Microscopic Colitis no More: HLA Association Discriminates Collagenous from Lymphocytic Colitis

Abstract

Introduction: Microscopic colitis (MC) is a relatively common condition characterized by chronic watery diarrhoea, which affects up to 0.5% of older adults, primarily women. It is currently regarded as an inflammatory bowel disease of unknown aetiology, which manifests as two clinically overlapping forms, namely collagenous colitis (CC, typified by a submucosal collagen deposition) and lymphocytic colitis (LC, with increased intraepithelial lymphocytes). A genetic component is suspected, and a CC predisposing role has been reported in previous studies for HLA variants from the extended 8.1 haplotype. However, broader large-scale, differential analyses of CC and LC risk across the whole genome (GWA studies) have never been performed. Aims & Methods: We conducted a GWAS meta-analysis of 7,5 million single nucleotide polymorphisms (SNPs) in 1,498 CC and 373 LC cases from tertiary centres across US and Europe (Sweden Germany, Lithuania, the Netherlands and Spain), and 13,487 ancestry-matched general population controls. Individual HLA alleles and polymorphic residues were imputed and tested for association, including sensitivity analyses performed on cases with documented exclusion of celiac disease diagnosis (via antitissue transglutaminase antibodies and/or duodenal biopsy). Genetic correlations with other traits and diagnoses (based on ICD10 codes) were studied using linkage disequilibrium score regression (LDSC). Results: We detected a single strong GWAS association signal for CC, mapped within the HLA region on chromosome 6 (lead SNP rs2844531, P=1.97×10−32; OR=2.00). This signal showed an even stronger genetic risk effect when only CC cases with confirmed exclusion of celiac disease were tested (N=688; P=4.3×10−17; OR=2.11), and was completely absent in LC, despite adequately powered sample size (confirmed via simulation analyses). HLA imputation mapped the CC risk signal to multiple alleles and polymor[...].