Evaluation of 22 genetic variants with Crohn's Disease risk in the Ashkenazi Jewish population: a case-control study

Inga Peter,Dana Doheny,Robert J Desnick,Laurie Ozelius,Maria T Abreu,Burton I Korelitz,Adele A Mitchell,Lloyd Mayer,Monica Erazo,Jianzhong Hu,Daniel H Present,Keith Benkov,Thomas Ullman

doi:10.1186/1471-2350-12-63

Abstract

BackgroundCrohn's disease (CD) has the highest prevalence among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Caucasian populations (NJ). We evaluated a set of well-established CD-susceptibility variants to determine if they can explain the increased CD risk in the AJ population.MethodsWe recruited 369 AJ CD patients and 503 AJ controls, genotyped 22 single nucleotide polymorphisms (SNPs) at or near 10 CD-associated genes, NOD2, IL23R, IRGM, ATG16L1, PTGER4, NKX2-3, IL12B, PTPN2, TNFSF15 and STAT3, and assessed their association with CD status. We generated genetic scores based on the risk allele count alone and the risk allele count weighed by the effect size, and evaluated their predictive value.ResultsThree NOD2 SNPs, two IL23R SNPs, and one SNP each at IRGM and PTGER4 were independently associated with CD risk. Carriage of 7 or more copies of these risk alleles or the weighted genetic risk score of 7 or greater correctly classified 92% (allelic count score) and 83% (weighted score) of the controls; however, only 29% and 47% of the cases were identified as having the disease, respectively. This cutoff was associated with a >4-fold increased disease risk (p < 10e-16).ConclusionsCD-associated genetic risks were similar to those reported in NJ population and are unlikely to explain the excess prevalence of the disease in AJ individuals. These results support the existence of novel, yet unidentified, genetic variants unique to this population. Understanding of ethnic and racial differences in disease susceptibility may help unravel the pathogenesis of CD leading to new personalized diagnostic and therapeutic approaches.

Highlights

Crohn’s disease (CD) has the highest prevalence among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Caucasian populations (NJ)
For the three extensively studied NOD2 variants, each high risk allele was associated with a significantly increased risk of CD, such as 1.9 for p
This study was designed to assess the contribution of established risk variants in selected CD-associated genes to CD risk in the AJ population, a group known to have an unusually high prevalence of the disease compared to NJ European or North American Caucasians

Summary

Introduction

Crohn’s disease (CD) has the highest prevalence among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Caucasian populations (NJ). We evaluated a set of well-established CD-susceptibility variants to determine if they can explain the increased CD risk in the AJ population. There are additional variants of the NOD2 gene that have been implicated to increase CD risk [16,17,18]. Another well-validated gene is the interleukin 23 receptor (IL23R), a regulatory cytokine involved in the initiation of innate and adaptive immune responses. Several common variants at the autophagyinducing genes, ATG16L1, autophagy-related 16-like 1, and IRGM, immunity-related guanosine triphosphatase, have been reported through GWAS to be associated with CD in Caucasian populations [17,19,20,21]. A locus on chromosome 5p13.1 in the vicinity of the prostaglandin E receptor 4 (subtype EP4) gene, PTGER4, emerged as having CD susceptibility [18,19]

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