MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
Bristol Medical School, University of Bristol, Bristol, UK.
BMC Med. 2022 Apr 19;20(1):125. doi: 10.1186/s12916-022-02322-3.
Endometrial cancer is the most common gynaecological cancer in high-income countries. Elevated body mass index (BMI) is an established modifiable risk factor for this condition and is estimated to confer a larger effect on endometrial cancer risk than any other cancer site. However, the molecular mechanisms underpinning this association remain unclear. We used Mendelian randomization (MR) to evaluate the causal role of 14 molecular risk factors (hormonal, metabolic and inflammatory markers) in endometrial cancer risk. We then evaluated and quantified the potential mediating role of these molecular traits in the relationship between BMI and endometrial cancer using multivariable MR.
Genetic instruments to proxy 14 molecular risk factors and BMI were constructed by identifying single-nucleotide polymorphisms (SNPs) reliably associated (P < 5.0 × 10) with each respective risk factor in previous genome-wide association studies (GWAS). Summary statistics for the association of these SNPs with overall and subtype-specific endometrial cancer risk (12,906 cases and 108,979 controls) were obtained from a GWAS meta-analysis of the Endometrial Cancer Association Consortium (ECAC), Epidemiology of Endometrial Cancer Consortium (E2C2) and UK Biobank. SNPs were combined into multi-allelic models and odds ratios (ORs) and 95% confidence intervals (95% CIs) were generated using inverse-variance weighted random-effects models. The mediating roles of the molecular risk factors in the relationship between BMI and endometrial cancer were then estimated using multivariable MR.
In MR analyses, there was strong evidence that BMI (OR per standard deviation (SD) increase 1.88, 95% CI 1.69 to 2.09, P = 3.87 × 10), total testosterone (OR per inverse-normal transformed nmol/L increase 1.64, 95% CI 1.43 to 1.88, P = 1.71 × 10), bioavailable testosterone (OR per natural log transformed nmol/L increase: 1.46, 95% CI 1.29 to 1.65, P = 3.48 × 10), fasting insulin (OR per natural log transformed pmol/L increase: 3.93, 95% CI 2.29 to 6.74, P = 7.18 × 10) and sex hormone-binding globulin (SHBG, OR per inverse-normal transformed nmol/L increase 0.71, 95% CI 0.59 to 0.85, P = 2.07 × 10) had a causal effect on endometrial cancer risk. Additionally, there was suggestive evidence that total serum cholesterol (OR per mg/dL increase 0.90, 95% CI 0.81 to 1.00, P = 4.01 × 10) had an effect on endometrial cancer risk. In mediation analysis, we found evidence for a mediating role of fasting insulin (19% total effect mediated, 95% CI 5 to 34%, P = 9.17 × 10), bioavailable testosterone (15% mediated, 95% CI 10 to 20%, P = 1.43 × 10) and SHBG (7% mediated, 95% CI 1 to 12%, P = 1.81 × 10) in the relationship between BMI and endometrial cancer risk.
Our comprehensive MR analysis provides insight into potential causal mechanisms linking BMI with endometrial cancer risk and suggests targeting of insulinemic and hormonal traits as a potential strategy for the prevention of endometrial cancer.
子宫内膜癌是高收入国家最常见的妇科癌症。已确定升高的体重指数（BMI）是这种疾病的一种可改变的风险因素，并且据估计，它对子宫内膜癌风险的影响大于任何其他癌症部位。然而，这种关联的潜在分子机制仍不清楚。我们使用孟德尔随机化（MR）来评估 14 种分子风险因素（激素、代谢和炎症标志物）与子宫内膜癌风险之间的因果关系。然后，我们使用多变量 MR 评估和量化这些分子特征在 BMI 与子宫内膜癌之间的关系中的潜在中介作用。
通过确定与之前全基因组关联研究（GWAS）中每个相应风险因素可靠相关（P < 5.0×10）的单核苷酸多态性（SNP），构建了代表 14 种分子风险因素和 BMI 的遗传工具。从子宫内膜癌协会联盟（ECAC）、子宫内膜癌流行病学协会联盟（E2C2）和英国生物银行的 GWAS 荟萃分析中获得了这些 SNP 与整体和亚型特异性子宫内膜癌风险（12906 例病例和 108979 例对照）的关联汇总统计数据。使用逆方差加权随机效应模型对多等位基因模型和比值比（OR）及其 95%置信区间（95%CI）进行了组合。然后，使用多变量 MR 估计了分子风险因素在 BMI 与子宫内膜癌之间的关系中的中介作用。
在 MR 分析中，有强有力的证据表明 BMI（每标准偏差（SD）增加 1.88，95%CI 1.69 至 2.09，P = 3.87×10）、总睾酮（每逆正态转换 nmol/L 增加 1.64，95%CI 1.43 至 1.88，P = 1.71×10）、生物可利用睾酮（每自然对数转换 nmol/L 增加：1.46，95%CI 1.29 至 1.65，P = 3.48×10）、空腹胰岛素（每自然对数转换 pmol/L 增加：3.93，95%CI 2.29 至 6.74，P = 7.18×10）和性激素结合球蛋白（SHBG，每逆正态转换 nmol/L 增加 0.71，95%CI 0.59 至 0.85，P = 2.07×10）对子宫内膜癌风险有因果影响。此外，有提示性证据表明总血清胆固醇（每增加 1mg/dL，OR 为 0.90，95%CI 0.81 至 1.00，P = 4.01×10）对子宫内膜癌风险有影响。在中介分析中，我们发现空腹胰岛素（19%的总效应被中介，95%CI 5%至 34%，P = 9.17×10）、生物可利用睾酮（15%被中介，95%CI 10%至 20%，P = 1.43×10）和 SHBG（7%被中介，95%CI 1%至 12%，P = 1.81×10）在 BMI 与子宫内膜癌风险之间的关系中具有中介作用。
我们的综合 MR 分析提供了关于 BMI 与子宫内膜癌风险之间潜在因果机制的见解，并表明针对胰岛素和激素特征可能是预防子宫内膜癌的一种潜在策略。
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