Confirmation of Multiple Crohn's Disease Susceptibility Loci in a Large Dutch–Belgian Cohort
Copyright policy )Confirmation of Multiple Crohn's Disease Susceptibility Loci in a Large Dutch–Belgian Cohort
Inflammatory bowel diseases (IBD)-Crohn's disease (CD) and ulcerative colitis (UC)-are chronic gastrointestinal inflammatory disorders with a complex genetic background. A genome-wide association scan by the Wellcome Trust Case Control Consortium (WTCCC) recently identified several novel susceptibility loci.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 genes IL23R, ATG16L1, and NELL1, were studied.We confirmed the associations with IL23R (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.We replicated genetic associations for CD with IL23R, ATG16L1, IRGM, NKX2-3, 1q24, 10q21, 5p13, and PTPN2 and report evidence for associations with HERC2 and CCNY. 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.
- Amsterdam UMC Netherlands
- University of Groningen Netherlands
- Institute of Molecular Biology Germany
- Katholieke Universiteit Leuven Belgium
- University of Amsterdam Netherlands
GENETIC SUSCEPTIBILITY, Genotype, Nod2 Signaling Adaptor Protein, ATG16L1, Autophagy-Related Proteins, Nerve Tissue Proteins, VARIANTS, Polymorphism, Single Nucleotide, IL23R, Belgium, Crohn Disease, Gene Frequency, GTP-Binding Proteins, Guanine Nucleotide Exchange Factors, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Netherlands, Homeodomain Proteins, Protein Tyrosine Phosphatase, Non-Receptor Type 2, Calcium-Binding Proteins, Receptors, Interleukin, ULCERATIVE-COLITIS, REPLICATION, AUTOPHAGY, Colitis, Ulcerative, Carrier Proteins, SCAN, INFLAMMATORY-BOWEL-DISEASE, Genome-Wide Association Study
GENETIC SUSCEPTIBILITY, Genotype, Nod2 Signaling Adaptor Protein, ATG16L1, Autophagy-Related Proteins, Nerve Tissue Proteins, VARIANTS, Polymorphism, Single Nucleotide, IL23R, Belgium, Crohn Disease, Gene Frequency, GTP-Binding Proteins, Guanine Nucleotide Exchange Factors, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Netherlands, Homeodomain Proteins, Protein Tyrosine Phosphatase, Non-Receptor Type 2, Calcium-Binding Proteins, Receptors, Interleukin, ULCERATIVE-COLITIS, REPLICATION, AUTOPHAGY, Colitis, Ulcerative, Carrier Proteins, SCAN, INFLAMMATORY-BOWEL-DISEASE, Genome-Wide Association Study
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