Tu1924 Profiling of IBD-Related Genes in Disease-Relevant Tissues From Patients With Known Genotypes Identifies Novel Patterns of Gene Epistasis and eQTLS

摘要: Introduction: Genome-wide association studies suggest that there is dysregulation of distinct biological circuits involved in the maintenance intestinal homeostasis patients with inflammatory bowel diseases (IBD). Broadly, we seek to understand relationship between patient genotype and disease-specific, tissue-dependent gene expression elucidate critical pathways at play health disease, identify novel, clinically-applicable biomarkers, guide therapeutic discovery, move towards personalized care for IBD. Methods: Using most-recent GWAS data IBD, identifying 163 risk loci, a custom NanoString probeset 683 IBD-associated genes 15 housekeeping was designed; 25% these were not assayed by conventional microarrays. Patients controls recruited five IBD centers nationwide as part Sinai-Helmsley Alliance Research Excellence (SHARE) consortium. To date, have collected 352 specimens from 172 unique (Crohn's n=142, ulcerative colitis, n=28, indeterminate n=2). Total mRNA isolated 2-3 mucosal biopsies obtained colonoscopy or taken surgical used downstream processing. A bioanalytic pipeline designed quality control normalization permit differential expression, data-driven clustering, genotype-based quantitative trait loci (eQTL) analysis. Results: serve basis analysis patients, defined patterns selected healthy multiple anatomic locations, including terminal ileum, ascending descending colon, observing ileum colon high correlation controls. In second phase this project, compared diseased tissue versus controls, inflamed uninflamed tissues same patient, colitis Crohn's colitis. Preliminary demonstrates strong pattern 120 upregulated 8 down-regulated tissue. Pathway suggests differences activity related cell adhesion, immune system signaling, biosynthetic With targeted examination eQTLs four disease-related SNPs (NOD2, ATG16L1, IRGM, MST1), identified genotype-dependent, fold-change paired specimens. Conclusions: Selected profiling IBD-related disease-relevant technology known genotypes can robustly detect novel epistasis, eQTLs, highlight dominant perturbed disease.