Abstract
BACKGROUND: Genetic factors increase the individual risk of colorectal cancer (CRC); however, the extent to which a healthy lifestyle can offset increased genetic risk is unknown. This study investigated whether a healthy lifestyle is associated with lower CRC risk, regardless of genetic risk. METHODS: We recruited 390,365 participants without cancer at baseline (2006-2010) from the UK Biobank. The primary outcome was CRC incidence. A healthy lifestyle score constructed using 16 factors of six dimensions (smoking, drinking, body mass index, diet, exercise, and sleep) was categorized into three risk categories: favorable, intermediate, and unfavorable. To calculate the polygenic risk scores (PRSs) of UK Biobank participants, we extracted 454,678 single nucleotide polymorphisms (SNPs) from the UK Biobank and FinnGen Biobank after quality control. Cox proportional hazards regression was performed to evaluate the associations and was expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: During a median follow-up of 10.90 years, 4,090 new CRC cases were reported in the UK Biobank. The "best-fit" PRSs were constructed using 59 SNPs based on the UK Biobank cohort and FinnGen genome-wide association study summary data (R(2) = 0.23%) and were divided into low (lowest quintile), intermediate (including second-fourth quintile), and high (highest quintile) genetic risk categories. The multivariate-adjusted Cox model revealed that participants with favorable lifestyles had HRs of 0.66 (95% CI = 0.60-0.72) for developing CRC vs. those with unfavorable lifestyles; low genetic risk was associated with a decreased risk of CRC (HR = 0.67, 95% CI =0.61-0.74) compared with those with high genetic risk. The HRs for low genetic risk participants with favorable lifestyles were 0.44 (95% CI =0.36-0.55) vs. participants with high genetic risk and unfavorable lifestyles. Among the participants with low, intermediate, or high genetic risk, the HRs of favorable vs. unfavorable lifestyles were 0.74, 0.64, and 0.72 (all p< 0.05). CONCLUSIONS: Low genetic risk and a favorable lifestyle were significantly associated with a decreased risk of CRC. A favorable lifestyle was associated with a lower CRC risk, regardless of genetic risk.