Comparative genetic analysis of inflammatory bowel disease and type 1 diabetes implicates multiple loci with opposite effects

Abstract

Inflammatory bowel disease, including Crohn's disease (CD) and ulcerative colitis (UC), and type 1 diabetes (T1D) are autoimmune diseases that may share common susceptibility pathways. We examined known susceptibility loci for these diseases in a cohort of 1689 CD cases, 777 UC cases, 989 T1D cases and 6197 shared control subjects of European ancestry, who were genotyped by the Illumina HumanHap550 SNP arrays. We identified multiple previously unreported or unconfirmed disease associations, including known CD loci (ICOSLG and TNFSF15) and T1D loci (TNFAIP3) that confer UC risk, known UC loci (HERC2 and IL26) that confer T1D risk and known UC loci (IL10 and CCNY) that confer CD risk. Additionally, we show that T1D risk alleles residing at the PTPN22, IL27, IL18RAP and IL10 loci protect against CD. Furthermore, the strongest risk alleles for T1D within the major histocompatibility complex (MHC) confer strong protection against CD and UC; however, given the multi-allelic nature of the MHC haplotypes, sequencing of the MHC locus will be required to interpret this observation. These results extend our current knowledge on genetic variants that predispose to autoimmunity, and suggest that many loci involved in autoimmunity may be under a balancing selection due to antagonistic pleiotropic effect. Our analysis implies that variants with opposite effects on different diseases may facilitate the maintenance of common susceptibility alleles in human populations, making autoimmune diseases especially amenable to genetic dissection by genome-wide association studies.

No association between TNFSF15 and IL23R with ulcerative colitis in Koreans

“…29,30 However, reports of an association of TNFSF15 with UC in Caucasians have been inconsistent. [24][25][26] In a previous report on Korean patients with CD, we replicated findings from studies on Caucasian populations, establishing interleukin 23 receptor (IL23R) and TNFSF15 as CD-susceptibility genes. 27,31 Because some CD candidate genes involved in the Th17 pathway were shown to be shared with UC in Caucasians, in this study we sought to test the association between IL23R or TNFSF15 polymorphisms and UC in Koreans.…”

“…Previous reports of TNFSF15 association with UC in Caucasians have been inconsistent, [24][25][26] although they did not test identical SNPs of TNFSF15. Franke et al 24 reported an 25 reported a significant association of rs4263839 with UC (P¼8.6Â10 À4 ).…”

“…[23][24][25][26] In the present study, we investigated the well-established CD-susceptibility genes TNFSF15 and IL23R in Korean UC patients.…”

“…29,30 The association of IL23R with CD is consistently observed in Caucasians, but among Asians, this association has been demonstrated only in Koreans. 31 Given that both IL23R and TNFSF15 were suggested to be associated with UC in Caucasians, 11,25,26,29 we sought to test the association between polymorphisms of IL23R and/or TNFSF15 and UC in Koreans.…”

“…22 Of those, NOD2, ATG16L1 and IRGM were CD specific, whereas genes involved in Th17 differentiation, including IL23R, IL12B, JAK2, STAT3 and TNFSF15 were shared between UC and CD in Caucasians. [23][24][25][26] TNFSF15 (tumor necrosis factor ligand superfamily, member 15) was the first CD-susceptibility gene identified through a genome-wide association screening of 72 738 single-nucleotide polymorphisms (SNPs) in Japanese population. 10 The association was well replicated by several studies, including our previous study in a Korean cohort, 27 an independent Japanese cohort 28 and a US cohort, 29 and metaanalyses of genome-wide association studies in European populations, 22 although the association was less significant in Europeans than in Japanese or Korean individuals.…”