Mendelian randomization analysis revealed potential metabolic causal factors for breast cancer

Observational studies showed that metabolic phenotypes were associated with the risk of developing breast cancer (BC). However, those results are inconsistent regarding the magnitude of the association, particularly by subtypes of breast cancer. Furthermore, the mechanisms of the association remain unclear. We performed two-sample Mendelian randomization (MR) analyses to evaluate the causal effect of metabolic risk factors on breast cancer in the European population. Assessed individually using MR, body mass index (BMI) (odds ratio [OR] 0.94, 95% Confidence interval [CI] 0.90-0.98, P = 0.007), high-density lipoprotein cholesterol (HDL-C) (OR 1.10, 95% CI 1.07-1.13, P = 6.10 × 10^-11) and triglycerides (TG) (OR 0.92, 95% CI 0.90-0.96, P = 1.58 × 10^-6) were causally related to breast cancer risk. In multivariable MR, only HDL-C (OR 1.08; 95% CI 1.02-1.14; P = 0.02) retained a robust effect, suggesting that the genetic association between BMI, HDL-C and TG with breast cancer risk in univariable analysis was explained via HDL-C. These findings suggest a possible causal role of HDL-C in breast cancer etiology.