Genetic Risk, Healthy Lifestyle, and Risk Stratification for Diverticulitis.

Abstract

A polygenic risk score approximates an individual's genetic susceptibility to disease, whereas the Life's Essential 8 (LE8) score captures a healthy lifestyle. This study applied the LE8 score and a polygenic risk score to severe diverticulitis. Multiple variations in lifestyle scores were compared. We hypothesized that genetics would complement lifestyle information in risk stratification. A polygenic risk score for severe diverticulitis (operative intervention or at least 2 inpatient admissions) was optimized in BioVU, followed by application to an independent prospective cohort from the UK Biobank. The LE8 score uses patterns in diet, exercise, smoking, sleep, weight, cholesterol, blood glucose, and blood pressure. Cox proportional hazards models evaluated relationships between high-risk groups and severe diverticulitis. Interactions were quantified through the relative excess risk due to interaction. A disease-specific lifestyle score was derived by assigning weights to LE8 components according to their association with the outcome. Among 225,592 eligible UK Biobank participants, 2,584 developed severe diverticulitis during a median of 14 years of follow-up. The at-risk group, from a lifestyle and genetic perspective, had a greater hazard of severe diverticulitis (hazard ratio [4.71; 95% CI 4.15 to 5.35; p < 0.01), with a cumulative incidence of 3.50% vs 0.75% in the rest of the cohort. The combined effect of genetic and lifestyle risk was greater than the sum of the individual effects (relative excess risk due to interaction 0.98, 95% CI 0.39 to 1.57). A diverticulitis-specific lifestyle score prioritized BMI, blood glucose, and smoking. Both polygenic risk and lifestyle scores were associated with severe diverticulitis; joint consideration yielded additional information relative to either variable alone. Future personalized profiles may inform shared decision-making discussions about operative intervention.