Mendelian Randomization Analysis of Circulating Adipokines and C-reactive Protein on Breast Cancer Risk
Menée à l'aide d'une méthode de randomisation mendélienne et des données d'une étude européenne d'association sur le génome entier portant sur 122 977 patientes atteintes d'un cancer du sein et sur 105 974 témoins, cette étude analyse la relation entre 6 adipokines (adiponectine, facteur de croissance des hépatocytes, interleukine-6, récepteur de la leptine, inhibiteur d'activateur du plasminogène-1, résistine) ou la protéine C-réactive et le risque de développer la maladie, en général et en fonction du statut des récepteurs à œstrogènes
Circulating adipokines and C-reactive protein have been linked to breast cancer risk in observational epidemiological studies. The causal nature of these associations is unclear because of the susceptibility of conventional observational designs to residual confounding, reverse causation, and other forms of bias. Mendelian randomization uses genetic variants as proxies for risk factors to strengthen causal inference in observational settings. We performed a Mendelian randomization analysis to evaluate the causal relevance of six previously reported circulating adipokines (adiponectin, hepatocyte growth factor, interleukin-6, leptin receptor, plasminogen activator inhibitor-1, resistin) and C-reactive protein in risk of overall and oestrogen receptor-stratified breast cancer in up to 122,977 cases and 105,974 controls of European ancestry. Genetic instruments were constructed from single-nucleotide polymorphisms robustly (P < 5 x 10−8) associated with risk factors in genome-wide association studies. Colocalisation was performed as a sensitivity analysis to examine whether findings reflected shared causal variants or genomic confounding. In Mendelian randomization analyses, there was evidence for an association of hepatocyte growth factor with oestrogen receptor-negative cancer (OR per standard deviation increase: 1.17, 95% CI: 1.01–1.35; P = 0.035) but little evidence for associations of other adipokines or C-reactive protein with overall or oestrogen receptor-stratified breast cancer. Colocalisation analysis suggested that the association of hepatocyte growth factor with oestrogen receptor-negative breast cancer was unlikely to reflect a causal association. Collectively, these findings do not support an important aetiological role of various adipokines or C-reactive protein in overall or oestrogen receptor-specific breast cancer risk.