Abstract
Circulating adipokines and C‐reactive protein (CRP) 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 randomisation (MR) uses genetic variants as proxies for risk factors to strengthen causal inference in observational settings. We performed a MR analysis to evaluate the causal relevance of six previously reported circulating adipokines [adiponectin, hepatocyte growth factor (HGF), interleukin‐6, leptin receptor, plasminogen activator inhibitor‐1 and resistin] and CRP 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 × 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 MR analyses, there was evidence for an association of HGF with oestrogen receptor‐negative cancer (odds ratio per standard deviation increase: 1.17, 95% confidence interval: 1.01–1.35; p = 0.035) but little evidence for associations of other adipokines or CRP with overall or oestrogen receptor‐stratified breast cancer. Colocalisation analysis suggested that the association of HGF 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 CRP in overall or oestrogen receptor‐specific breast cancer risk.
Highlights
Elevated body mass index is an important modifiable risk factor for breast cancer.[1]
In ER status-stratified analyses, there was evidence for an association of leptin receptor and resistin (HGF) with ER− breast cancer risk [odds ratio (OR) per standard deviation (SD) increase: 1.17, 95% confidence interval (CI): 1.01–1.35; p = 0.035]
Regional Manhattan plots examining the association of all singlenucleotide polymorphisms (SNPs) Æ100 kb from the SNP used to instrument HGF for their association with this adipokine (Fig. 1) and with ER − breast cancer (Fig. 2) did not appear to support the presence of one or more independent causal variants for SNP-ER − breast cancer analyses
Summary
Prediagnostic C-reactive protein (CRP), a systemic marker of inflammation that is synthesised in part by adipose tissue,[11] has been associated with breast cancer risk in prospective observational studies.[12] Collectively, these observational findings suggest that pharmacological targeting of adipokines or CRP could be an effective strategy for breast cancer prevention among overweight or obese women. The causal nature of these risk factors in breast cancer risk, and their suitability as intervention targets, is unclear This is because of the uncertain relevance of in vitro studies to humans, and the susceptibility of conventional observational analyses to residual confounding and reverse causation, all of which undermines causal inference.[13,14]. Adipokines and C-reactive protein have been linked to breast cancer risk in observational studies While these molecular mediators potentially connect excess adiposity with breast cancer, whether the associations are causal in nature is uncertain. Given uncertainty surrounding the role of various previously reported adipokines and CRP in breast cancer aetiology, we performed two-sample MR analyses to evaluate the causal relevance of circulating adiponectin, HGF, IL-6, leptin receptor, PAI-1, resistin and CRP in overall and oestrogen receptor-stratified breast cancer risk
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