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Genome Wide Association Study Identifies the HMGCS2 Locus to be Associated With Chlorthalidone Induced Glucose Increase in Hypertensive Patients
Background Thiazide and thiazide‐like diuretics are first‐line medications for treating uncomplicated hypertension. However, their use has been associated with adverse metabolic events, including hyperglycemia and incident diabetes mellitus, with incompletely understood mechanisms. Our goal was to i...
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| Published in: | Journal of the American Heart Association 2018-03, Vol.7 (6), p.n/a |
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| creator | Singh, Sonal McDonough, Caitrin W. Gong, Yan Alghamdi, Wael A. Arwood, Meghan J. Bargal, Salma A. Dumeny, Leanne Li, Wen‐Yi Mehanna, Mai Stockard, Bradley Yang, Guang Oliveira, Felipe A. Fredette, Natalie C. Shahin, Mohamed H. Bailey, Kent R. Beitelshees, Amber L. Boerwinkle, Eric Chapman, Arlene B. Gums, John G. Turner, Stephen T. Cooper‐DeHoff, Rhonda M. Johnson, Julie A. |
| description | Background
Thiazide and thiazide‐like diuretics are first‐line medications for treating uncomplicated hypertension. However, their use has been associated with adverse metabolic events, including hyperglycemia and incident diabetes mellitus, with incompletely understood mechanisms. Our goal was to identify genomic variants associated with thiazide‐like diuretic/chlorthalidone‐induced glucose change.
Methods and Results
Genome‐wide analysis of glucose change after treatment with chlorthalidone was performed by race among the white (n=175) and black (n=135) participants from the PEAR‐2 (Pharmacogenomic Evaluation of Antihypertensive Responses‐2). Single‐nucleotide polymorphisms with P |
| doi_str_mv | 10.1161/JAHA.117.007339 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_doaj_</sourceid><recordid>TN_cdi_doaj_primary_oai_doaj_org_article_0e153f59120e48da9c830be27b434af3</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><doaj_id>oai_doaj_org_article_0e153f59120e48da9c830be27b434af3</doaj_id><sourcerecordid>2012910897</sourcerecordid><originalsourceid>FETCH-LOGICAL-c5050-d90617da0695bef9c860c21b8107fd1a34a4d3f8ab0d4f7afd2ba54966d0f1193</originalsourceid><addsrcrecordid>eNqFUsFuEzEQXSEQrUrP3JCPXNKO7fV6fUGKIkiCgkAqiKPltceNq8262LtF-Qs-GYeU0p7wxW9m3rxnS6-qXlO4oLShlx_nq3lB8gJAcq6eVacMajlTqoXnj_BJdZ7zDZTTMMmFelmdMCUYF6w-rX4tcYg7JN-DQzLPOdpgxhAHcjVObk_WDocx-ICZjFskq0_LxRUjm2in0oik-7eDrmiMW7LY9jGNW9MHFwck68FNtsyW_WRjPtQ2oSkgDGS1v8U04pDDHZIvxbZ45VfVC2_6jOf391n17cP7r4vVbPN5uV7MNzMrQMDMKWiodAYaJTr0yrYNWEa7loL0jhpem9px35oOXO2l8Y51RtSqaRx4ShU_q9ZHXRfNjb5NYWfSXkcT9J9GTNfapDHYHjUgFdwLRRlg3TpTzDh0yGRXFxvPi9a7o9bt1O3Q2fKPZPonok8nQ9jq63inhQIp6roIvL0XSPHHhHnUu5At9r0ZME5ZM6BMUWiVLNTLI9WmmHNC_2BDQR9ioQ-xKEjqYyzKxpvHr3vg_w1BIYgj4Wfocf8_vUPNOTDgvwHgasRK</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2012910897</pqid></control><display><type>article</type><title>Genome Wide Association Study Identifies the HMGCS2 Locus to be Associated With Chlorthalidone