Association analysis of genetic variants in IL23R, ATG16L1 and 5p13.1 loci with Crohn’s disease in Japanese patients

Abstract

Inflammatory bowel diseases, Crohn's disease (CD) and ulcerative colitis are characterised by chronic transmural, segmental and typically granulomatous inflammation of the gut. Each has a peak age of onset in the second to fourth decades of life and prevalence has been increasing significantly in both Western countries and Japan over the last decade, while their pathogenesis remains largely unknown. Recently, positive association of CD with the variants in interleukin 23 receptor (IL23R), autophagyrelated 16-like 1 (ATG16L1) genes and chromosome 5p13.1 locus was reported through genome-wide association studies which are now recognised as a robust tool for the identification of susceptibility genes for complex diseases. To examine an association of reported susceptible variants in the three loci with Japanese CD patients, a total of 484 CD patients and 439 controls were genotyped. No evidence of positive association for any of these loci with CD was found in the Japanese population, even after clinically stratified subgroups of CD were used. Our result revealed a distinct ethnic difference of genetic background of CD that we reported previously in other genes between Japanese and Caucasian populations. Further genetic studies are required to confirm our findings with ethnically divergent populations.

Association of ATG16L1 and IRGM genes polymorphisms with inflammatory bowel disease: a meta-analysis approach

“…Interestingly, in a very recent study McCarroll et al 56 have shown that the causal variant responsible for IRGM Figure 1 Pooled data for the ATG16L1 rs2241880 susceptibility allele frequency (SAF). (a) Pooled data of Australian, 39 Belgian, 16 British, 14,21,23,25 Canadian, 31 Dutch, 28 German, 14,29,30 Italian, 27,33 Hungarian, 34 Japanese, 22 New Zealander, 26 North American 15,24 and Spanish cohorts for Crohn's disease (CD). (b) Pooled data of Australian, 39 British, 21,23,37 Canadian, 31 Dutch, 28 German, 14,29,30 Italian, 33 Hungarian, 34 New Zealander, 26,39 North American 15 and Spanish cohorts for ulcerative colitis (UC).…”

“…[14][15][16][21][22][23][24][25][26][27][28][29][30][31][32][33][34]38,39 Funnel plots and Egger tests were performed to analyse the publication bias of the meta-analysis. No statistically significant values were observed in CD studies (P ¼ 0.6) or UC studies (P ¼ 0.4), with symmetric funnel plots for both studies (Supplementary Figure 1).…”

“…[14][15][16] A large number of subsequent association studies have replicated the strong association of this gene with CD. [21][22][23][24][25][26][27][28][29][30][31][32][33][34] IRGM (immunity-related guanosine triphosphatase, the human homologue of mouse Irgm/Lrg47) encodes a GTP-binding protein that induces autophagy and plays an important role in innate immunity against intracellular pathogens. 35,36 Association of two immediately flanking IRGM gene polymorphisms (rs13361189 and rs4958847) with CD has recently been reported.…”

ATG16L1: A multifunctional susceptibility factor in Crohn disease

“…57,60,68 Nevertheless, the described ATG16L1 association with Crohn disease has not been observed in any Asian meta-analyses. [69][70][71] The rs2241880 variant can be observed in all isoforms of ATG16L1 72 and comprises a nonsynonymous coding SNP (adenine (A) ! guanine (G) polymorphism) in the coiled-coil domain encoding a threonine-to-alanine substitution.…”

The Genetic Basis of Spondyloarthritis: SPARTAN/IGAS 2009

“…Strong association also was observed with rs11465817 (p = 1.2 x 10 -10 ), compared with rs11209026 (p = 2.3 x 10 -9 ). Among East Asians, IL23R is not associated with Crohn's disease (CD) in Japanese 10 , nor with psoriasis in Han Chinese 11 or AS in Koreans 12 or Han Chinese 13 .…”