Characterization of genotype-phenotype relationships and stratification by the CARD15 variant genotype for inflammatory bowel disease susceptibility loci using multiple short tandem repeat genetic markers

The classification of ulcerative colitis (UC), Crohn disease (CD), and indeterminate colitis (IC) as forms of inflammatory bowel disease (IBD) is based on clinical, radiological, and histological criteria. The genetic basis of IBD is well founded, and susceptibility loci have been identified on several different chromosomes. We aimed to define genotype-phenotype relationships and interactions with the IBD susceptibility gene CARD15for various IBD susceptibility loci (IBD1, IBD2, IBD5, IBD6, IBD7, and chromosome 4) by characterizing previously described peak LOD score short tandem repeat (STR) markers. The study population consisted of 484 severely affected Caucasian patients with IBD, 144 healthy controls, and 348 nonaffected first-degree relatives of IBD patients. Associations were defined with the use of population- and family-based methodology. Correction for multiple testing was performed with a method based on an experimental false discovery rate. We provide novel evidence to show that IBD2 is involved in susceptibility to IC and terminal ileal CD in this population, with overrepresentation of IBD2 STR D12S83 (GenBank Z16592.1) allele 7 (g.49_60del[CA](6)) in IC (q = 0.038, P = 0.014) and underrepresentation of allele 8 (g.51_60del[CA](5)) in terminal ileal CD (q = 0.038, P = 0.016). The association of IBD2 with IC was confirmed by family-based testing. We also provide novel evidence to show that IBD5 is involved in susceptibility to IC and colonic/ileocolonic CD in this population, with overrepresentation of IBD5 STR D5S1984 (GenBank Z52623.1) allele 5 (g.183_186del[CA](2)) in both IC (q = 0.040, P = 0.005) and colonic/ileocolonic CD (q = 0.040, P = 0.004). Evidence is also given for potential interactions between CARD15and IBD2/IBD5. Other findings include an association of IBD2 with UC, and an association of IBD1 with terminal ileal and colonic/ileocolonic CD.