Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China.
Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Int J Epidemiol. 2023 Feb 8;52(1):58-70. doi: 10.1093/ije/dyac143.
Previous Mendelian randomization (MR) studies on obesity and risk of breast cancer adopted a small number of instrumental variables and focused mainly on the crude total effect. We aim to investigate the independent causal effect of obesity on breast cancer susceptibility, considering the distribution of fat, covering both early and late life.
Using an enlarged set of female-specific genetic variants associated with adult general [body mass index (BMI)] and abdominal obesity [waist-to-hip ratio (WHR) with and without adjustment for BMI, WHR and WHRadjBMI] as well as using sex-combined genetic variants of childhood obesity (childhood BMI), we performed a two-sample univariable MR to re-evaluate the total effect of each obesity-related exposure on overall breast cancer (Ncase = 133 384, Ncontrol = 113 789). We further looked into its oestrogen receptor (ER)-defined subtypes (NER+ = 69 501, NER- = 21 468, Ncontrol = 105 974). Multivariable MR was applied to estimate the independent causal effect of each obesity-related exposure on breast cancer taking into account confounders as well as to investigate the independent effect of adult and childhood obesity considering their inter-correlation.
In univariable MR, the protective effects of both adult BMI [odds ratio (OR) = 0.89, 95% CI = 0.83-0.96, P = 2.06 × 10-3] and childhood BMI (OR = 0.78, 95% CI = 0.70-0.87, P = 4.58 × 10-6) were observed for breast cancer overall. Comparable effects were found in ER+ and ER- subtypes. Similarly, genetically predicted adult WHR was also associated with a decreased risk of breast cancer overall (OR = 0.87, 95% CI = 0.80-0.96, P = 3.77 × 10-3), restricting to ER+ subtype (OR = 0.88, 95% CI = 0.80-0.98, P = 1.84 × 10-2). Conditional on childhood BMI, the effect of adult general obesity on breast cancer overall attenuated to null (BMI: OR = 1.00, 95% CI = 0.90-1.10, P = 0.96), whereas the effect of adult abdominal obesity attenuated to some extent (WHR: OR = 0.90, 95% CI = 0.82-0.98, P = 1.49 × 10-2; WHRadjBMI: OR = 0.92, 95% CI = 0.86-0.99, P = 1.98 × 10-2). On the contrary, an independent protective effect of childhood BMI was observed in breast cancer overall, irrespective of adult measures (adjusted for adult BMI: OR = 0.84, 95% CI = 0.77-0.93, P = 3.93 × 10-4; adjusted for adult WHR: OR = 0.84, 95% CI = 0.76-0.91, P = 6.57 × 10-5; adjusted for adult WHRadjBMI: OR = 0.80, 95% CI = 0.74-0.87, P = 1.24 × 10-7).
Although successfully replicating the inverse causal relationship between adult obesity-related exposures and risk of breast cancer, our study demonstrated such effects to be largely (adult BMI) or partly (adult WHR or WHRadjBMI) attributed to childhood obesity. Our findings highlighted an independent role of childhood obesity in affecting the risk of breast cancer as well as the importance of taking into account the complex interplay underlying correlated exposures.
先前的孟德尔随机化（MR）研究采用了少量的工具变量，主要关注肥胖与乳腺癌风险的总效应。我们旨在研究肥胖对乳腺癌易感性的独立因果效应，同时考虑脂肪的分布，涵盖早期和晚期生活。
我们使用一组更大的女性特异性遗传变异，这些变异与成人一般（体重指数（BMI））和腹部肥胖（腰围与臀围比（WHR），包括 BMI、WHR 和 WHRadjBMI 的调整）以及儿童肥胖（儿童 BMI）的性别混合遗传变异相关，我们进行了两样本单变量 MR，重新评估了每种肥胖相关暴露对整体乳腺癌（病例数=133384，对照组=113789）的总效应。我们进一步研究了其雌激素受体（ER）定义的亚型（NER+ = 69501，NER- = 21468，对照组= 105974）。多变量 MR 用于估计在考虑混杂因素的情况下，每种肥胖相关暴露对乳腺癌的独立因果效应，以及在考虑到它们之间的相互关联的情况下，对成人和儿童肥胖的独立影响。
在单变量 MR 中，观察到成人 BMI（比值比（OR）= 0.89，95%置信区间（CI）= 0.83-0.96，P = 2.06×10-3）和儿童 BMI（OR = 0.78，95% CI = 0.70-0.87，P = 4.58×10-6）对乳腺癌整体具有保护作用。在 ER+和 ER-亚型中也发现了类似的效果。同样，遗传预测的成人 WHR 也与乳腺癌整体风险降低相关（OR = 0.87，95% CI = 0.80-0.96，P = 3.77×10-3），限制在 ER+亚型（OR = 0.88，95% CI = 0.80-0.98，P = 1.84×10-2）。在儿童 BMI 条件下，成人一般肥胖对乳腺癌整体的影响减弱为无效（BMI：OR = 1.00，95% CI = 0.90-1.10，P = 0.96），而成人腹部肥胖的影响在一定程度上减弱（WHR：OR = 0.90，95% CI = 0.82-0.98，P = 1.49×10-2；WHRadjBMI：OR = 0.92，95% CI = 0.86-0.99，P = 1.98×10-2）。相反，儿童 BMI 对乳腺癌整体具有独立的保护作用，而与成人措施无关（调整成人 BMI：OR = 0.84，95% CI = 0.77-0.93，P = 3.93×10-4；调整成人 WHR：OR = 0.84，95% CI = 0.76-0.91，P = 6.57×10-5；调整成人 WHRadjBMI：OR = 0.80，95% CI = 0.74-0.87，P = 1.24×10-7）。
尽管成功复制了成人肥胖相关暴露与乳腺癌风险之间的逆因果关系，但我们的研究表明，这些效应在很大程度上（成人 BMI）或部分上（成人 WHR 或 WHRadjBMI）归因于儿童肥胖。我们的研究结果强调了儿童肥胖在影响乳腺癌风险方面的独立作用，以及考虑相关暴露之间复杂相互作用的重要性。
