DOP014 Impact of genetic variation on gene and protein expression in Crohn’s disease

Abstract

Understanding the genetic landscape of Crohn’s disease (CD) may help shed light on disease aetiology to inform disease understanding and aid biomarker identification. Towards this end, we evaluated the association of genetic polymorphisms with baseline intestinal and blood gene and protein expression in the phase 3 UNITI program. The UNITI studies assessed the safety and efficacy of ustekinumab induction and maintenance therapies in patients with moderate-to-severe CD who had previously failed TNF-antagonist therapy (UNITI-1) or conventional therapies (UNITI-2). Gene expression was profiled using RNA extracted from intestinal biopsies and whole blood using Affymetrix HG U133 Plus 2 arrays and 11 protein analytes were measured in serum. Additionally, subjects were genotyped on the Illumina Infinium Omni5Exome platform. Gene expression quantitative trait loci (eQTL) mapping was performed separately in rectum (n = 161), ileum (n = 142), and whole blood (n = 132). Protein quantitative trait loci (pQTL) mapping was performed in 864 serum samples. At a false discovery rate of 5%, we identified local cis-eQTLs for 1308 genes in rectum, 806 in ileum, and 1499 in whole blood. We observed highly significant overlap of the cis-eQTL gene sets between biopsy regions and between blood and biopsy. Furthermore, we found significant enrichment of genome-wide association study (GWAS) associated single-nucleotide polymorphisms (SNPs) within all eQTL sets, particularly from SNPs associated with inflammatory bowel disease and other immune-mediated diseases. In the limited set of proteins we tested for association with genetic variants, we identified four highly significant pQTLs: two independent cis-pQTLs for MMP1, one cis-pQTL for MMP3, and one cis-pQTL for IL17F. These serum analytes were significantly elevated in CD compared with healthy subjects, and these pQTLs explained a portion of the variance in their serum levels: 13% for MMP1, 6% for MMP3, and 8% for IL17F. There was a trend for association between the MMP1 pQTL SNPs with MMP1 gene expression in blood, but no association of the MMP3 and IL17F pQTL SNPs with gene expression. We integrated genetic information, gene and protein expression, and existing data from GWAS to provide insights into the molecular mechanisms underlying CD. From these analyses, we found eQTLs in both biopsy and blood that are enriched for disease-associated genetic variants and also identified highly significant associations between genetic variants and protein biomarkers of CD disease activity.