{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T12:25:17Z","timestamp":1774268717948,"version":"3.50.1"},"reference-count":56,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T00:00:00Z","timestamp":1752796800000},"content-version":"vor","delay-in-days":17,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T00:00:00Z","timestamp":1751328000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001322","name":"South African Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001322","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Africa bears the largest burden of morbidity and mortality from hypertension (HT) and related cardiovascular diseases. Thiazide diuretics, including hydrochlorothiazide (HCTZ), are the most prescribed hypertension medicines globally due to their cost effectiveness and minimal side effects. However, studies investigating the genetic variation in HCTZ\u2010related genes and their effect on drug response have been mainly conducted in European, American, and Asian populations. This study aimed to examine genetic variation in HCTZ response\u2010related genes among newly diagnosed hypertensives from Soweto, South Africa, irrespective of the treatment approach, and to assess its potential impact on medication response. Using targeted NGS on 364 newly diagnosed hypertensives with at least one follow\u2010up visit, we identified 1258 unique variants in 16 key HCTZ response genes. Among these, 89 were novel variants, of which 12 were protein\u2010altering, including 8 predicted to be deleterious. Association analyses with 882 independent variants revealed that carriers of the intronic variant rs1025450259 in\n                    <jats:italic>GNB3<\/jats:italic>\n                    had significantly greater reduction in BP compared to other patients on heterogeneous treatment strategies, but no significant associations were detected in the subset of individuals treated with HCTZ monotherapy only (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009103). For variants previously associated with HCTZ response, we did not replicate prior associations (e.g., rs2611316 in\n                    <jats:italic>ALDH1A2<\/jats:italic>\n                    ) but highlight important allele frequency differences across global populations. Despite the limitations, the study outcomes support the need for larger, controlled trials to assess genetic influences on HT treatment outcomes, advancing personalized medicine for African populations. This research further underscores the importance of pharmacogenetic studies in continental African populations.\n                  <\/jats:p>","DOI":"10.1111\/cts.70302","type":"journal-article","created":{"date-parts":[[2025,7,19]],"date-time":"2025-07-19T02:34:46Z","timestamp":1752892486000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic Variation in Hydrochlorothiazide Response\u2010Related Genes Among Hypertensive Individuals in Soweto, South Africa"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3877-2132","authenticated-orcid":false,"given":"Kudakwashe","family":"Nyamupangedengu","sequence":"first","affiliation":[{"name":"Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences University of the Witwatersrand  Johannesburg South Africa"},{"name":"Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences University of the Witwatersrand  Johannesburg South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5421-5512","authenticated-orcid":false,"given":"David","family":"Twesigomwe","sequence":"additional","affiliation":[{"name":"Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences University of the Witwatersrand  Johannesburg South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7045-1566","authenticated-orcid":false,"given":"Andrew","family":"May","sequence":"additional","affiliation":[{"name":"Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences University of the Witwatersrand  Johannesburg South Africa"},{"name":"Department of Biomolecular Sciences, School of Life Science, Pharmacy, and Chemistry Kingston University London  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4053-212X","authenticated-orcid":false,"given":"Collen","family":"Masimirembwa","sequence":"additional","affiliation":[{"name":"Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences University of the Witwatersrand  Johannesburg South Africa"},{"name":"African Institute of Biomedical Science &amp; Technology  Harare Zimbabwe"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neil","family":"Martinson","sequence":"additional","affiliation":[{"name":"Perinatal HIV Research Unit (PHRU) University of the Witwatersrand  Johannesburg South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8717-9039","authenticated-orcid":false,"given":"Ziyaad","family":"Waja","sequence":"additional","affiliation":[{"name":"Perinatal HIV Research Unit (PHRU) University of the Witwatersrand  Johannesburg South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matebogo","family":"Letutu","sequence":"additional","affiliation":[{"name":"Perinatal HIV Research Unit (PHRU) University of the Witwatersrand  Johannesburg South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4156-4801","authenticated-orcid":false,"given":"Mich\u00e8le","family":"Ramsay","sequence":"additional","affiliation":[{"name":"Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences University of the Witwatersrand  Johannesburg South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,7,18]]},"reference":[{"key":"e_1_2_10_2_1","unstructured":"WHO \u201cCardiovascular Diseases (CVDs) \u201d(2021)."},{"key":"e_1_2_10_3_1","volume-title":"Global Burden of Disease Study 2021 (GBD 2021)","author":"Global Burden of Disease Collaborative Network","year":"2024"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-020-01530-z"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gheart.2017.01.007"},{"issue":"3","key":"e_1_2_10_6_1","first-page":"156","article-title":"National Prevalence of Coronary Heart Disease and Stroke in South Africa From 1990\u20132017: A Systematic Review and Meta\u2010Analysis","volume":"32","author":"Abdelatif N.","year":"2021","journal-title":"Cardiovascular Journal of Africa"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.5830\/CVJA-2014-062"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.120.15026"},{"key":"e_1_2_10_9_1","volume-title":"Guideline for the Pharmacological Treatment of Hypertension in Adults","author":"WHO","year":"2021"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1097\/HJH.0000000000002403"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.107.704023"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1097\/MAJ.0000000000000308"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1901113"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sapharm.2019.05.002"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-021-03163-4"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.5830\/CVJA-2022-065"},{"key":"e_1_2_10_17_1","volume-title":"StatPearls","author":"Herman L. 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