Induced Glucose Increase in Hypertensive Patients</title><source>Wiley Open Access</source><source>PubMed Central</source><creator>Singh, Sonal ; McDonough, Caitrin W. ; Gong, Yan ; Alghamdi, Wael A. ; Arwood, Meghan J. ; Bargal, Salma A. ; Dumeny, Leanne ; Li, Wen‐Yi ; Mehanna, Mai ; Stockard, Bradley ; Yang, Guang ; Oliveira, Felipe A. ; Fredette, Natalie C. ; Shahin, Mohamed H. ; Bailey, Kent R. ; Beitelshees, Amber L. ; Boerwinkle, Eric ; Chapman, Arlene B. ; Gums, John G. ; Turner, Stephen T. ; Cooper‐DeHoff, Rhonda M. ; Johnson, Julie A.</creator><creatorcontrib>Singh, Sonal ; McDonough, Caitrin W. ; Gong, Yan ; Alghamdi, Wael A. ; Arwood, Meghan J. ; Bargal, Salma A. ; Dumeny, Leanne ; Li, Wen‐Yi ; Mehanna, Mai ; Stockard, Bradley ; Yang, Guang ; Oliveira, Felipe A. ; Fredette, Natalie C. ; Shahin, Mohamed H. ; Bailey, Kent R. ; Beitelshees, Amber L. ; Boerwinkle, Eric ; Chapman, Arlene B. ; Gums, John G. ; Turner, Stephen T. ; Cooper‐DeHoff, Rhonda M. ; Johnson, Julie A.</creatorcontrib><description>Background
Thiazide and thiazide‐like diuretics are first‐line medications for treating uncomplicated hypertension. However, their use has been associated with adverse metabolic events, including hyperglycemia and incident diabetes mellitus, with incompletely understood mechanisms. Our goal was to identify genomic variants associated with thiazide‐like diuretic/chlorthalidone‐induced glucose change.
Methods and Results
Genome‐wide analysis of glucose change after treatment with chlorthalidone was performed by race among the white (n=175) and black (n=135) participants from the PEAR‐2 (Pharmacogenomic Evaluation of Antihypertensive Responses‐2). Single‐nucleotide polymorphisms with P<5×10−8 were further prioritized using in silico analysis based on their expression quantitative trait loci function. Among blacks, an intronic single‐nucleotide polymorphism (rs9943291) in the HMGCS2 was associated with increase in glucose levels following chlorthalidone treatment (ß=12.5; P=4.17×10−8). G‐allele carriers of HMGCS2 had higher glucose levels (glucose change=+16.29 mg/dL) post chlorthalidone treatment compared with noncarriers of G allele (glucose change=+2.80 mg/dL). This association was successfully replicated in an independent replication cohort of hydrochlorothiazide‐treated participants from the PEAR study (ß=5.54; P=0.023). A meta‐analysis of the 2 studies was performed by race in Meta‐Analysis Helper, where this single‐nucleotide polymorphism, rs9943291, was genome‐wide significant with a meta‐analysis P value of 3.71×10−8. HMGCS2, a part of the HMG‐CoA synthase family, is important for ketogenesis and cholesterol synthesis pathways that are essential in glucose homeostasis.
Conclusions
These results suggest that HMGCS2 is a promising candidate gene involved in chlorthalidone and Hydrochlorothiazide (HCTZ)‐induced glucose change. This may provide insights into the mechanisms involved in thiazide‐induced hyperglycemia that may ultimately facilitate personalized approaches to antihypertensive selection for hypertension treatment.
