = 2.6 x 10(-7) and P = 2 x 10(-5), respectively). We also show that the CD risk haplotype is associated with a significant decrease in IRGM expression (P < 10(-12)) in untransformed lymphocytes from CD patients. Further analysis of these variants in a Japanese CD case-control 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 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. |
| Databáze: | OpenAIRE |
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