Genome-Wide and Gene-Based Meta-Analyses Identify Novel Loci Influencing Blood Pressure Response to Hydrochlorothiazide
This study aimed to identify novel loci influencing the antihypertensive response to hydrochlorothiazide monotherapy. A genome-wide meta-analysis of blood pressure (BP) response to hydrochlorothiazide was performed in 1739 white hypertensives from 6 clinical trials within the International Consortiu...
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| Veröffentlicht in: | Hypertension (Dallas, Tex. 1979) Tex. 1979), 2017-01, Vol.69 (1), p.51-59 |
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| creator | Salvi, Erika Wang, Zhiying Rizzi, Federica Gong, Yan McDonough, Caitrin W Padmanabhan, Sandosh Hiltunen, Timo P Lanzani, Chiara Zaninello, Roberta Chittani, Martina Bailey, Kent R Sarin, Antti-Pekka Barcella, Matteo Melander, Olle Chapman, Arlene B Manunta, Paolo Kontula, Kimmo K Glorioso, Nicola Cusi, Daniele Dominiczak, Anna F Johnson, Julie A Barlassina, Cristina Boerwinkle, Eric Cooper-DeHoff, Rhonda M Turner, Stephen T |
| description | This study aimed to identify novel loci influencing the antihypertensive response to hydrochlorothiazide monotherapy. A genome-wide meta-analysis of blood pressure (BP) response to hydrochlorothiazide was performed in 1739 white hypertensives from 6 clinical trials within the International Consortium for Antihypertensive Pharmacogenomics Studies, making it the largest study to date of its kind. No signals reached genome-wide significance (P |
| doi_str_mv | 10.1161/HYPERTENSIONAHA.116.08267 |
| format | Article |
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A genome-wide meta-analysis of blood pressure (BP) response to hydrochlorothiazide was performed in 1739 white hypertensives from 6 clinical trials within the International Consortium for Antihypertensive Pharmacogenomics Studies, making it the largest study to date of its kind. No signals reached genome-wide significance (P<5×10), and the suggestive regions (P<10) were cross-validated in 2 black cohorts treated with hydrochlorothiazide. In addition, a gene-based analysis was performed on candidate genes with previous evidence of involvement in diuretic response, in BP regulation, or in hypertension susceptibility. Using the genome-wide meta-analysis approach, with validation in blacks, we identified 2 suggestive regulatory regions linked to gap junction protein α1 gene (GJA1) and forkhead box A1 gene (FOXA1), relevant for cardiovascular and kidney function. With the gene-based approach, we identified hydroxy-delta-5-steroid dehydrogenase, 3 β- and steroid δ-isomerase 1 gene (HSD3B1) as significantly associated with BP response (P<2.28×10). HSD3B1 encodes the 3β-hydroxysteroid dehydrogenase enzyme and plays a crucial role in the biosynthesis of aldosterone and endogenous ouabain. By amassing all of the available pharmacogenomic studies of BP response to hydrochlorothiazide, and using 2 different analytic approaches, we identified 3 novel loci influencing BP response to hydrochlorothiazide. The gene-based analysis, never before applied to pharmacogenomics of antihypertensive drugs to our knowledge, provided a powerful strategy to identify a locus of interest, which was not identified in the genome-wide meta-analysis because of high allelic heterogeneity. These data pave the way for future investigations on new pathways and drug targets to enhance the current understanding of personalized antihypertensive treatment.