Confirmation of Multiple Crohnʼs Disease Susceptibility Loci in a Large Dutch-Belgian Cohort

Abstract

OBJECTIVES: Inflammatory bowel diseases (IBD)—Crohn's disease (CD) and ulcerative colitis (UC)—are chronic gastrointestinal inflammatory disorders with a complex genetic background. A genomewide association scan by the Wellcome Trust Case Control Consortium (WTCCC) recently identified several novel susceptibility loci. METHODS: We performed a large replication study in 2,731 Dutch and Belgian IBD patients (1,656 CD and 1,075 UC) and 1,086 controls. In total, 40 single nucleotide polymorphisms (SNPs) that showed moderate or strong association in the WTCCC study, along with SNPs in the previously identified genesIL23R, ATG16L1,andNELL1,were studied. RESULTS: We confirmed the associations withIL23R(rs11209026,P= 2.69E-12),ATG16L1(rs2241880,P=4.82E-07),IRGM(rs4958847,P= 2.26E-05),NKX2-3(rs10883365,P= 5.91E-06), 1q24 (rs12035082,P=1.51E-05), 5p13 (rs17234657,P= 2.62E-05), and 10q21 (rs10761659,P=8.95E-04). We also identified associations with cyclin Y (CCNY; rs3936503,P=2.09 E-04) and Hect domain and RCC1-like domain 2 (HERC2; rs916977,P= 1.12E-04). Pooling our data with the original WTCCC data substantiated these associations. Several SNPs were also moderately associated with UC. Two genetic risk profiles based on the number of risk alleles and based on a weighted score were created. On the basis of these results, we calculated sensitivities, specificities, positive and negative predictive values, and likelihood ratios for CD. CONCLUSIONS: We replicated genetic associations for CD withIL23R, ATG16L1, IRGM, NKX2-3,1q24, 10q21, 5p13, andPTPN2and report evidence for associations withHERC2andCCNY.Pooling our data with the results of the WTCCC strengthened the results, suggesting genuine genetic associations. We show that a genetic risk profile can be constructed that is clinically useful and that can aid in making treatment decisions.