Independent and population-specific association of risk variants at the IRGM locus with Crohn's disease.
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.
Prescott
Natalie J
NJ
Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London SE1 9RT, UK. natalie.prescott@genetics.kcl.ac.uk
Dominy
Katherine M
KM
Kubo
Michiaki
M
Lewis
Cathryn M
CM
Fisher
Sheila A
SA
Redon
Richard
R
Huang
Ni
N
Stranger
Barbara E
BE
Blaszczyk
Katarzyna
K
Hudspith
Barry
B
Parkes
Gareth
G
Hosono
Naoya
N
Yamazaki
Keiko
K
Onnie
Clive M
CM
Forbes
Alastair
A
Dermitzakis
Emmanouil T
ET
Nakamura
Yusuke
Y
Mansfield
John C
JC
Sanderson
Jeremy
J
Hurles
Matthew E
ME
Roberts
Roland G
RG
Mathew
Christopher G
CG
D044466:Asian People / Q000235:genetics*; D001483:Base Sequence; D003424:Crohn Disease / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D019204:GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics; D016015:Logistic Models; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D006113:United Kingdom; D044465:White People / Q000235:genetics*
D017931:DNA Primers; D019204:GTP-Binding Proteins; C513539:IRGM protein, human