内脏脂肪组织对癌症风险因果关系的评估：一项孟德尔随机化研究。
Assessment of causal effects of visceral adipose tissue on risk of cancers: a Mendelian randomization study.
机构信息
Health Management Center, The Third Xiangya Hospital, Central South University, Changsha, China.
Schools of Life Course Sciences, King's College London, London, UK.
出版信息
Int J Epidemiol. 2022 Aug 10;51(4):1204-1218. doi: 10.1093/ije/dyac025.
BACKGROUND
Despite the established association between obesity and cancer risk, it remains unclear whether visceral obesity is causally related to cancer risk and whether it is more pro-oncogenic than total body fat.
METHODS
We conducted two-sample Mendelian randomization (MR) analysis to assess the causal effects of visceral adipose tissue (VAT) on six common cancers. For exposure data, 221 genetic variants associated with the predicted volume of VAT in 325 153 Europeans from UK Biobank were used as instrumental variables. Genetic association data of six common cancers (breast, lung, colorectal, ovarian, pancreatic and prostate cancers) were obtained from large-scale consortia with an average of 19 576 cases and 43 272 controls. We performed univariable MR with five MR methods [inverse-variance weighted (IVW), MR-Egger regression, weighted median, MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO) and Radial MR] and multivariable MR to estimate the effect of VAT independent of body mass index (BMI). Finally, we performed a series of sensitivity analyses as validation of primary MR results.
RESULTS
Two associations survived the false discovery rate correction for multiple testing (q-value < 0.05): in IVW, the odds ratios (95% CIs) per unit increase in genetically determined VAT were 1.65 (1.03 to 2.62) for pancreatic cancer and 1.47 (1.20 to 1.82) for lung squamous-cell carcinoma, respectively, which showed the same directions and overlapped confidence intervals with MR-Egger regression and weighted median results. There were no outlier variants identified by MR-PRESSO and no evidence supporting the presence of heterogeneity and pleiotropy in sensitivity analyses, although with wider confidence intervals that included the null, multivariable MR results for these two cancers showed the same directions and similar effect sizes as in IVW, which were independent of the effect from BMI. There was no evidence for a causal effect of VAT on the risk of other types of cancer.
CONCLUSION
Our findings suggest that lifelong exposure to elevated volumes of VAT might increase the risk of pancreatic cancer and lung squamous-cell carcinoma, highlighting the importance of revealing the underlying mechanisms for intervention targets.
背景
尽管肥胖与癌症风险之间存在明确的关联，但内脏肥胖是否与癌症风险存在因果关系，以及它是否比全身脂肪更具致癌性，目前仍不清楚。
方法
我们进行了两样本 Mendelian 随机化（MR）分析，以评估内脏脂肪组织（VAT）对六种常见癌症的因果影响。对于暴露数据，我们使用来自英国生物库的 325153 名欧洲人的 221 个与预测 VAT 体积相关的遗传变异作为工具变量。六种常见癌症（乳腺癌、肺癌、结直肠癌、卵巢癌、胰腺癌和前列腺癌）的遗传关联数据来自大型联盟，平均每个联盟包含 19576 例病例和 43272 例对照。我们使用五种 MR 方法（逆方差加权法[IVW]、MR-Egger 回归法、加权中位数法、MR-Pleiotropy Residual Sum and Outlier[MR-PRESSO] 和 Radial MR）进行单变量 MR，并进行多变量 MR 以估计 VAT 对 BMI 的独立影响。最后，我们进行了一系列敏感性分析，以验证主要 MR 结果。
结果
有两个关联在多重检验的错误发现率校正后仍然存在（q 值<0.05）：在 IVW 中，每单位遗传决定的 VAT 增加的比值比（95%置信区间）分别为 1.65（1.03 至 2.62）胰腺癌和 1.47（1.20 至 1.82）肺鳞癌，这与 MR-Egger 回归和加权中位数的结果方向相同，置信区间重叠。在 MR-PRESSO 中没有发现异常变异，在敏感性分析中也没有证据支持存在异质性和 pleiotropy，尽管置信区间较宽，包括零值，但多变量 MR 结果表明这两种癌症的方向和效应大小与 IVW 相同，且独立于 BMI 的影响。没有证据表明 VAT 对其他类型癌症的风险有因果关系。
结论
我们的研究结果表明，终生暴露于升高的 VAT 水平可能会增加胰腺癌和肺鳞癌的风险，这凸显了揭示潜在机制以作为干预靶点的重要性。
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