Genetic Analysis of Ulcerative Colitis in Japanese Individuals Using Population-specific SNP Array

Area of Science:

• Genetics
• Gastroenterology
• Immunology

Background:

• Ulcerative colitis (UC) is a chronic inflammatory bowel disease with a complex genetic etiology.
• Understanding the genetic underpinnings of UC in diverse populations, such as the Japanese population, is crucial for targeted therapies.
• Previous genetic studies in UC have primarily focused on European cohorts, necessitating population-specific investigations.

Purpose of the Study:

• To elucidate the genetic architecture of ulcerative colitis (UC) within the Japanese population.
• To identify novel genetic loci associated with UC susceptibility and clinical course.
• To investigate the role of specific genetic variants and microRNAs in UC pathogenesis.

Main Methods:

• A genome-wide association study (GWAS) was conducted using a Japanese-specific SNP array, including 1676 UC patients and 2381 healthy controls.
• Replication studies and statistical analyses, including Kaplan-Meier method for colectomy probability and quantitative reverse-transcription polymerase chain reaction for gene expression, were performed.
• Genotyping of single nucleotide polymorphisms (SNPs) and serum microRNA (miR-622) expression levels were analyzed.

Main Results:

• The HLA loci, specifically rs117506082, demonstrated a strong genome-wide association with UC (P = 6.69E-28).
• Seven significant regions were identified, including known loci IL23R and IRF8, and five novel loci: MIR622, 14q31, KAT6B, PAX3-CCDC140-SGPP2, and KCNA2.
• The IL23R p.G149R variant (rs76418789) showed genome-wide significance (P = 9.03E-11), and the GG genotype of rs117506082 was associated with a lower probability of colectomy (P = 1.72E-2).
• Serum miR-622 expression was higher in patients with inactive UC compared to healthy controls and active UC patients.

Conclusions:

• The IL23R p.G149R variant represents a significant susceptibility locus for ulcerative colitis in the Japanese population.
• The GG genotype at the rs117506082 locus within the HLA region may serve as a predictive marker for a better clinical course in UC patients.
• miR-622 warrants further investigation as a potential biomarker for UC activity.