A Meta-Analysis of Genome-Wide Association Scans Identifies IL18RAP, PTPN2, TAGAP, and PUS10 As Shared Risk Loci for Crohn's Disease and Celiac Disease

Abstract

Crohn's disease (CD) and celiac disease (CelD) are chronic intestinal inflammatory diseases, involving genetic and environmental factors in their pathogenesis. The two diseases can co-occur within families, and studies suggest that CelD patients have a higher risk to develop CD than the general population. These observations suggest that CD and CelD may share common genetic risk loci. Two such shared loci, IL18RAP and PTPN2, have already been identified independently in these two diseases. The aim of our study was to explicitly identify shared risk loci for these diseases by combining results from genome-wide association study (GWAS) datasets of CD and CelD. Specifically, GWAS results from CelD (768 cases, 1,422 controls) and CD (3,230 cases, 4,829 controls) were combined in a meta-analysis. Nine independent regions had nominal association p-value <1.0×10−5 in this meta-analysis and showed evidence of association to the individual diseases in the original scans (p-value <1×10−2 in CelD and <1×10−3 in CD). These include the two previously reported shared loci, IL18RAP and PTPN2, with p-values of 3.37×10−8 and 6.39×10−9, respectively, in the meta-analysis. The other seven had not been reported as shared loci and thus were tested in additional CelD (3,149 cases and 4,714 controls) and CD (1,835 cases and 1,669 controls) cohorts. Two of these loci, TAGAP and PUS10, showed significant evidence of replication (Bonferroni corrected p-values <0.0071) in the combined CelD and CD replication cohorts and were firmly established as shared risk loci of genome-wide significance, with overall combined p-values of 1.55×10−10 and 1.38×10−11 respectively. Through a meta-analysis of GWAS data from CD and CelD, we have identified four shared risk loci: PTPN2, IL18RAP, TAGAP, and PUS10. The combined analysis of the two datasets provided the power, lacking in the individual GWAS for single diseases, to detect shared loci with a relatively small effect.

Association of celiac disease genes with inflammatory bowel disease in Finnish and Swedish patients

“…This is in contrast to the study by Festen et al, 9 where TAGAP was reported to be a common susceptibility locus for CD and CelD. 6,9 Nonetheless, the lack of association with CD in our study may depend upon smaller sample size, however, differences in risk effect between the studied populations cannot be excluded. The association with TAGAP was even stronger (OR: 1.59) when looking only at the meta-analysis of UC patients with a familial history of the disease.…”

“…UBE2L3 participates in ubiquitylation and has a key role in the regulation of innate and adaptive immune systems. A previous study by Festen et al 9 failed to identify the UBE2L3 or YDJC genes as shared risk factors for CelD and CD. This inconsistency with the current study may be due to population/haplotype structure differences.…”

“…8 A subset of these CelD risk loci may also be associated with increased risk for other autoimmune diseases, including IBD. 9,10 In this study, we investigated systematically whether any of the CelD risk loci highlighted by Dubois et al 8 also affect susceptibility to IBD in the Finnish population. A meta-analysis in a combined Finnish and Swedish UC data set was also performed.…”

PTPN2 attenuates T-cell lymphopenia-induced proliferation

“…Genome-wide association studies have identified the PTP gene PTPN2 as an important non-MHC gene for autoimmunity [17][18][19][20][21] . Single nucleotide polymorphisms (SNPs) in PTPN2 have been linked with the development of Crohn's disease, rheumatoid arthritis and type 1 diabetes [17][18][19][20][21] .…”

“…Single nucleotide polymorphisms (SNPs) in PTPN2 have been linked with the development of Crohn's disease, rheumatoid arthritis and type 1 diabetes [17][18][19][20][21] . At least one of the PTPN2 SNPs implicated in type 1 diabetes has been associated with a B40% decrease in PTPN2 expression in T cells 22 .…”