BMC Cancer · Mar 10, 2026

Genetic evidence for potential molecular mediators underlying the causal relationship between obesity and breast cancer: a two-step, two-sample Mendelian randomization study

By Hao Y, Jiang X, Xiao J et al.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

doi.org/10.1186/s12885-026-15744-6Open accessPubMed 41807932Mechanisms