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A cross-sectional study was conducted among 29,662 hypertensive patients from primary care centers in Changsha County, China. Seven gene loci (ACE(I\/D), CYP2C9*3,AGTR1(1166\u00a0A\u2009&gt;\u2009C), CYP2D6*10,ADRB1(1165G\u2009&gt;\u2009C), CYP3A5*3, and NPPA(2238T\u2009&gt;\u2009C))were genotyped.Patients were stratified into sensitive or non-sensitive genotype groups. Logistic regression and interaction analysis were employed to assess gene-drug interactions on cardiovascular outcomes. The prevalence of stroke and CHD was 2.8% and 19.5%, respectively. Carriers of sensitive genotypes for AGTR1, CYP2D6*10, and ADRB1 taking sensitive drugs exhibited a significantly lower risk of stroke (ORs: 0.39, 0.67, 0.68; all\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.01). Similarly, sensitive genotype carriers for CYP2D6*10, CYP3A5*3, and NPPA taking sensitive drugs had a reduced risk of CHD (ORs: 0.92, 0.88, 0.53; all\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.05). A significant additive interaction was identified between AGTR1(1166\u00a0A\u2009&gt;\u2009C) and sensitive drug use on CHD risk (AP\u2009=\u20090.08). Pharmacogenomics-guided antihypertensive therapy is associated with a reduced risk of stroke and CHD in hypertensive patients. The interaction between AGTR1(1166\u00a0A\u2009&gt;\u2009C) genotype and drug use underscores the potential of personalized medicine in optimizing cardiovascular disease prevention strategies in primary care.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-48528-w","type":"journal-article","created":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T08:22:35Z","timestamp":1775982155000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Associations between antihypertensive drug-related gene polymorphisms and cardiovascular outcomes in hypertensive patients: a gene-drug interaction study"],"prefix":"10.1038","volume":"16","author":[{"given":"Zetong","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huixia","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengshi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyu","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ge","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,12]]},"reference":[{"issue":"10440","key":"48528_CR1","doi-asserted-by":"publisher","first-page":"2100","DOI":"10.1016\/S0140-6736(24)00367-2","volume":"403","author":"Global burden of","year":"2024","unstructured":"Global burden of. 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990\u20132021: a systematic analysis for the Global Burden of Disease Study 2021. 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