</description><identifier>ISSN: 0194-911X</identifier><identifier>EISSN: 1524-4563</identifier><identifier>DOI: 10.1161/HYPERTENSIONAHA.116.08267</identifier><identifier>PMID: 27802415</identifier><language>eng</language><publisher>United States: American Heart Association, Inc</publisher><subject>Diuretics - pharmacology ; Genome-Wide Association Study - methods ; Humans ; Hydrochlorothiazide - pharmacology ; Hypertension - drug therapy ; Hypertension - genetics ; Hypertension - physiopathology</subject><ispartof>Hypertension (Dallas, Tex. 1979), 2017-01, Vol.69 (1), p.51-59</ispartof><rights>2017 American Heart Association, Inc</rights><rights>2016 American Heart Association, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5477-1973c01723c86983d9bd907ef1b8727c054cd177fa7d864cf9f3241402ccb3f03</citedby><cites>FETCH-LOGICAL-c5477-1973c01723c86983d9bd907ef1b8727c054cd177fa7d864cf9f3241402ccb3f03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,3686,27923,27924</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27802415$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Salvi, Erika</creatorcontrib><creatorcontrib>Wang, Zhiying</creatorcontrib><creatorcontrib>Rizzi, Federica</creatorcontrib><creatorcontrib>Gong, Yan</creatorcontrib><creatorcontrib>McDonough, Caitrin W</creatorcontrib><creatorcontrib>Padmanabhan, Sandosh</creatorcontrib><creatorcontrib>Hiltunen, Timo P</creatorcontrib><creatorcontrib>Lanzani, Chiara</creatorcontrib><creatorcontrib>Zaninello, Roberta</creatorcontrib><creatorcontrib>Chittani, Martina</creatorcontrib><creatorcontrib>Bailey, Kent R</creatorcontrib><creatorcontrib>Sarin, Antti-Pekka</creatorcontrib><creatorcontrib>Barcella, Matteo</creatorcontrib><creatorcontrib>Melander, Olle</creatorcontrib><creatorcontrib>Chapman, Arlene B</creatorcontrib><creatorcontrib>Manunta, Paolo</creatorcontrib><creatorcontrib>Kontula, Kimmo K</creatorcontrib><creatorcontrib>Glorioso, Nicola</creatorcontrib><creatorcontrib>Cusi, Daniele</creatorcontrib><creatorcontrib>Dominiczak, Anna F</creatorcontrib><creatorcontrib>Johnson, Julie A</creatorcontrib><creatorcontrib>Barlassina, Cristina</creatorcontrib><creatorcontrib>Boerwinkle, Eric</creatorcontrib><creatorcontrib>Cooper-DeHoff, Rhonda M</creatorcontrib><creatorcontrib>Turner, Stephen T</creatorcontrib><title>Genome-Wide and Gene-Based Meta-Analyses Identify Novel Loci Influencing Blood Pressure Response to Hydrochlorothiazide</title><title>Hypertension (Dallas, Tex. 1979)</title><addtitle>Hypertension</addtitle><description>This study aimed to identify novel loci influencing the antihypertensive response to hydrochlorothiazide monotherapy. A genome-wide meta-analysis of blood pressure (BP) response to hydrochlorothiazide was performed in 1739 white hypertensives from 6 clinical trials within the International Consortium for Antihypertensive Pharmacogenomics Studies, making it the largest study to date of its kind. No signals reached genome-wide significance (P<5×10), and the suggestive regions (P<10) were cross-validated in 2 black cohorts treated with hydrochlorothiazide. In addition, a gene-based analysis was performed on candidate genes with previous evidence of involvement in diuretic response, in BP regulation, or in hypertension susceptibility. Using the genome-wide meta-analysis approach, with validation in blacks, we identified 2 suggestive regulatory regions linked to gap junction protein α1 gene (GJA1) and forkhead box A1 gene (FOXA1), relevant for cardiovascular and kidney function. With the gene-based approach, we identified hydroxy-delta-5-steroid dehydrogenase, 3 β- and steroid δ-isomerase 1 gene (HSD3B1) as significantly associated with BP response (P<2.28×10). HSD3B1 encodes the 3β-hydroxysteroid dehydrogenase enzyme and plays a crucial role in the biosynthesis of aldosterone and endogenous ouabain. By amassing all of the available pharmacogenomic studies of BP response to hydrochlorothiazide, and using 2 different analytic approaches, we identified 3 novel loci influencing BP response to hydrochlorothiazide. The gene-based analysis, never before applied to pharmacogenomics of antihypertensive drugs to our knowledge, provided a powerful strategy to identify a locus of interest, which was not identified in the genome-wide meta-analysis because of high allelic heterogeneity. These data pave the way for future investigations on new pathways and drug targets to enhance the current understanding of personalized antihypertensive treatment.