GENETIC SUSCEPTIBILITY INCREASES THE RISK WITH THE PRESENCE OF OBESITY FOR INCIDENT DIVERTICULITIS

Background: We derived a polygenic risk score (PRS) for diverticulitis based on known susceptibility loci for diverticular disease and investigated its joint association with body mass index (BMI), a risk factor for diverticulitis.

Methods: We included 37,763 participants in three prospective cohorts, the Nurses’ Health Study (NHS; 1990-2016), the NHSII (2003-2017), and the Health Professionals Follow-up Study (HPFS; 1986-2020), who were free of diverticulitis and had previously been profiled in genome-wide association studies (GWAS). They were biennially queried for lifestyle and health data. PRS was derived by the weighted sum of 51 diverticular disease-associated single-nucleotide polymorphisms (SNPs) identified in a prior GWAS. We documented self-reported episodes of incident diverticulitis, which was validated by medical records. We estimated hazard ratio (HR) and 95% confidence interval (CI) for diverticulitis per 1 standard deviation (SD) increase in PRS through Cox proportional hazards models. We validated our findings in the Mass General Brigham Biobank (MGBB), an electronic health records-linked biobank. Among 59,911 individuals with GWAS data, we identified 2,748 diverticulitis patients diagnosed from 1990 to 2023 with ICD-9/10 codes and matched them to 13,740 controls by age, sex, and the year of last encounter. The association of PRS with diverticulitis was assessed by conditional logistic regression. Additive interactions between PRS and BMI were tested by relative excess risk due to interactions (RERIs).

Results: In the pooled cohort of NHS, NHSII, and HPFS, 2,205 individuals developed diverticulitis over 1,759,958 person-years. The multivariable HR of diverticulitis was 1.29 (95% CI, 1.24-1.34) per 1SD increase in PRS and 1.41 (95% CI, 1.26-1.59) for those with BMI ≥30 kg/m² versus BMI <25 kg/m². We found a statistically significant additive interaction between PRS and BMI (RERI, 0.007; 95% CI, 0.002-0.011). Individuals in the highest PRS tertile and BMI ≥30 kg/m² had a 2.54-fold (95% CI, 2.09-3.09) higher risk of diverticulitis than those with the lowest PRS and BMI ≤25 kg/m². The association of PRS and diverticulitis was stronger in individuals aged ≤60 years (HR, 1.42; 95% CI, 1.32-1.53) than those aged >60 years (HR, 1.23; 95% CI, 1.17-1.29; P interaction, .001). In our validation MGBB cohort, PRS was associated with diverticulitis (odds ratio, 1.29; 95% CI, 1.24-1.35) and we also identified an additive interaction between PRS and BMI (RERI, 0.011; 95% CI, 0.008-0.015).

Conclusion: A PRS based on 51 SNPs was associated with diverticulitis, particularly among younger individuals. The excess risk attributable to the combined influence of genetic susceptibility and greater BMI was higher than the sum of each. Our results underscore the importance of gene-environment associations for precision prevention for diverticulitis.