The contribution of genetic risk and lifestyle factors in the development of adult-onset inflammatory bowel disease: a prospective cohort study

Summary Objective There are few prospective data exploring the combined effect of genetic and lifestyle factors on the incidence of inflammatory bowel disease (IBD), and whether genetic risk of IBD may be mitigated by lifestyle remains unclear. Design We conducted a prospective cohort study based on the UK Biobank to examine the associations across genetic risk, modifiable lifestyle factors, and risk of Crohn’s disease (CD) and ulcerative colitis (UC). Genetic susceptibility to CD and UC was estimated by polygenic risk scores using common genetic variants identified by genome-wide association studies and was further categorized into high, intermediate, and low genetic risk categories. Weighted unhealthy lifestyle scores were constructed based on disease-related lifestyle factors, including ever smoking, unhealthy diet, physical inactivity, obesity, and abnormal sleep duration, and were categorized into ‘favorable’, ‘intermediate’, and ‘unfavorable’ categories. The Cox proportional hazard regression model was used to estimate the HRs and 95% CIs for their associations and accumulative risk for developing CD and UC were estimated for each risk group. Results During a median follow-up of 12.0 years, 707 CD and 1576 UC cases were diagnosed. Genetic risk and unhealthy lifestyle categories were monotonically associated with CD and UC risk and there was no multiplicative interaction between them. Compared with participants with low genetic risk, the hazard ratios (HRs) of CD and UC were 2.24 (95% confidence interval [CI] 1.75-2.86) and 2.15 (95% CI 1.82-2.53) for those with high genetic risk, respectively. The HRs of CD and UC for individuals in unfavorable lifestyle category were 1.94 (95% CI 1.61-2.33) and 1.98 (95% CI 1.73-2.27), respectively, compared with those in favorable category. When considering genetic risk and lifestyle jointly, the HRs of individuals with high genetic risk but a favorable lifestyle (2.33, 95% CI 1.58-3.44 for CD, and 2.05, 95% CI, 1.58-2.66 for UC) were reduced nearly by half comparing to those with high genetic risk but an unfavorable lifestyle (4.40, 95% CI, 2.91-6.66 for CD and 4.44, 95% CI, 3.34-5.91 for UC). Conclusion Genetic and lifestyle factors were independently associated with susceptibility to CD and UC. Participants at high genetic risk could reduce nearly 50% risk of CD and UC by adherence to a favorable lifestyle. Funding XL: the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001). XYW: National Natural Science Foundation of China (81970494) and Key Project of Research and Development Plan of Hunan Province(2019SK2041); SCL: the Swedish Heart-Lung Foundation (Hjärt-Lungfonden, 20210351), the Swedish Research Council (Vetenskapsrådet, 2019-00977), and the Swedish Cancer Society (Cancerfonden); ET: CRUK Career Development Fellowship (C31250/A22804); KFD: Project of the regional diagnosis and treatment center of the Health Planning Committee (No. JBZX-201903). What is already known on this topic Previous studies have identified a number of genetic variants and several modifiable risk factors for IBD. However, there is a lack of studies on the combined effects of genetic and lifestyle factors on IBD risk. What this study adds In this prospective cohort study, genetic risk and modifiable lifestyle factors were independently associated with the risk of incident Crohn’s disease and ulcerative colitis. Participants at high genetic risk could reduce nearly 50% of their genetic susceptibility to Crohn’s disease and ulcerative colitis by adherence to a favorable lifestyle. How this study might affect research, practice or policy Promoting a healthy lifestyle is an effective strategy to lower the incidence of these diseases, especially among those with high-risk genetic background.