{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T02:55:57Z","timestamp":1788836157996,"version":"build-2803163510"},"reference-count":50,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2023,5,25]],"date-time":"2023-05-25T00:00:00Z","timestamp":1684972800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:p>Resistant hypertension is defined as uncontrolled blood pressure (BP) despite the use of three or more antihypertensive drugs of different classes. Although genetic factors may greatly contribute to hypertension with resistance to multiple drug classes, more than for general hypertension, its pathogenesis remains unknown. To reveal the genetic background of resistant hypertension, we categorized 32,239 patients whose data were obtained from the BioBank Japan Project, by prescription of 7 classes of antihypertensive drugs and performed genome\u2010wide association studies (GWAS). Our GWAS identified four loci with significant association (<jats:italic>P<\/jats:italic>\u2009&lt;\u20095\u2009\u00d7\u200910<jats:sup>\u22128<\/jats:sup>): rs6445583 in <jats:italic>CACNA1D<\/jats:italic> and rs12308051 in the intergenic region on chromosome 12 for angiotensin II receptor blockers, rs35497065 in <jats:italic>FOXA3<\/jats:italic> for calcium channel blockers, and rs11066280 in <jats:italic>HECTD4<\/jats:italic> for \u03b1\u03b2\u2010blockers. Because these loci are known to be susceptibility loci for hypertension and\/or BP, our results indicate that resistant hypertension is caused by a combination of excessive BP and drug resistance to each antihypertensive pharmacological class. Furthermore, to investigate the genetic difference between BP traits and the treatment effectiveness of antihypertensive drugs, we performed gene\u2010set analysis and calculated the genetic correlation continuously. Most of the genetic factors were in common between BP traits and antihypertensive effectiveness, but it seems that the genetic architecture of the drug response to antihypertensive treatment is more complicated than BP traits. This corresponds to the well\u2010known mosaic theory of hypertension. Our findings reveal the complex pathogenesis of hypertension with resistance to multiple classes of antihypertensive drugs.<\/jats:p>","DOI":"10.1002\/cpt.2934","type":"journal-article","created":{"date-parts":[[2023,5,8]],"date-time":"2023-05-08T05:24:23Z","timestamp":1683523463000},"page":"393-403","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Genome\u2010wide Association Studies Categorized by Class of Antihypertensive Drugs Reveal Complex Pathogenesis of Hypertension with Drug Resistance"],"prefix":"10.1111","volume":"114","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8217-0799","authenticated-orcid":false,"given":"Keiko","family":"Yamazaki","sequence":"first","affiliation":[{"name":"Division of Genomic Epidemiology and Clinical Trials, Clinical Trials Research Center Nihon University School of Medicine  Tokyo Japan"},{"name":"Department of Public Health, Graduate School of Medicine Chiba University  Chiba Japan"},{"name":"Laboratory for Autoimmune Diseases RIKEN Center for Integrative Medical Sciences  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6452-4095","authenticated-orcid":false,"given":"Chikashi","family":"Terao","sequence":"additional","affiliation":[{"name":"Laboratory for Statistical Analysis RIKEN Center for Integrative Medical Sciences  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7099-8767","authenticated-orcid":false,"given":"Atsushi","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Laboratory for Statistical Analysis RIKEN Center for Integrative Medical Sciences  Yokohama Japan"},{"name":"Department of Genomic Medicine, Research Institute National Cerebral and Cardiovascular Center  Osaka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8748-5597","authenticated-orcid":false,"given":"Yoichiro","family":"Kamatani","sequence":"additional","affiliation":[{"name":"Laboratory for Statistical Analysis RIKEN Center for Integrative Medical Sciences  Yokohama Japan"},{"name":"Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences The University of Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7292-2686","authenticated-orcid":false,"given":"Koichi","family":"Matsuda","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences The University of Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Asai","sequence":"additional","affiliation":[{"name":"Division of Genomic Epidemiology and Clinical Trials, Clinical Trials Research Center Nihon University School of Medicine  Tokyo Japan"},{"name":"Division of Pharmacology Nihon University School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2543-7543","authenticated-orcid":false,"given":"Yasuo","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Division of Genomic Epidemiology and Clinical Trials, Clinical Trials Research Center Nihon University School of Medicine  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,5,25]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(15)00805-3"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2020.11.010"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41440-020-0508-z"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.119.314991"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11906-022-01173-w"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1161\/HYP.0000000000000084"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/ajh\/hpu151"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21134709"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0205-x"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cjca.2020.03.001"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2012.260"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/ajh\/hpz150"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41397-018-0049-x"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-98144-z"},{"key":"e_1_2_9_15_1","first-page":"696","article-title":"The BioBank Japan project","volume":"5","author":"Nakamura Y.","year":"2007","journal-title":"Clin. 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