BACKGROUND Colorectal cancer (CRC) is the third-most-common cancer worldwide and its rates are increasing. Elevated body mass index (BMI) is an established risk factor for CRC, although the molecular mechanisms behind this association remain unclear. Using the Mendelian randomization (MR) framework, we aimed to investigate the mediating effects of putative biomarkers and other CRC risk factors in the association between BMI and CRC. METHODS We selected as mediators biomarkers of established cancer-related mechanisms and other CRC risk factors for which a plausible association with obesity exists, such as inflammatory biomarkers, glucose homeostasis traits, lipids, adipokines, insulin-like growth factor 1 (IGF1), sex hormones, 25-hydroxy-vitamin D, smoking, physical activity (PA) and alcohol consumption. We used inverse-variance weighted MR in the main univariable analyses and performed sensitivity analyses (weighted-median, MR-Egger, Contamination Mixture). We used multivariable MR for the mediation analyses. RESULTS Genetically predicted BMI was positively associated with CRC risk [odds ratio per SD (5 kg/m2) = 1.17, 95% CI: 1.08-1.24, P-value = 1.4 × 10-5] and robustly associated with nearly all potential mediators. Genetically predicted IGF1, fasting insulin, low-density lipoprotein cholesterol, smoking, PA and alcohol were associated with CRC risk. Evidence for attenuation was found for IGF1 [explained 7% (95% CI: 2-13%) of the association], smoking (31%, 4-57%) and PA (7%, 2-11%). There was little evidence for pleiotropy, although smoking was bidirectionally associated with BMI and instruments were weak for PA. CONCLUSIONS The effect of BMI on CRC risk is possibly partly mediated through plasma IGF1, whereas the attenuation of the BMI-CRC association by smoking and PA may reflect confounding and shared underlying mechanisms rather than mediation.

中文翻译：

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体重指数与结直肠癌之间关系的潜在调节因素的识别：孟德尔随机分析。


背景技术结直肠癌（CRC）是全世界第三大常见癌症，并且其发病率正在增加。体重指数 (BMI) 升高是结直肠癌的一个确定的危险因素，尽管这种关联背后的分子机制仍不清楚。使用孟德尔随机化 (MR) 框架，我们旨在研究假定的生物标志物和其他 CRC 危险因素在 BMI 和 CRC 之间的关联中的中介作用。方法 我们选择已确定的癌症相关机制的生物标志物和其他可能与肥胖相关的结直肠癌危险因素作为介质，例如炎症生物标志物、葡萄糖稳态特征、血脂、脂肪因子、胰岛素样生长因子 1 (IGF1)、性别激素、25-羟基维生素 D、吸烟、体力活动 (PA) 和饮酒。我们在主要单变量分析中使用了反方差加权 MR，并进行了敏感性分析（加权中值、MR-Egger、污染混合物）。我们使用多变量 MR 进行中介分析。结果 基因预测的 BMI 与 CRC 风险呈正相关 [每 SD 的比值比 (5 kg/m2) = 1.17，95% CI：1.08-1.24，P 值 = 1.4 × 10-5]，并且与几乎所有潜在中介因素均呈稳健相关。基因预测 IGF1、空腹胰岛素、低密度脂蛋白胆固醇、吸烟、PA 和酒精与 CRC 风险相关。发现了 IGF1 减弱的证据[解释了 7% (95% CI: 2-13%) 的关联]、吸烟 (31%, 4-57%) 和 PA (7%, 2-11%)。尽管吸烟与 BMI 双向相关并且仪器对 PA 的检测能力较弱，但几乎没有证据表明多效性。 结论 BMI 对 CRC 风险的影响可能部分是通过血浆 IGF1 介导的，而吸烟和 PA 对 BMI-CRC 关联的减弱可能反映了混杂和共同的潜在机制，而不是中介作用。