Mendelian Randomization Analysis of Circulating Adipokines and C-reactive Protein on Breast Cancer Risk

Adipokines and C-reactive protein (CRP) have been proposed as molecular mediators linking adiposity to breast cancer (BCa). Mendelian randomization (MR) uses genetic variants as proxies for risk factors to strengthen causal inference in observational studies. We performed a MR analysis to evaluate the causal relevance of six circulating adipokines (adiponectin, hepatocyte growth factor, interleukin-6, leptin receptor, plasminogen activator inhibitor-1, resistin) and CRP in risk of overall and oestrogen receptor-stratified BCa in up to 122,977 cases and 105,974 controls. Genetic instruments were constructed from single-nucleotide polymorphisms robustly ( P <5×10 −8 ) associated with risk factors in genome-wide association studies. In MR analyses, there was evidence for a causal effect of hepatocyte growth factor on ER- BCa (OR per SD increase:1.17, 95% CI: 1.01-1.35; P =0.035) but little evidence for effects of other adipokines or CRP on overall or oestrogen receptor-stratified BCa. Collectively, these findings do not support an important etiological role of various adipokines or CRP in BCa risk.