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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\n                    <jats:italic>SLC12A2<\/jats:italic>\n                    gene expression at a Bonferroni-corrected threshold. One standard deviation (SD) decrease of\n                    <jats:italic>SLC12A2<\/jats:italic>\n                    gene expression in blood was associated with a decrease of 1.12 (95%CI, 0.80\u20131.58) mmHg of systolic blood pressure, but a 16% increased BC risk (odds ratio, 1.16, 95% confidential interval, 1.06\u20131.28). This signal was further observed for estrogen receptor positive (ER\u2009+) BC (1.17, 1.06\u20131.28). In addition, one SD decrease in expression of\n                    <jats:italic>PDE1B<\/jats:italic>\n                    in blood was associated with 7% decreased risk of ER\u2009+\u2009BC (0.93, 0.90\u20130.97). 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\n                    <jats:italic>SLC12A2<\/jats:italic>\n                    and\n                    <jats:italic>PDE1B<\/jats:italic>\n                    mediated possibly via antihypertensive drugs may result in increased and decreased BC risk, respectively.\n                  <\/jats:p>","DOI":"10.1007\/s10654-024-01103-x","type":"journal-article","created":{"date-parts":[[2024,2,23]],"date-time":"2024-02-23T21:38:59Z","timestamp":1708724339000},"page":"535-548","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Antihypertensive drug targets and breast cancer risk: a two-sample Mendelian randomization study"],"prefix":"10.1007","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4337-9017","authenticated-orcid":false,"given":"Guoqiao","family":"Zheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subhayan","family":"Chattopadhyay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Sundquist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Sundquist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianguang","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,24]]},"reference":[{"issue":"10304","key":"1103_CR1","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1016\/S0140-6736(21)01330-1","volume":"398","author":"B Zhou","year":"2021","unstructured":"Zhou B, et al. 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