{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T11:37:39Z","timestamp":1776685059612,"version":"3.51.2"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T00:00:00Z","timestamp":1748995200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"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":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Genetic variation in genes coding for enzymes metabolising antihypertensive drugs, may affect the efficacy of angiotensin converting enzyme (ACE) inhibitors such as enalapril, potentially leading to resistant hypertension (RHTN). We set out to evaluate the contribution of genetic variation in <jats:italic>CES1<\/jats:italic> and <jats:italic>NOS3<\/jats:italic> genes on susceptibility to RHTN, as well as estimate the frequencies of <jats:italic>CES1<\/jats:italic> copy number variation (CNV) in African and Mixed Ancestry (MA) populations of South Africa.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Using a retrospective age, sex and ethnicity matched case-control study design, 379 participants with hypertension belonging to the African and MA ethnic groups were recruited. Cases were participants with RHTN (i.e., blood pressure (BP) \u2265140\/90\u00a0mmHg on \u22653 antihypertensive drugs or BP &amp;lt; 140\/90\u00a0mmHg on &amp;gt;3 antihypertensive drugs, including a diuretic). Cases were matched to controls with similar characteristics (age (\u00b15\u00a0years), sex and ethnicity) in a 1:1 ratio. Controls were participants with hypertension that was under control (BP &amp;lt; 140\/90\u00a0mmHg on \u22643 antihypertensive drugs). Five polymorphisms in <jats:italic>CES1<\/jats:italic> and <jats:italic>NOS3<\/jats:italic> were characterized using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), quantitative PCR and validated using Sanger sequencing. The additive model of inheritance and multivariable logistic regression were used to determine associations between genotypes and RHTN while adjusting for potential confounding variables.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results and discussion<\/jats:title><jats:p><jats:italic>NOS3<\/jats:italic> rs3918188A\/A (aOR: 0.13; CI: 0.04\u20130.41; P = 0.0009) genotype and <jats:italic>NOS3<\/jats:italic> rs2070744\u2013rs1798883\u2013rs3918188G\u2013T\u2013A haplotype (OR: 0.54; CI: 0.37\u20130.78; P = 0.001) appeared to confer protection against RHTN among MA participants only. <jats:italic>CES1<\/jats:italic> rs2244613C&amp;gt;A and <jats:italic>CES1<\/jats:italic> CNV were not significantly associated with RHTN. However, there appeared to be quantitative differences in <jats:italic>CES1<\/jats:italic> CNV profiles across ethnic groups. We speculate that <jats:italic>NOS3<\/jats:italic> rs3918188A allele may affect <jats:italic>NOS3<\/jats:italic> gene expression, potentially leading to increased amounts of the vasodilator, nitric oxide (NO) and favourable outcomes in individuals taking antihypertensives drugs such as enalapril.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p><jats:italic>NOS3<\/jats:italic> genetic variation seems important in the susceptibility to RHTN among Africans and requires further studies.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fgene.2025.1608423","type":"journal-article","created":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T05:38:32Z","timestamp":1749015512000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["NOS3 rs3918188C&gt;A is associated with susceptibility to resistant hypertension while CES1 genetic variation was not associated with resistant hypertension among South Africans"],"prefix":"10.3389","volume":"16","author":[{"given":"Jonathan N.","family":"Katsukunya","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Revina","family":"Naicker","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nyarai D.","family":"Soko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dirk","family":"Blom","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Phumla","family":"Sinxadi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emile R.","family":"Chimusa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian","family":"Rayner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erika","family":"Jones","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Collet","family":"Dandara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1111\/j.1751-7176.2011.00556.x","article-title":"Refractory hypertension: definition, prevalence, and patient characteristics","volume":"14","author":"Acelajado","year":"2012","journal-title":"J. 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