Irritable Bowel Syndrome and Incident Hypertension: Epidemiologic and Genetic Insights.

Background/Objectives: Irritable bowel syndrome (IBS) may have health implications beyond the gastrointestinal tract, but its association with incident hypertension remains unclear. Methods: We analyzed 355,404 UK Biobank participants without recorded hypertension at baseline using multivariable Cox regression, propensity score matching, and sensitivity analyses addressing early events, baseline medication use and blood pressure, and competing mortality. Bidirectional Mendelian randomization (MR), Bayesian colocalization, and intestinal transcriptomic analyses examined genetic and tissue-level evidence. Results: During a median follow-up of 14.09 years, IBS was associated with incident hypertension (HR, 1.26; 95% CI, 1.22-1.30). The association persisted after matching (HR, 1.22; 95% CI, 1.16-1.28) and across sensitivity analyses. Forward MR provided suggestive support: the primary inverse-variance weighted estimate was positive but imprecise (OR, 1.18; 95% CI, 0.78-1.77), while weighted median and outlier-corrected analyses showed positive associations. Reverse MR showed no clear association. SuSiE-based colocalization supported shared signals for IBS with diastolic and systolic blood pressure at the NCAM1 locus (PP.H4, 0.903 and 0.890, respectively). Intestinal NCAM1 expression was lower in IBS, and correlated transcriptional programs involved epithelial remodeling, adhesion, and mucosal immune processes. Conclusions: IBS was associated with increased long-term hypertension risk, with suggestive genetic support and shared susceptibility signals at NCAM1. These findings support a potential biological link and prioritize NCAM1 for mechanistic investigation.