Genetic evidence for potential molecular mediators underlying the causal relationship between obesity and breast...

Relationships between BMI and breast cancer risk have been widely reported in previous Mendelian randomization (MR) studies, but the underlying molecular mechanisms remain unclear. We conducted this comprehensive two-sample MR to investigate the mediating role of 8 circulating biomarkers linking genetically predicted BMI to breast cancer risk both individually and simultaneously.

A total of 281 BMI-associated single-nucleotide polymorphisms (SNPs) were used to estimate the associations of BMI with biomarker levels and breast cancer susceptibility. Instruments involving 8 ~ 364 SNPs were used to proxy 8 circulating biomarkers related to adipocytokine imbalance, chronic low-grade inflammation and insulin/insulin-like growth factor (IGF) axis dysregulation. Two-step MR mediation analyses were conducted to evaluate the indirect effects of a single biomarker in the relationship between genetically predicted BMI and breast cancer risk, and stepwise MR mediation analyses were employed to identify potential pathways involving multiple mediators.

Genetically predicted BMI was positively correlated with genetically predicted circulating leptin (LEP), insulin (INS), and C-reactive protein (CRP) levels, with β values ranging from 0.166 to 0.453, and negatively correlated with IGF-1 levels (β=-0.118), whereas no statistically significant associations were found for adiponectin, resistin, soluble leptin receptor or insulin-like growth factor binding protein-3 levels. Two-step MR mediation analyses showed that in the association between genetically predicted BMI and breast cancer susceptibility (OR: 0.894; 95%CI: 0.832, 0.960; P = 2.06 × 10^- 3), the indirect effect mediated by CRP was statistically significant (OR: 1.046; 95%CI: 1.014, 1.079; P = 4.83 × 10^- 3), while no statistically significant indirect effects were detected for LEP, INS or IGF-1. Furthermore, stepwise MR mediation analyses with multiple mediators revealed that both the indirect effect mediated by CRP alone (OR: 1.040; 95%CI: 1.012, 1.070; P = 5.73 × 10^- 3) and by the sequential combination of IGF-1 and CRP (OR: 1.003; 95%CI: 1.000, 1.005; P = 2.38 × 10^- 2) were statistically significant.

Chronic low-grade inflammation is a vital pathway linking genetically predicted BMI to breast cancer risk. Genetically predicted BMI is associated with higher genetically predicted CRP levels, potentially through a pathway involving reduced IGF-1 levels, which may attenuate the inverse association between genetically predicted BMI and breast cancer risk.