Genetic risk, metabolic syndrome, and gastrointestinal cancer risk: A prospective cohort study

Abstract

Background: Gastrointestinal (GI) cancer risk has been associated with metabolic syndrome (MetS), a surrogate indicator for unhealthy lifestyles, and a number of genetic loci, but the combined effect of MetS and genetic variants on GI cancer risk is uncertain. Methods: We included 430,036 participants with available MetS and genotype data from UK Biobank. During the follow-up time, 5494 incident GI cancer cases, including esophageal cancer, gastric cancer, and colorectal cancer, were identified. We created a GI polygenic risk score (GI-PRS) for overall GI cancer derived from three site-specific cancer PRSs. Cox proportional hazards regression was used to estimate the associations of MetS and GI-PRS with the risk of GI cancer. Results: MetS was significantly associated with 28% increment in GI cancer risk (hazard ratio [HR]MetS vs. non-MetS: 1.28, 95% confidence interval [CI]: 1.21–1.35, p < 0.0001), whereas a high GI-PRS (top quintile) was associated with 2.28-fold increase in risk (HRhigh vs. low: 2.28, 95% CI: 2.09–2.49, p < 0.0001). Compared with participants without MetS and at low genetic risk (bottom quintile of GI-PRS), those with MetS and at high genetic risk had 2.75-fold increase in GI cancer risk (HR: 2.75, 95% CI: 2.43–3.12, p < 0.0001). Additionally, MetS in comparison with no MetS had 1.49‰, 2.75‰, and 3.37‰ absolute risk increases in 5 years among participants at low, intermediate (quintiles 2–4 of GI-PRS) and high genetic risk, respectively, representing the number of subjects diagnosed as MetS causing a new GI cancer case in 5 years were 669, 364, and 296, respectively. Conclusions: Metabolic and genetic factors may jointly contribute to GI cancer risk and may serve as predictors by quantitative measurements to identify high-risk populations of GI cancer for precise prevention.