Differential Impact of BMI-Associated Genetic Variants on Breast Cancer Risk: Insights From Mediation Analysis

Obesity is a known risk factor for breast cancer, particularly in postmenopausal women. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) associated with body mass index (BMI). We conducted a case-control study with 1273 breast cancer cases and 4816 controls to examine whether five BMI-associated SNPs (rs939584 [TMEM18], rs4409766 [BORCS7-ASMT], rs6265 [BDNF], rs1927790 [HS6ST3], rs1421085 [FTO]) influence breast cancer risk through BMI-dependent or -independent pathways using mediation analysis. For postmenopausal breast cancer, rs6265 (C > T) exhibited a carcinogenic direct effect (odds ratio [OR] = 1.18, 95% confidence interval [CI]: 1.04-1.34) along with a protective indirect effect through changes in BMI (OR = 0.98, 95% CI 0.96-0.99), while rs1421085 (T > C) showed a carcinogenic indirect effect (OR = 1.03, 95% CI 1.00-1.05). No significant associations were observed for any SNPs in premenopausal breast cancer. These findings suggest that two BMI-associated genetic variants, rs6265 and rs1421085, influence postmenopausal breast cancer risk through changes in BMI, and that rs6265 also exerts a direct effect through pathways independent of BMI, providing insight into a previously uncharacterized association between obesity-related genetic factors and breast cancer and highlighting the potential utility of genetic profiling in personalized risk assessment.