Clinical Trial Registration
URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00246519 and NCT01203852.</description><identifier>ISSN: 2047-9980</identifier><identifier>EISSN: 2047-9980</identifier><identifier>DOI: 10.1161/JAHA.117.007339</identifier><identifier>PMID: 29523524</identifier><language>eng</language><publisher>England: John Wiley and Sons Inc</publisher><subject>Adult ; African Americans - genetics ; Antihypertensive Agents - adverse effects ; Biomarkers - blood ; Blood Glucose - drug effects ; Blood Glucose - metabolism ; Blood Pressure - drug effects ; chlorthalidone ; Chlorthalidone - adverse effects ; diabetes mellitus ; Essential Hypertension - drug therapy ; Essential Hypertension - ethnology ; Essential Hypertension - physiopathology ; European Continental Ancestry Group - genetics ; Female ; Genome-Wide Association Study ; glucose ; Humans ; hydrochlorothiazide ; Hydroxymethylglutaryl-CoA Synthase - genetics ; hyperglycemia ; Hyperglycemia - blood ; Hyperglycemia - chemically induced ; Hyperglycemia - ethnology ; Hyperglycemia - genetics ; Male ; Middle Aged ; Original Research ; Pharmacogenomic Variants ; pharmacogenomics ; Phenotype ; Polymorphism, Single Nucleotide ; Randomized Controlled Trials as Topic ; Risk Factors ; Sodium Chloride Symporter Inhibitors - adverse effects ; United States - epidemiology</subject><ispartof>Journal of the American Heart Association, 2018-03, Vol.7 (6), p.n/a</ispartof><rights>2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5050-d90617da0695bef9c860c21b8107fd1a34a4d3f8ab0d4f7afd2ba54966d0f1193</citedby><cites>FETCH-LOGICAL-c5050-d90617da0695bef9c860c21b8107fd1a34a4d3f8ab0d4f7afd2ba54966d0f1193</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5907544/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5907544/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,11562,27924,27925,46052,46476,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29523524$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Singh, Sonal</creatorcontrib><creatorcontrib>McDonough, Caitrin W.</creatorcontrib><creatorcontrib>Gong, Yan</creatorcontrib><creatorcontrib>Alghamdi, Wael A.</creatorcontrib><creatorcontrib>Arwood, Meghan J.</creatorcontrib><creatorcontrib>Bargal, Salma A.</creatorcontrib><creatorcontrib>Dumeny, Leanne</creatorcontrib><creatorcontrib>Li, Wen‐Yi</creatorcontrib><creatorcontrib>Mehanna, Mai</creatorcontrib><creatorcontrib>Stockard, Bradley</creatorcontrib><creatorcontrib>Yang, Guang</creatorcontrib><creatorcontrib>Oliveira, Felipe A.</creatorcontrib><creatorcontrib>Fredette, Natalie C.</creatorcontrib><creatorcontrib>Shahin, Mohamed H.</creatorcontrib><creatorcontrib>Bailey, Kent R.</creatorcontrib><creatorcontrib>Beitelshees, Amber L.</creatorcontrib><creatorcontrib>Boerwinkle, Eric</creatorcontrib><creatorcontrib>Chapman, Arlene B.</creatorcontrib><creatorcontrib>Gums, John G.</creatorcontrib><creatorcontrib>Turner, Stephen T.</creatorcontrib><creatorcontrib>Cooper‐DeHoff, Rhonda M.</creatorcontrib><creatorcontrib>Johnson, Julie A.</creatorcontrib><title>Genome Wide Association Study Identifies the HMGCS2 Locus to be Associated With Chlorthalidone Induced Glucose Increase in Hypertensive Patients</title><title>Journal of the American Heart Association</title><addtitle>J Am Heart Assoc</addtitle><description>Background
Thiazide and thiazide‐like diuretics are first‐line medications for treating uncomplicated hypertension. However, their use has been associated with adverse metabolic events, including hyperglycemia and incident diabetes mellitus, with incompletely understood mechanisms. Our goal was to identify genomic variants associated with thiazide‐like diuretic/chlorthalidone‐induced glucose change.
