Use of antihypertensive drugs and breast cancer risk: a two-sample Mendelian randomization study

BackgroundObservational studies regarding the correlation between the use of antihypertensive medication and the risk of breast cancer (BC) reported inconsistent findings. We performed a two-sample Mendelian randomization using instrumental variables to proxy changes in gene expressions of antihypertensive medication targets to interrogate this. MethodsWe assessed the association between single-nucleotide polymorphisms (SNPs) and drug targetable gene expression with expression quantitative trait loci in blood. Further, we investigated association between the SNPs and BC risk with genome-wide association study summary statistics. We then confirmed the hits from Mendelian randomization with tissue-specific analyses along with additional sensitivity assessments (horizontal pleiotropy, colocalization, multiple tissue enrichment etc.). ResultsThe overall BC risk was decreased 16% with one standard deviation (SD) increase of SLC12A2 gene expression in blood (odds ratio, 0.86, 95% confidential interval, 0.78-0.94). This signal was further confirmed in estrogen receptor positive (ER+) BC (0.85, 0.78-0.94). In addition, one SD increase in expression of PDE1B in blood was associated with 7% increased risk of ER+ BC (1.07, 1.03-1.11). 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. We failed to observe any significant association between other targeted genes and BC risk. ConclusionsUse of antihypertensive medications that target SLC12A2 and PDE1B is associated with increased and decreased BC risk, respectively. FundingThis work was supported by the Swedish Research Council [2018-02400 to K.S., 2020-01175 to J.S., 2021-01187 to J.J.], Cancerfonden [2017 CAN2017/340 to J.J.], Crafoordska Stiftelsen [to J.J.], MAS Cancer [to J.J.], ALF funding from Region Sk[a]ne [to J.J. and K.S.]. The funding body was not involved in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.