TY - JOUR
T1 - Independent and population-specific association of risk variants at the IRGM locus with Crohn's disease
AU - Prescott, Natalie J.
AU - Dominy, Katherine M.
AU - Kubo, Michiaki
AU - Lewis, Cathryn M.
AU - Fisher, Sheila A.
AU - Redon, Richard
AU - Huang, Ni
AU - Stranger, Barbara E.
AU - Blaszczyk, Katarzyna
AU - Hudspith, Barry
AU - Parkes, Gareth
AU - Hosono, Naoya
AU - Yamazaki, Keiko
AU - Onnie, Clive M.
AU - Forbes, Alastair
AU - Dermitzakis, Emmanouil T.
AU - Nakamura, Yusuke
AU - Mansfield, John C.
AU - Sanderson, Jeremy
AU - Hurles, Matthew E.
AU - Roberts, Roland G.
AU - Mathew, Christopher G.
N1 - Funding Information:
This work was supported by the Wellcome Trust (081808/ C.G.M.), the National Institutes of Health Research Biomedical Research Centres at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London and University College Hospital Trust with University College London; and the Guy’s and St Thomas’ Charity. We acknowledge use of the British 1958 Birth Cohort DNA collection, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. Funding to pay the Open Access charge was provided by the Wellcome Trust.
PY - 2010/1/27
Y1 - 2010/1/27
N2 - 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) upstreamof IRGM was recently shown to be in strong linkage disequilibrium(LD)withtheCD-associated single nucleotide polymorphisms and is itself associatedwithCD (P < 0.01). The deletionwas correlatedwith increased or reduced expression of IRGMin transformed cells in a cell line-dependentmanner, 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 × 10-5 to 1.40 × 10-9), and that the CNV and the 5′-untranslated region variant -308(GTTT)5 contribute independently to CD susceptibility (P = 2.6 × 10-7 and P = 2 × 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.
AB - 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) upstreamof IRGM was recently shown to be in strong linkage disequilibrium(LD)withtheCD-associated single nucleotide polymorphisms and is itself associatedwithCD (P < 0.01). The deletionwas correlatedwith increased or reduced expression of IRGMin transformed cells in a cell line-dependentmanner, 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 × 10-5 to 1.40 × 10-9), and that the CNV and the 5′-untranslated region variant -308(GTTT)5 contribute independently to CD susceptibility (P = 2.6 × 10-7 and P = 2 × 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.
UR - https://www.scopus.com/pages/publications/77952515610
UR - https://www.scopus.com/pages/publications/77952515610#tab=citedBy
U2 - 10.1093/hmg/ddq041
DO - 10.1093/hmg/ddq041
M3 - Article
C2 - 20106866
AN - SCOPUS:77952515610
SN - 0964-6906
VL - 19
SP - 1828
EP - 1839
JO - Human molecular genetics
JF - Human molecular genetics
IS - 9
M1 - ddq041
ER -