Methods and Results
Genome‐wide analysis of glucose change after treatment with chlorthalidone was performed by race among the white (n=175) and black (n=135) participants from the PEAR‐2 (Pharmacogenomic Evaluation of Antihypertensive Responses‐2). Single‐nucleotide polymorphisms with P<5×10−8 were further prioritized using in silico analysis based on their expression quantitative trait loci function. Among blacks, an intronic single‐nucleotide polymorphism (rs9943291) in the HMGCS2 was associated with increase in glucose levels following chlorthalidone treatment (ß=12.5; P=4.17×10−8). G‐allele carriers of HMGCS2 had higher glucose levels (glucose change=+16.29 mg/dL) post chlorthalidone treatment compared with noncarriers of G allele (glucose change=+2.80 mg/dL). This association was successfully replicated in an independent replication cohort of hydrochlorothiazide‐treated participants from the PEAR study (ß=5.54; P=0.023). A meta‐analysis of the 2 studies was performed by race in Meta‐Analysis Helper, where this single‐nucleotide polymorphism, rs9943291, was genome‐wide significant with a meta‐analysis P value of 3.71×10−8. HMGCS2, a part of the HMG‐CoA synthase family, is important for ketogenesis and cholesterol synthesis pathways that are essential in glucose homeostasis.
Conclusions
These results suggest that HMGCS2 is a promising candidate gene involved in chlorthalidone and Hydrochlorothiazide (HCTZ)‐induced glucose change. This may provide insights into the mechanisms involved in thiazide‐induced hyperglycemia that may ultimately facilitate personalized approaches to antihypertensive selection for hypertension treatment.
Clinical Trial Registration
URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00246519 and NCT01203852.</description><subject>Adult</subject><subject>African Americans - genetics</subject><subject>Antihypertensive Agents - adverse effects</subject><subject>Biomarkers - blood</subject><subject>Blood Glucose - drug effects</subject><subject>Blood Glucose - metabolism</subject><subject>Blood Pressure - drug effects</subject><subject>chlorthalidone</subject><subject>Chlorthalidone - adverse effects</subject><subject>diabetes mellitus</subject><subject>Essential Hypertension - drug therapy</subject><subject>Essential Hypertension - ethnology</subject><subject>Essential Hypertension - physiopathology</subject><subject>European Continental Ancestry Group - genetics</subject><subject>Female</subject><subject>Genome-Wide Association Study</subject><subject>glucose</subject><subject>Humans</subject><subject>hydrochlorothiazide</subject><subject>Hydroxymethylglutaryl-CoA Synthase - genetics</subject><subject>hyperglycemia</subject><subject>Hyperglycemia - blood</subject><subject>Hyperglycemia - chemically induced</subject><subject>Hyperglycemia - ethnology</subject><subject>Hyperglycemia - genetics</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Original Research</subject><subject>Pharmacogenomic Variants</subject><subject>pharmacogenomics</subject><subject>Phenotype</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Randomized Controlled Trials as Topic</subject><subject>Risk Factors</subject><subject>Sodium Chloride Symporter Inhibitors - adverse effects</subject><subject>United States - epidemiology</subject><issn>2047-9980</issn><issn>2047-9980</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>DOA</sourceid><recordid>eNqFUsFuEzEQXSEQrUrP3JCPXNKO7fV6fUGKIkiCgkAqiKPltceNq8262LtF-Qs-GYeU0p7wxW9m3rxnS6-qXlO4oLShlx_nq3lB8gJAcq6eVacMajlTqoXnj_BJdZ7zDZTTMMmFelmdMCUYF6w-rX4tcYg7JN-DQzLPOdpgxhAHcjVObk_WDocx-ICZjFskq0_LxRUjm2in0oik-7eDrmiMW7LY9jGNW9MHFwck68FNtsyW_WRjPtQ2oSkgDGS1v8U04pDDHZIvxbZ45VfVC2_6jOf391n17cP7r4vVbPN5uV7MNzMrQMDMKWiodAYaJTr0yrYNWEa7loL0jhpem9px35oOXO2l8Y51RtSqaRx4ShU_q9ZHXRfNjb5NYWfSXkcT9J9GTNfapDHYHjUgFdwLRRlg3TpTzDh0yGRXFxvPi9a7o9bt1O3Q2fKPZPonok8nQ9jq63inhQIp6roIvL0XSPHHhHnUu5At9r0ZME5ZM6BMUWiVLNTLI9WmmHNC_2BDQR9ioQ-xKEjqYyzKxpvHr3vg_w1BIYgj4Wfocf8_vUPNOTDgvwHgasRK</recordid><startdate>20180320</startdate><enddate>20180320</enddate><creator>Singh, Sonal</creator><creator>McDonough, Caitrin W.</creator><creator>Gong, Yan</creator><creator>Alghamdi, Wael A.</creator><creator>Arwood, Meghan J.</creator><creator>Bargal, Salma A.</creator><creator>Dumeny, Leanne</creator><creator>Li, Wen‐Yi</creator><creator>Mehanna, Mai</creator><creator>Stockard, Bradley</creator><creator>Yang, Guang</creator><creator>Oliveira, Felipe A.</creator><creator>Fredette, Natalie C.</creator><creator>Shahin, Mohamed H.</creator><creator>Bailey, Kent R.</creator><creator>Beitelshees, Amber L.</creator><creator>Boerwinkle, Eric</creator><creator>Chapman, Arlene B.</creator><creator>Gums, John G.</creator><creator>Turner, Stephen T.</creator><creator>Cooper‐DeHoff, Rhonda M.</creator><creator>Johnson, Julie A.</creator><general>John Wiley and Sons Inc</general><general>Wiley</general><scope>24P</scope><scope>WIN</scope><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><scope>DOA</scope></search><sort><creationdate>20180320</creationdate><title>Genome Wide Association Study Identifies the HMGCS2 Locus to be Associated With Chlorthalidone Induced Glucose Increase in Hypertensive Patients</title><author>Singh, Sonal ; McDonough, Caitrin W. ; Gong, Yan ; Alghamdi, Wael A. ; Arwood, Meghan J. ; Bargal, Salma A. ; Dumeny, Leanne ; Li, Wen‐Yi ; Mehanna, Mai ; Stockard, Bradley ; Yang, Guang ; Oliveira, Felipe A. ; Fredette, Natalie C. ; Shahin, Mohamed H. ; Bailey, Kent R. ; Beitelshees, Amber L. ; Boerwinkle, Eric ; Chapman, Arlene B. ; Gums, John G. ; Turner, Stephen T. ; Cooper‐DeHoff, Rhonda M. ; Johnson, Julie A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5050-d90617da0695bef9c860c21b8107fd1a34a4d3f8ab0d4f7afd2ba54966d0f1193</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adult</topic><topic>African Americans - genetics</topic><topic>Antihypertensive Agents - adverse effects</topic><topic>Biomarkers - blood</topic><topic>Blood Glucose - drug effects</topic><topic>Blood Glucose - metabolism</topic><topic>Blood Pressure - drug effects</topic><topic>chlorthalidone</topic><topic>Chlorthalidone - adverse effects</topic><topic>diabetes mellitus</topic><topic>Essential Hypertension - drug therapy</topic><topic>Essential Hypertension - ethnology</topic><topic>Essential Hypertension - physiopathology</topic><topic>European Continental Ancestry Group - genetics</topic><topic>Female</topic><topic>Genome-Wide Association Study</topic><topic>glucose</topic><topic>Humans</topic><topic>hydrochlorothiazide</topic><topic>Hydroxymethylglutaryl-CoA Synthase - genetics</topic><topic>hyperglycemia</topic><topic>Hyperglycemia - blood</topic><topic>Hyperglycemia - chemically induced</topic><topic>Hyperglycemia - ethnology</topic><topic>Hyperglycemia - genetics</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Original Research</topic><topic>Pharmacogenomic Variants</topic><topic>pharmacogenomics</topic><topic>Phenotype</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Randomized Controlled Trials as Topic</topic><topic>Risk Factors</topic><topic>Sodium Chloride Symporter Inhibitors - adverse effects</topic><topic>United States - epidemiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Singh, Sonal</creatorcontrib><creatorcontrib>McDonough, Caitrin W.</creatorcontrib><creatorcontrib>Gong, Yan</creatorcontrib><creatorcontrib>Alghamdi, Wael A.</creatorcontrib><creatorcontrib>Arwood, Meghan J.</creatorcontrib><creatorcontrib>Bargal, Salma A.</creatorcontrib><creatorcontrib>Dumeny, Leanne</creatorcontrib><creatorcontrib>Li, Wen‐Yi</creatorcontrib><creatorcontrib>Mehanna, Mai</creatorcontrib><creatorcontrib>Stockard, Bradley</creatorcontrib><creatorcontrib>Yang, Guang</creatorcontrib><creatorcontrib>Oliveira, Felipe A.</creatorcontrib><creatorcontrib>Fredette, Natalie C.</creatorcontrib><creatorcontrib>Shahin, Mohamed H.</creatorcontrib><creatorcontrib>Bailey, Kent R.</creatorcontrib><creatorcontrib>Beitelshees, Amber L.</creatorcontrib><creatorcontrib>Boerwinkle, Eric</creatorcontrib><creatorcontrib>Chapman, Arlene B.</creatorcontrib><creatorcontrib>Gums, John G.</creatorcontrib><creatorcontrib>Turner, Stephen T.</creatorcontrib><creatorcontrib>Cooper‐DeHoff, Rhonda M.</creatorcontrib><creatorcontrib>Johnson, Julie A.</creatorcontrib><collection>Wiley Open Access</collection><collection>Wiley Free Archive</collection><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><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Journal of the American Heart Association</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Singh, Sonal</au><au>McDonough, Caitrin W.</au><au>Gong, Yan</au><au>Alghamdi, Wael A.</au><au>Arwood, Meghan J.</au><au>Bargal, Salma A.</au><au>Dumeny, Leanne</au><au>Li, Wen‐Yi</au><au>Mehanna, Mai</au><au>Stockard, Bradley</au><au>Yang, Guang</au><au>Oliveira, Felipe A.</au><au>Fredette, Natalie C.</au><au>Shahin, Mohamed H.</au><au>Bailey, Kent R.</au><au>Beitelshees, Amber L.</au><au>Boerwinkle, Eric</au><au>Chapman, Arlene B.</au><au>Gums, John G.</au><au>Turner, Stephen T.</au><au>Cooper‐DeHoff, Rhonda M.</au><au>Johnson, Julie A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genome Wide Association Study Identifies the HMGCS2 Locus to be Associated With Chlorthalidone Induced Glucose Increase in Hypertensive Patients</atitle><jtitle>Journal of the American Heart Association</jtitle><addtitle>J Am Heart Assoc</addtitle><date>2018-03-20</date><risdate>2018</risdate><volume>7</volume><issue>6</issue><epage>n/a</epage><issn>2047-9980</issn><eissn>2047-9980</eissn><abstract>Background
Thiazide and thiazide‐like diuretics are first‐line medications for treating uncomplicated hypertension. However, their use has been associated with adverse metabolic events, including hyperglycemia and incident diabetes mellitus, with incompletely understood mechanisms. Our goal was to identify genomic variants associated with thiazide‐like diuretic/chlorthalidone‐induced glucose change.
