Findings on the correlation between the use of antihypertensive medication and the risk of breast cancer (BC) have been inconsistent. We performed a two-sample Mendelian randomization (MR) using instrumental variables to proxy changes in gene expressions of antihypertensive medication targets to interrogate this. Genetic instruments for expression of antihypertensive drug target genes were identified with expression quantitative trait loci in blood, which should be associated with systolic blood pressure to proxy for the effect of antihypertensive drug. The association between genetic variants and BC risk were obtained from genome-wide association study summary statistics. The summary-based MR was employed to estimate the drug effects on BC risk. We further performed sensitivity analyses to confirm the discovered MR associations such as assessment of horizontal pleiotropy, colocalization, and multiple tissue enrichment analyses. The overall BC risk was only associated with SLC12A2 gene expression at a Bonferroni-corrected threshold. One standard deviation (SD) decrease of SLC12A2 gene expression in blood was associated with a decrease of 1.12 (95%CI, 0.80–1.58) mmHg of systolic blood pressure, but a 16% increased BC risk (odds ratio, 1.16, 95% confidential interval, 1.06–1.28). This signal was further observed for estrogen receptor positive (ER +) BC (1.17, 1.06–1.28). In addition, one SD decrease in expression of PDE1B in blood was associated with 7% decreased risk of ER + BC (0.93, 0.90–0.97). We detected no evidence of horizontal pleiotropy for these associations and the probability of the causal variants being shared between the gene expression and BC risk was 81.5, 40.5 and 66.8%, respectively. No significant association was observed between other target gene expressions and BC risk. Changes in expression of SLC12A2 and PDE1B mediated possibly via antihypertensive drugs may result in increased and decreased BC risk, respectively.

关于抗高血压药物的使用与乳腺癌 (BC) 风险之间的相关性的研究结果并不一致。我们使用工具变量来代理抗高血压药物靶点基因表达的变化，进行了两个样本孟德尔随机化（MR），以对此进行探究。抗高血压药物靶基因表达的遗传工具通过血液中的表达数量性状位点进行鉴定，该基因座应与收缩压相关以代表抗高血压药物的效果。遗传变异与 BC 风险之间的关联是从全基因组关联研究汇总统计中获得的。采用基于摘要的 MR 来估计药物对 BC 风险的影响。我们进一步进行了敏感性分析，以确认所发现的 MR 关联，例如水平多效性评估、共定位和多组织富集分析。总体 BC 风险仅与 Bonferroni 校正阈值下的SLC12A2基因表达相关。血液中SLC12A2基因表达的一个标准差 (SD) 降低与收缩压降低 1.12 (95%CI, 0.80–1.58) mmHg 相关，但 BC 风险增加 16%（比值比，1.16，95%）保密区间，1.06–1.28）。在雌激素受体阳性 (ER +) BC 中进一步观察到该信号 (1.17, 1.06–1.28)。此外，血液中PDE1B表达每降低 1 个 SD，ER + BC 风险就会降低 7%（0.93、0.90-0.97）。我们没有检测到这些关联存在水平多效性的证据，并且基因表达和 BC 风险之间共享因果变异的概率分别为 81.5%、40.5% 和 66.8%。 其他靶基因表达与 BC 风险之间没有观察到显着关联。可能通过抗高血压药物介导的SLC12A2和PDE1B表达变化可能分别导致 BC 风险增加和降低。