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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 x 10?? in this meta-analysis and showed evidence of association to the individual diseases in the original scans (p-value < 1 x 10?² in CelD and < 1 x 10?³ in CD). These include the two previously reported shared loci, IL18RAP and PTPN2, with p-values of 3.37 x 10?? and 6.39 x 10??, 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 x 10?¹? and 1.38 x 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.

SUBMITTER: Festen EA

PROVIDER: S-EPMC3029251 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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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.

Festen Eleonora A M EA Goyette Philippe P Green Todd T Boucher Gabrielle G Beauchamp Claudine C Trynka Gosia G Dubois Patrick C PC Lagacé Caroline C Stokkers Pieter C F PC Hommes Daan W DW Barisani Donatella D Palmieri Orazio O Annese Vito V van Heel David A DA Weersma Rinse K RK Daly Mark J MJ Wijmenga Cisca C Rioux John D JD

PLoS genetics 20110127 1

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 a ...[more]

PMID: 21298027

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Project description:To establish the relationship of protein tyrosine phosphatase non-receptor type 2 and 22 (PTPN2/22) polymorphisms and mycobacterial infections in Crohn's disease (CD).All 133 subjects' blood samples were genotyped for nine single nucleotide polymorphisms (SNPs) in PTPN2/22 using TaqMan™ genotyping, while the effect of the SNPs on PTPN2/22 and IFN-? gene expression was determined using RT-PCR. Detection of Mycobacterium avium subspecies paratuberculosis (MAP) IS900 gene was done by nPCR after DNA extraction from the isolated leukocytes of each subjects' blood samples. T-cells isolated from the patient samples were tested for response to phytohematoagglutonin (PHA) mitogen or mycobacterial antigens by BrdU proliferation assays for T-cell activity.Out of the nine SNPs examined, subjects with either heterozygous (TC)/minor (CC) alleles in PTPN2:rs478582 occurred in 83% of CD subjects compared to 61% healthy controls (P-values < 0.05; OR = 3.03). Subjects with either heterozygous (GA)/minor (AA) alleles in PTPN22:rs2476601 occurred in 16% of CD compared to 6% healthy controls (OR = 2.7). Gene expression in PTPN2/22 in CD subjects was significantly decreased by 2 folds compared to healthy controls (P-values < 0.05). IFN-? expression levels were found to be significantly increased by approxiately 2 folds in subjects when either heterozygous or minor alleles in PTPN2:rs478582 and/or PTPN22:rs2476601 were found (P-values < 0.05). MAP DNA was detected in 61% of CD compared to only 8% of healthy controls (P-values < 0.05, OR = 17.52), where subjects with either heterozygous or minor alleles in PTPN2:rs478582 and/or PTPN22:rs2476601 had more MAPbacteremia presence than subjects without SNPs did. The average T-cell proliferation in CD treated with PHA or mycobacteria antigens was, respectively, 1.3 folds and 1.5 folds higher than healthy controls without any significant SNP.The data suggests that SNPs in PTPN2/22 affect the negative regulation of the immune response in CD patients, thus leading to an increase in inflammation/apoptosis and susceptibility of mycobacteria.

Project description:BACKGROUND: Genome-wide association studies identified PTPN2 (protein tyrosine phosphatase, non-receptor type 2) as susceptibility gene for inflammatory bowel diseases (IBD). However, the exact role of PTPN2 in Crohn's disease (CD) and ulcerative colitis (UC) and its phenotypic effect are unclear. We therefore performed a detailed genotype-phenotype and epistasis analysis of PTPN2 gene variants. METHODOLOGY/PRINCIPAL FINDINGS: Genomic DNA from 2131 individuals of Caucasian origin (905 patients with CD, 318 patients with UC, and 908 healthy, unrelated controls) was analyzed for two SNPs in the PTPN2 region (rs2542151, rs7234029) for which associations with IBD were found in previous studies in other cohorts. Our analysis revealed a significant association of PTPN2 SNP rs2542151 with both susceptibility to CD (p?=?1.95×10??; OR 1.49 [1.34-1.79]) and UC (p?=?3.87×10?², OR 1.31 [1.02-1.68]). Moreover, PTPN2 SNP rs7234029 demonstrated a significant association with susceptibility to CD (p?=?1.30×10?³; OR 1.35 [1.13-1.62]) and a trend towards association with UC (p?=?7.53×10?²; OR 1.26 [0.98-1.62]). Genotype-phenotype analysis revealed an association of PTPN2 SNP rs7234029 with a stricturing disease phenotype (B2) in CD patients (p?=?6.62×10?³). Epistasis analysis showed weak epistasis between the ATG16L1 SNP rs2241879 and PTPN2 SNP rs2542151 (p?=?0.024) in CD and between ATG16L1 SNP rs4663396 and PTPN2 SNP rs7234029 (p?=?4.68×10?³) in UC. There was no evidence of epistasis between PTPN2 and NOD2 and PTPN2 and IL23R. In silico analysis revealed that the SNP rs7234029 modulates potentially the binding sites of several transcription factors involved in inflammation including GATA-3, NF-?B, C/EBP, and E4BP4. CONCLUSIONS/SIGNIFICANCE: Our data confirm the association of PTPN2 variants with susceptibility to both CD and UC, suggesting a common disease pathomechanism for these diseases. Given recent evidence that PTPN2 regulates autophagosome formation in intestinal epithelial cells, the potential link between PTPN2 and ATG16L1 should be further investigated.

Project description:BackgroundBased on age of presentation, celiac disease (CD) is categorised as pediatric CD and adult CD. It however remains unclear if these are genetically and/or phenotypically distinct disorders or just different spectrum of the same disease. We therefore explored the common genetic components underlying pediatric and adult CD in a well characterized north Indian cohort.MethodsA retrospective analysis of children (n = 531) and adult (n = 871) patients with CD between January 2001 and December 2010 was done. The database included basic demographic characteristics, clinical presentations, associated diseases and complications, if any. The genotype dataset was acquired for children (n = 217) and adult CD patients (n = 340) and controls (n = 736) using Immunochip. Association analysis was performed using logistic regression model to identify susceptibility genetic variants.ResultsThe predominant form of CD was classical CD in both pediatric and adult CD groups. There was remarkable similarity between pediatric and adult CD except for quantitative differences between the two groups such as female preponderance, non-classical presentation, co-occurrence of other autoimmune diseases being more common amongst adult CD. Notably, same HLA-DQ2 and -DQ8 haplotypes were established as the major risk factors in both types of CD. In addition, a few suggestively associated (p < 5 × 10(-4)) non-HLA markers were identified of which only ANK3 (rs4948256-A; rs10994257-T) was found to be shared and explain risk for ~45 % of CD patients with HLA allele.DiscussionOverall phenotypic similarity between pediatric and adult CD groups can be explained by contribution of same HLA risk alleles. Different non-HLA genes/loci with minor risk seem to play crucial role in disease onset and extra intestinal manifestation of CD. None of the non-HLA risk variants reached genome-wide significance, however most of them were shown to have functional implication to disease pathogenesis. Functional relevance of our findings needs to be investigated to address clinical heterogeneity of CD.ConclusionsThis present study is the first comparative study based on common genetic markers to suggest that CD in pediatric age group and in adults are the spectrum of the same disease with novel and shared genetic risk determinants. Follow-up fine mapping studies with larger study cohorts are warranted for further genetic investigation.

Dataset Information

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.

Publications

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.

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