Methods and Results
Genome‐wide analysis of glucose change after treatment with chlorthalidone was performed by race among the white (n=175) and black (n=135) participants from the PEAR‐2 (Pharmacogenomic Evaluation of Antihypertensive Responses‐2). Single‐nucleotide polymorphisms with P<5×10−8 were further prioritized using in silico analysis based on their expression quantitative trait loci function. Among blacks, an intronic single‐nucleotide polymorphism (rs9943291) in the HMGCS2 was associated with increase in glucose levels following chlorthalidone treatment (ß=12.5; P=4.17×10−8). G‐allele carriers of HMGCS2 had higher glucose levels (glucose change=+16.29 mg/dL) post chlorthalidone treatment compared with noncarriers of G allele (glucose change=+2.80 mg/dL). This association was successfully replicated in an independent replication cohort of hydrochlorothiazide‐treated participants from the PEAR study (ß=5.54; P=0.023). A meta‐analysis of the 2 studies was performed by race in Meta‐Analysis Helper, where this single‐nucleotide polymorphism, rs9943291, was genome‐wide significant with a meta‐analysis P value of 3.71×10−8. HMGCS2, a part of the HMG‐CoA synthase family, is important for ketogenesis and cholesterol synthesis pathways that are essential in glucose homeostasis.
Conclusions
These results suggest that HMGCS2 is a promising candidate gene involved in chlorthalidone and Hydrochlorothiazide (HCTZ)‐induced glucose change. This may provide insights into the mechanisms involved in thiazide‐induced hyperglycemia that may ultimately facilitate personalized approaches to antihypertensive selection for hypertension treatment.
Clinical Trial Registration
URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00246519 and NCT01203852.</abstract><cop>England</cop><pub>John Wiley and Sons Inc</pub><pmid>29523524</pmid><doi>10.1161/JAHA.117.007339</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 2047-9980 |
| ispartof | Journal of the American Heart Association, 2018-03, Vol.7 (6), p.n/a |
| issn | 2047-9980 2047-9980 |
| language | eng |
| recordid | cdi_doaj_primary_oai_doaj_org_article_0e153f59120e48da9c830be27b434af3 |
| source | Wiley Open Access; PubMed Central |
| subjects | Adult African Americans - genetics Antihypertensive Agents - adverse effects Biomarkers - blood Blood Glucose - drug effects Blood Glucose - metabolism Blood Pressure - drug effects chlorthalidone Chlorthalidone - adverse effects diabetes mellitus Essential Hypertension - drug therapy Essential Hypertension - ethnology Essential Hypertension - physiopathology European Continental Ancestry Group - genetics Female Genome-Wide Association Study glucose Humans hydrochlorothiazide Hydroxymethylglutaryl-CoA Synthase - genetics hyperglycemia Hyperglycemia - blood Hyperglycemia - chemically induced Hyperglycemia - ethnology Hyperglycemia - genetics Male Middle Aged Original Research Pharmacogenomic Variants pharmacogenomics Phenotype Polymorphism, Single Nucleotide Randomized Controlled Trials as Topic Risk Factors Sodium Chloride Symporter Inhibitors - adverse effects United States - epidemiology |
| title | Genome Wide Association Study Identifies the HMGCS2 Locus to be Associated With Chlorthalidone Induced Glucose Increase in Hypertensive Patients |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-07T14%3A54%3A37IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_doaj_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Genome%20Wide%20Association%20Study%20Identifies%20the%20HMGCS2%20Locus%20to%20be%20Associated%20With%20Chlorthalidone%20Induced%20Glucose%20Increase%20in%20Hypertensive%20Patients&rft.jtitle=Journal%20of%20the%20American%20Heart%20Association&rft.au=Singh,%20Sonal&rft.date=2018-03-20&rft.volume=7&rft.issue=6&rft.epage=n/a&rft.issn=2047-9980&rft.eissn=2047-9980&rft_id=info:doi/10.1161/JAHA.117.007339&rft_dat=%3Cproquest_doaj_%3E2012910897%3C/proquest_doaj_%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c5050-d90617da0695bef9c860c21b8107fd1a34a4d3f8ab0d4f7afd2ba54966d0f1193%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2012910897&rft_id=info:pmid/29523524&rfr_iscdi=true |