The hidden pathway: biological aging as a mediator between diabetes and breast cancer risk: a Mendelian randomized...

To explore the relationship between type 2 diabetes mellitus and the risk of developing breast cancer and its subtypes, and the mediating role of biological aging in it.

A two-sample Mendelian randomized analyses were performed to assess the effect of type 2 diabetes mellitus on breast cancer and its subtypes, and the mediating effect of biological aging between type 2 diabetes mellitus with breast cancer and its subtypes was explored by mediation analysis. All the data were based on genome-wide association studies. The data of type 2 diabetes mellitus were obtained from meta-analyses with the UK Biobank and FinnGen. The data of biological aging and breast cancer were obtained from UK Biobank, Breast Cancer Association Consortium, respectively.

The results of univariate Mendelian randomized showed that type 2 diabetes mellitus was positively causally associated with the risk of triple-negative breast cancer (OR = 1.076, 95%CI 1.022 ~ 1.132, P = 0.005), and positively associated with the biological aging phenotype PhenoAgeAccel (OR = 1.311, 95%CI 1.221 ~ 1.407, P < 0.001) and BioAgeAccel (OR = 1.083, 95%CI 1.054 ~ 1.113, P < 0.001) were both positively causal. The results of mediation analysis showed that BioAgeAccel played a fully mediating role in the causal effect of type 2 diabetes mellitus and triple-negative breast cancer, with a mediating effect of -0.010 (95%CI -0.020 ~ -0.001).

Through Mendelian randomized analyses, this study explores the potential causal link between type 2 diabetes mellitus and the risk of triple-negative breast cancer, as well as the possible mediating role of biological ageing. The findings indicate a potential association between type 2 diabetes mellitus and an increased risk of triple-negative breast cancer, with BioAgeAccel possibly acting as a mediator. However, given the limitations of the study and the current evidence, it is premature to definitively establish a causal relationship and the precise mediating effect. Further research is necessary to substantiate these findings.