Abstract
Observational studies have reported inconsistent associations between circulating lipids and breast cancer risk. Using results from >400,000 participants in two-sample Mendelian randomization, we show that genetically raised LDL-cholesterol is associated with higher risk of breast cancer (odds ratio, OR, per standard deviation, 1.09, 95% confidence interval, 1.02–1.18, P = 0.020) and estrogen receptor (ER)-positive breast cancer (OR 1.14 [1.05–1.24] P = 0.004). Genetically raised HDL-cholesterol is associated with higher risk of ER-positive breast cancer (OR 1.13 [1.01–1.26] P = 0.037). HDL-cholesterol-raising variants in the gene encoding the target of CETP inhibitors are associated with higher risk of breast cancer (OR 1.07 [1.03–1.11] P = 0.001) and ER-positive breast cancer (OR 1.08 [1.03–1.13] P = 0.001). LDL-cholesterol-lowering variants mimicking PCSK9 inhibitors are associated (P = 0.014) with lower breast cancer risk. We find no effects related to the statin and ezetimibe target genes. The possible risk-promoting effects of raised LDL-cholesterol and CETP-mediated raised HDL-cholesterol have implications for breast cancer prevention and clinical trials.
Highlights
ResultsFollowing exclusion of pleiotropic variants in restrictive MR (Supplementary Table 4), raised LDL-cholesterol was associated with higher risk of any breast cancer (OR 1.12, 95% CI, 1.02–1.23, P = 0.017) and ER-positive breast cancer (OR 1.17, 95% CI, 1.05–1.29, P = 0.004) with consistent estimates across the Egger and median methods but evidence of remaining heterogeneity (Q′ P-values < 10−4)
Persons of European ancestry from 47 studies genotyped with different genome-wide association study arrays (n = 94,595) or on the Metabochip array (n = 93,982) with imputation to the 1000 Genomes Project reference were studied
Traits were adjusted for age, age-squared, sex and principle components, as well as quantile-normalized within each cohort
Summary
Following exclusion of pleiotropic variants in restrictive MR (Supplementary Table 4), raised LDL-cholesterol was associated with higher risk of any breast cancer (OR 1.12, 95% CI, 1.02–1.23, P = 0.017) and ER-positive breast cancer (OR 1.17, 95% CI, 1.05–1.29, P = 0.004) with consistent estimates across the Egger and median methods but evidence of remaining heterogeneity (Q′ P-values < 10−4). LDL-raising variants in PCSK9 were associated with increased risk of breast cancer (OR 1.10, 95% CI, 1.02–1.19, P = 0.014) but not with ER-positive (OR 1.08, 95% CI, 0.99–1.18, P = 0.099) or ERnegative breast cancer (OR 1.13, 95% CI, 0.98–1.30, P = 0.089) at the nominal significance level 185 Independent variants associated with plasma lipids (rs4332136 excluded, no proxies available) Genetic variants associated at P < 5×10–8
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