Interaction of genetic and lifestyle risk scores on colorectal cancer risk across 5 racial and ethnic populations

BACKGROUND: Integrating genetic and lifestyle information has the potential to greatly improve the prediction of colorectal cancer (CRC) risk. However, racial and ethnic minorities are generally underrepresented in gene-environment studies of CRC risk. METHODS: We investigated the interplay of genetics and lifestyle on CRC risk in a prospective analysis of 68 397 African American, Japanese American, Latino, Native Hawaiian, and White individuals from the Multiethnic Cohort Study. Genetic predisposition was assessed using a 205-variant polygenic risk score. Lifestyle was assessed using a lifestyle risk score based on smoking, alcohol consumption, body mass index, physical activity, and diet. The independent and joint associations of the polygenic risk score and lifestyle risk score on CRC risk were evaluated using Cox regression. RESULTS: We identified 1303 incident CRC cases (median 15.1-year follow-up). The highest quintile of the polygenic risk score was associated with a 2.4-fold increase in CRC risk compared with the lowest quintile (Q5 vs Q1: hazard ratio [HR] = 2.40, 95% confidence interval [CI] = 1.99 to 2.89). The highest quintile of the lifestyle risk score was associated with a 54% increased risk (Q5 vs Q1: HR = 1.54, 95% CI = 1.26 to 1.88). This association was stronger among those with high genetic risk (polygenic risk score ≥ 50%; Q5 vs Q1: HR = 1.82, 95% CI = 1.41 to 2.35) and statistically nonsignificant among those with low genetic risk (polygenic risk score < 50%; Q5 vs Q1: HR = 1.20, 95% CI = 0.88 to 1.64; P for interaction = 0.01). Results were similar across race and ethnicity. CONCLUSIONS: Our study suggests that lifestyle modification may offer greater risk reduction among those at higher genetic risk. Future research is warranted to enhance the integration of genetics and lifestyle in CRC risk stratification and screening approaches across populations.