Interleukin23 Receptor Genetic Variants Associate With Crohn’s Disease Risk and Microbiome Changes in Healthy First-Degree Relatives

Background & Aims Single nucleotide polymorphisms in the interleukin 23 receptor gene are associated with Crohn's disease, suggesting a role in pathogenesis, and several biologic agents targeting this pathway are now established therapies. Interleukin23 has been suggested to be involved in regulation of intestinal barrier function and may impact gut microbial composition. We investigated whether interleukin 23 receptor genetic variants predict Crohn’s disease risk and influence gut barrier function and microbiome composition in healthy first-degree relatives. Methods A total of 3055 healthy first-degree relatives with genotypic data from the Crohn’s and Colitis Canada Genetic, Environmental, Microbial (CCC-GEM) cohort were included. A weighted interleukin 23 receptor genetic risk score was generated from 7 Crohn’s disease–associated interleukin 23 receptor single nucleotide polymorphisms and dichotomized as high (top quintile) vs low interleukin 23 receptor genetic risk score. A subset of this cohort was assessed for intestinal permeability (n = 1698) and microbiome profiling (n = 2523). Cox proportional hazards models evaluated Crohn’s disease onset risk. Results High interleukin 23 receptor genetic risk score was associated with increased Crohn’s disease risk (hazard ratio, 1.67; 95% confidence interval, 1.01–2.75; P = .044). This association remained significant after adjusting for fecal calprotectin, indicating genetic risk independent of subclinical inflammation. High interleukin 23 receptor genetic risk score was not associated with intestinal permeability ( P = .84) but was associated with differences in 15 genera, including decreased Faecalibacterium and increased Akkermansia (q < 0.1). Conclusions High interleukin 23 receptor genetic risk score was associated with increased Crohn’s disease risk in healthy first-degree relatives and was associated with microbial differences, but not with intestinal permeability. These findings suggest potential clinical applications for interleukin 23 receptor genetic risk score in identifying high-risk individuals who may benefit from closer monitoring or future interleukin23 pathway–targeted preventive interventions.