Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN.
Am J Clin Nutr. 2021 Apr 6;113(4):810-820. doi: 10.1093/ajcn/nqaa404.
Both genetic and lifestyle factors play an etiologic role in colorectal cancer (CRC).
We evaluated potential gene-environment interactions in CRC risk.
We used data from 346,297 participants in the UK Biobank cohort. Healthy lifestyle scores (HLSs) were constructed using 8 lifestyle factors, primarily according to the American Cancer Society guidelines, and were categorized into unhealthy, intermediate, and healthy groups. A polygenic risk score (PRS) was created using 95 genetic risk variants identified by genome-wide association studies of CRC and was categorized by tertile. Cox models were used to estimate the HRs and 95% CIs of CRC risk associated with the HLS and PRS.
During a median follow-up of 5.8 y, 2066 incident cases of CRC were identified. Healthier HLSs were associated with reduced risk of CRC in a dose-response manner. The risk reduction was more apparent among those with high PRS (HRhealthy vs. unhealthy HLS1: 0.58; 95% CI: 0.43, 0.79 for men and 0.71; 0.58, 0.85 for men and women combined) than those with low PRS. Although no multiplicative interactions were identified, the HLS1 and PRS showed a significant additive interaction (P = 0.02 for all participants combined, 0.04 for men). In analyses including all participants, the adjusted CRC cumulative risk from age 40 to 75 y was 6.40% for those with high PRS/unhealthy HLS1, with a relative excess risk due to interaction of 0.58 (95% CI: 0.06, 1.10), compared with 2.09% among those with low PRS/healthy HLS1. This pattern was more apparent among those who reported not having received any bowel screening before baseline.
Although the observational nature of the study precludes proof of causality, our findings suggest that individuals with a high genetic susceptibility could benefit more substantially than those with a low genetic risk from lifestyle modification in reducing CRC risk.
遗传和生活方式因素都在结直肠癌（CRC）的发病机制中起作用。
我们评估了 CRC 风险中潜在的基因-环境相互作用。
我们使用了英国生物库队列中 346297 名参与者的数据。健康生活方式评分（HLS）是根据美国癌症协会的指南，主要使用 8 种生活方式因素构建的，并分为不健康、中等和健康组。多基因风险评分（PRS）是使用 95 种通过 CRC 全基因组关联研究确定的遗传风险变异创建的，并按三分位分类。Cox 模型用于估计与 HLS 和 PRS 相关的 CRC 风险的 HRs 和 95%CI。
在中位随访 5.8 年期间，确定了 2066 例 CRC 事件。HLS 越健康，CRC 的风险呈剂量反应式降低。在 PRS 较高的人群中，这种风险降低更为明显（男性健康与不健康 HLS1：0.58；95%CI：0.43，0.79；男性和男女合并：0.71；0.58，0.85），PRS 较低的人群则不然。虽然没有发现乘法交互作用，但 HLS1 和 PRS 显示出显著的加法交互作用（所有参与者合并：0.02，男性：0.04）。在包括所有参与者的分析中，40 岁至 75 岁时，PRS 较高/不健康 HLS1 的参与者的 CRC 累积风险为 6.40%，由于交互作用的相对超额风险为 0.58（95%CI：0.06，1.10），而 PRS 较低/健康 HLS1 的参与者的 CRC 累积风险为 2.09%。在基线前没有接受过任何肠道筛查的人群中，这种模式更为明显。
尽管该研究的观察性质排除了因果关系的证明，但我们的发现表明，与遗传风险较低的个体相比，遗传易感性较高的个体通过生活方式改变降低 CRC 风险可能获益更大。
