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

Area of Science:

• Genetics
• Immunology
• Gastroenterology

Background:

• Ulcerative colitis (UC) is a global inflammatory bowel disease with varied patient phenotypes.
• The genetic underpinnings of UC disease severity are not well understood.
• Genome-wide association studies (GWAS) are crucial for identifying genetic risk factors.

Purpose of the Study:

• To investigate the genetic basis of UC disease severity using a GWAS.
• To identify genetic variants associated with medically refractory UC (MRUC).
• To compare genetic risk profiles between MRUC, non-MRUC, and control groups.

Main Methods:

• Conducted GWAS in 311 MRUC patients, 287 non-MRUC patients, and 583 controls.
• Calculated odds ratios (ORs) for known UC risk variants.
• Utilized an 'extremes of phenotype' strategy focusing on disease severity.

Main Results:

• GWAS identified significant single nucleotide polymorphisms (SNPs) in MRUC patients, particularly near MMEL1 and in the human leukocyte antigen (HLA) region.
• Lead SNP rs144717024 in the HLA region showed a strong association (OR = 12.23, p = 1.7 × 10-19).
• Replicated findings for Complement Factor B (CFB) and observed altered CFB gene expression in active UC.

Conclusions:

• The MRUC subgroup replicates known UC risk variants with different effect sizes than previously reported.
• Non-MRUC cases showed effect sizes consistent with existing literature.
• Targeted recruitment of severe UC cases may uncover additional risk and prognostic loci.