Body mass index and type 2 diabetes and breast cancer survival: a Mendelian randomization study.

The causal relationship between body mass index (BMI) and type 2 diabetes (T2D) and breast cancer prognosis is still ambiguous. The aim of this study was to investigate the prognostic effect of BMI and T2D on breast cancer disease-free survival (DFS) among Asian individuals. In this two-sample Mendelian randomization (MR) study, the instrumental variables (IVs) were identified using a genome-wide association study (GWAS) among 24,000 participants in the Taiwan Biobank. Importantly, the validity of these IVs was confirmed with a previous large-scale GWAS (Biobank Japan Project, BBJ). In this study, we found that a genetic predisposition toward higher BMI (as indicated by BMI IVs, F = 86.88) was associated with poor breast cancer DFS (hazard ratio [HR] = 6.11; P < 0.001). Furthermore, higher level of genetically predicted T2D (as indicated by T2D IVs) was associated with an increased risk of recurrence of and mortality from breast cancer (HR = 1.43; P < 0.001). Sensitivity analyses, including the weighted-median approach, MR-Egger regression, Radial regression and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) supported the consistency of our findings. Finally, the causal relationship between BMI and poor breast cancer prognosis was confirmed in a prospective cohort study. Our MR analyses demonstrated the causal relationship between the genetic prediction of elevated BMI and a greater risk of T2D with poor breast cancer prognosis. BMI and T2D have important clinical implications and may be used as prognostic indicators of breast cancer.