</description><subject>Diuretics - pharmacology</subject><subject>Genome-Wide Association Study - methods</subject><subject>Humans</subject><subject>Hydrochlorothiazide - pharmacology</subject><subject>Hypertension - drug therapy</subject><subject>Hypertension - genetics</subject><subject>Hypertension - physiopathology</subject><issn>0194-911X</issn><issn>1524-4563</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNUU1vEzEQtRCIhsJfQObGZYu9a693DyClVWgihbTqh4CT5dizXYNjp_Zuo_Dr2TSlAk49jWbmzXvz9BB6R8kRpSX9MP1-Prm4miwuZ2eL8XS8Gx6RKi_FMzSiPGcZ42XxHI0IrVlWU_rtAL1K6QchlDEmXqKDXFQkZ5SP0OYUfFhB9tUawMobPPSQHasEBn-BTmVjr9w2QcIzA76zzRYvwh04PA_a4plvXA9eW3-Dj10IBp9HSKmPgC8grYNPgLuAp1sTg25diKFrrfo1aL1GLxrlErx5qIfo-vPk6mSazc9OZyfjeaY5EyKjtSg0oSIvdFXWVWHqpamJgIYuK5ELTTjThgrRKGGqkummborBGCO51suiIcUh-rTnXffLFRg9eIjKyXW0KxW3Migr_91428qbcCc5ZVzk1UDw_oEghtseUidXNmlwTnkIfZK0Kjgvcl6WA7TeQ3UMKUVoHmUokbvg5H_B7YbyPrjh9u3ffz5e_klqAHzcAzbBdRDTT9dvIMoWlOvaJwj8BiyhrBU</recordid><startdate>201701</startdate><enddate>201701</enddate><creator>Salvi, Erika</creator><creator>Wang, Zhiying</creator><creator>Rizzi, Federica</creator><creator>Gong, Yan</creator><creator>McDonough, Caitrin W</creator><creator>Padmanabhan, Sandosh</creator><creator>Hiltunen, Timo P</creator><creator>Lanzani, Chiara</creator><creator>Zaninello, Roberta</creator><creator>Chittani, Martina</creator><creator>Bailey, Kent R</creator><creator>Sarin, Antti-Pekka</creator><creator>Barcella, Matteo</creator><creator>Melander, Olle</creator><creator>Chapman, Arlene B</creator><creator>Manunta, Paolo</creator><creator>Kontula, Kimmo K</creator><creator>Glorioso, Nicola</creator><creator>Cusi, Daniele</creator><creator>Dominiczak, Anna F</creator><creator>Johnson, Julie A</creator><creator>Barlassina, Cristina</creator><creator>Boerwinkle, Eric</creator><creator>Cooper-DeHoff, Rhonda M</creator><creator>Turner, Stephen T</creator><general>American Heart Association, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201701</creationdate><title>Genome-Wide and Gene-Based Meta-Analyses Identify Novel Loci Influencing Blood Pressure Response to Hydrochlorothiazide</title><author>Salvi, Erika ; Wang, Zhiying ; Rizzi, Federica ; Gong, Yan ; McDonough, Caitrin W ; Padmanabhan, Sandosh ; Hiltunen, Timo P ; Lanzani, Chiara ; Zaninello, Roberta ; Chittani, Martina ; Bailey, Kent R ; Sarin, Antti-Pekka ; Barcella, Matteo ; Melander, Olle ; Chapman, Arlene B ; Manunta, Paolo ; Kontula, Kimmo K ; Glorioso, Nicola ; Cusi, Daniele ; Dominiczak, Anna F ; Johnson, Julie A ; Barlassina, Cristina ; Boerwinkle, Eric ; Cooper-DeHoff, Rhonda M ; Turner, Stephen T</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5477-1973c01723c86983d9bd907ef1b8727c054cd177fa7d864cf9f3241402ccb3f03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Diuretics - pharmacology</topic><topic>Genome-Wide Association Study - methods</topic><topic>Humans</topic><topic>Hydrochlorothiazide - pharmacology</topic><topic>Hypertension - drug therapy</topic><topic>Hypertension - genetics</topic><topic>Hypertension - physiopathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Salvi, Erika</creatorcontrib><creatorcontrib>Wang, Zhiying</creatorcontrib><creatorcontrib>Rizzi, Federica</creatorcontrib><creatorcontrib>Gong, Yan</creatorcontrib><creatorcontrib>McDonough, Caitrin W</creatorcontrib><creatorcontrib>Padmanabhan, Sandosh</creatorcontrib><creatorcontrib>Hiltunen, Timo