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

Abstract 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 (PRS). 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 PRS and lifestyle risk score on CRC risk were evaluated using Cox regression. Results We identified 1,303 incident CRC cases (median 15.1-year follow-up). The highest quintile of the PRS was associated with a 2.4-fold increase in CRC risk compared to the lowest quintile (HRQ5vQ1 2.40, 95% CI 1.99-2.89). The highest quintile of the lifestyle risk score was associated with a 54% increased risk (HRQ5vQ1 1.54, 95% CI 1.26-1.88). This association was stronger among those with high genetic risk (PRS≥50%) (HRQ5vQ1 1.82, 95% CI 1.41-2.35) and non-significant among those with low genetic risk (PRS50%) (HRQ5vQ1 1.20, 95% CI 0.88-1.64; p-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.