Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent

BackgroundObservational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors.MethodsWe applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases = 46,325, controls = 42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively.ResultsIn the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR] = 0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56–0.75, p = 3.32 × 10−10). The associations were similar for both premenopausal (OR = 0.44, 95% CI:0.31–0.62, p = 9.91 × 10−8) and postmenopausal breast cancer (OR = 0.57, 95% CI: 0.46–0.71, p = 1.88 × 10−8). This association was replicated in the data from the DRIVE consortium (OR = 0.72, 95% CI: 0.60–0.84, p = 1.64 × 10−7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p ConclusionsBMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.

**背景** 观察性流行病学研究表明，绝经前女性较高的体重指数（BMI，Body Mass Index）与乳腺癌风险降低相关，而绝经后女性较高的BMI则与乳腺癌风险升高相关。目前尚不清楚这种关联是否由共享的遗传或环境因素所介导。
**方法** 本研究借助两大乳腺癌研究联盟的数据，采用孟德尔随机化（Mendelian randomization）方法评估BMI与乳腺癌发病风险的关联。我们构建了包含84个与BMI相关的遗传变异的加权BMI遗传评分，用于预测BMI水平。我们利用乳腺癌协会联盟（BCAC，Breast Cancer Association Consortium）的个体水平数据（病例数46325例，对照数42482例），分析了遗传预测BMI与乳腺癌风险的关联。此外，我们还使用乳腺癌遗传变异的发现、生物学与风险研究项目（DRIVE Project）的汇总统计数据（16003例病例、41335例对照），进一步验证遗传预测BMI与乳腺癌风险的关联。由于多数研究均在癌症确诊后测量BMI，我们无法开展平行分析以前瞻性充分评估实测BMI与乳腺癌风险的关联。
**结果** 在BCAC数据集中，遗传预测BMI与乳腺癌风险呈负相关（每5 kg/m²的BMI升高对应的比值比[OR]为0.65，95%置信区间[CI]：0.56~0.75，P=3.32×10⁻¹⁰）。绝经前乳腺癌亚组（OR=0.44，95%CI：0.31~0.62，P=9.91×10⁻⁸）与绝经后乳腺癌亚组（OR=0.57，95%CI：0.46~0.71，P=1.88×10⁻⁸）的关联趋势一致。该关联在DRIVE项目的数据中得到了重复验证（OR=0.72，95%CI：0.60~0.84，P=1.64×10⁻⁷）。单标记分析显示，84个与BMI相关的单核苷酸多态性（SNPs，single nucleotide polymorphisms）中有17个在P<0.05水平下与乳腺癌风险存在关联。
**结论** 由全基因组关联研究（GWAS，genome-wide association studies）鉴定的变异所预测的BMI，与绝经前和绝经后乳腺癌的发病风险均呈负相关。本研究中观察到的遗传预测BMI与绝经后乳腺癌风险降低的关联，与既往使用成人实测BMI开展的研究报道的正相关结果不一致。阐明这一差异的成因，或可揭示体重遗传决定因素与乳腺癌病因学之间的复杂关联机制。