P</creatorcontrib><creatorcontrib>Lanzani, Chiara</creatorcontrib><creatorcontrib>Zaninello, Roberta</creatorcontrib><creatorcontrib>Chittani, Martina</creatorcontrib><creatorcontrib>Bailey, Kent R</creatorcontrib><creatorcontrib>Sarin, Antti-Pekka</creatorcontrib><creatorcontrib>Barcella, Matteo</creatorcontrib><creatorcontrib>Melander, Olle</creatorcontrib><creatorcontrib>Chapman, Arlene B</creatorcontrib><creatorcontrib>Manunta, Paolo</creatorcontrib><creatorcontrib>Kontula, Kimmo K</creatorcontrib><creatorcontrib>Glorioso, Nicola</creatorcontrib><creatorcontrib>Cusi, Daniele</creatorcontrib><creatorcontrib>Dominiczak, Anna F</creatorcontrib><creatorcontrib>Johnson, Julie A</creatorcontrib><creatorcontrib>Barlassina, Cristina</creatorcontrib><creatorcontrib>Boerwinkle, Eric</creatorcontrib><creatorcontrib>Cooper-DeHoff, Rhonda M</creatorcontrib><creatorcontrib>Turner, Stephen T</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Hypertension (Dallas, Tex. 1979)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Salvi, Erika</au><au>Wang, Zhiying</au><au>Rizzi, Federica</au><au>Gong, Yan</au><au>McDonough, Caitrin W</au><au>Padmanabhan, Sandosh</au><au>Hiltunen, Timo P</au><au>Lanzani, Chiara</au><au>Zaninello, Roberta</au><au>Chittani, Martina</au><au>Bailey, Kent R</au><au>Sarin, Antti-Pekka</au><au>Barcella, Matteo</au><au>Melander, Olle</au><au>Chapman, Arlene B</au><au>Manunta, Paolo</au><au>Kontula, Kimmo K</au><au>Glorioso, Nicola</au><au>Cusi, Daniele</au><au>Dominiczak, Anna F</au><au>Johnson, Julie A</au><au>Barlassina, Cristina</au><au>Boerwinkle, Eric</au><au>Cooper-DeHoff, Rhonda M</au><au>Turner, Stephen T</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genome-Wide and Gene-Based Meta-Analyses Identify Novel Loci Influencing Blood Pressure Response to Hydrochlorothiazide</atitle><jtitle>Hypertension (Dallas, Tex. 1979)</jtitle><addtitle>Hypertension</addtitle><date>2017-01</date><risdate>2017</risdate><volume>69</volume><issue>1</issue><spage>51</spage><epage>59</epage><pages>51-59</pages><issn>0194-911X</issn><eissn>1524-4563</eissn><abstract>This study aimed to identify novel loci influencing the antihypertensive response to hydrochlorothiazide monotherapy. 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With the gene-based approach, we identified hydroxy-delta-5-steroid dehydrogenase, 3 β- and steroid δ-isomerase 1 gene (HSD3B1) as significantly associated with BP response (P<2.28×10). HSD3B1 encodes the 3β-hydroxysteroid dehydrogenase enzyme and plays a crucial role in the biosynthesis of aldosterone and endogenous ouabain. By amassing all of the available pharmacogenomic studies of BP response to hydrochlorothiazide, and using 2 different analytic approaches, we identified 3 novel loci influencing BP response to hydrochlorothiazide. The gene-based analysis, never before applied to pharmacogenomics of antihypertensive drugs to our knowledge, provided a powerful strategy to identify a locus of interest, which was not identified in the genome-wide meta-analysis because of high allelic heterogeneity. These data pave the way for future investigations on new pathways and drug targets to enhance the current understanding of personalized antihypertensive treatment.</abstract><cop>United States</cop><pub>American Heart Association, Inc</pub><pmid>27802415</pmid><doi>10.1161/HYPERTENSIONAHA.116.08267</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Diuretics - pharmacology Genome-Wide Association Study - methods Humans Hydrochlorothiazide - pharmacology Hypertension - drug therapy Hypertension - genetics Hypertension - physiopathology |
| title | Genome-Wide and Gene-Based Meta-Analyses Identify Novel Loci Influencing Blood Pressure Response to Hydrochlorothiazide |
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