An Extremes of Phenotype Approach Confirms Significant Genetic Heterogeneity in Patients with Ulcerative Colitis

Abstract

Background and aims: Ulcerative colitis [UC] is a major form of inflammatory bowel disease globally. Phenotypic heterogeneity is defined by several variables including age of onset and disease extent. The genetics of disease severity remains poorly understood. To further investigate this, we performed a genome wide association [GWA] study using an extremes of phenotype strategy.

Methods: We conducted GWA analyses in 311 patients with medically refractory UC [MRUC], 287 with non-medically refractory UC [non-MRUC] and 583 controls. Odds ratios [ORs] were calculated for known risk variants comparing MRUC and non-MRUC, and controls.

Results: MRUC-control analysis had the greatest yield of genome-wide significant single nucleotide polymorphisms [SNPs] [2018], including lead SNP = rs111838972 [OR = 1.82, p = 6.28 × 10-9] near MMEL1 and a locus in the human leukocyte antigen [HLA] region [lead SNP = rs144717024, OR = 12.23, p = 1.7 × 10-19]. ORs for the lead SNPs were significantly higher in MRUC compared to non-MRUC [p < 9.0 × 10-6]. No SNPs reached significance in the non-MRUC-control analysis (top SNP, rs7680780 [OR 2.70, p = 5.56 × 10-8). We replicate findings for rs4151651 in the Complement Factor B [CFB] gene and demonstrate significant changes in CFB gene expression in active UC. Detailed HLA analyses support the strong associations with MHC II genes, particularly HLA-DQA1, HLA-DQB1 and HLA-DRB1 in MRUC.

Conclusions: Our MRUC subgroup replicates multiple known UC risk variants in contrast to non-MRUC and demonstrates significant differences in effect sizes compared to those published. Non-MRUC cases demonstrate lower ORs similar to those published. Additional risk and prognostic loci may be identified by targeted recruitment of individuals with severe disease.

Keywords: Ulcerative colitis; disease severity; genetics.

Graphical Abstract

Figure 1.

Odds ratios with 95% confidence intervals for eight published SNPs associated with ulcerative colitis [UC] and replicated in association analyses for combined UC cases, non-medically refractory UC [non-MRUC] only, MRUC only, acute severe UC only and chronic refractory UC only.

Figure 2.

Distribution of ulcerative colitis [UC] genetic risk scores for controls, all UC patients [All UC], non-MRUC patients only, MRUC patients only, chronic refractory UC patients only and acute severe UC patients only. Sub-phenotypes are ordered from lowest mean risk score [left] to highest mean risk score [right].

Figure 3.

Patients divided into deciles according to ulcerative colitis [UC] genetic risk score and the proportion of patients with medically refractory UC [MRUC] with colectomy [red], MRUC without colectomy [green], non-MRUC [blue] and unaffected [purple].

Figure 4.

Microarray gene expression levels for CFB using probe 202357_s_at, for controls [C], non-inflamed ulcerative colitis [UC.NI], mild UC [UC.1] and moderate to severe UC [UC.2.3].