title: Transethnic meta-analysis suggests genetic variation in the HEME pathway influences potassium response in patients treated with hydrochlorothiazide.
abstract: Hypokalemia is a recognized adverse effect of thiazide diuretic treatment. This phenomenon, which may impair insulin secretion, has been suggested to be a reason for the adverse effects on glucose metabolism associated with thiazide diuretic treatment of hypertension. However, the mechanisms underlying thiazide diuretic-induced hypokalemia are not well understood. In an effort to identify genes or genomic regions associated with potassium response to hydrochlorothiazide, without a priori knowledge of biologic effects, we performed a genome-wide association study and a multiethnic meta-analysis in 718 European- and African-American hypertensive participants from two different pharmacogenetic studies. Single-nucleotide polymorphisms rs10845697 (Bayes factor=5.560) on chromosome 12, near to the HEME binding protein 1 gene, and rs11135740 (Bayes factor=5.258) on chromosome 8, near to the Mitoferrin-1 gene, reached genome-wide association study significance (Bayes factor >5). These results, if replicated, suggest a novel mechanism involving effects of genes in the HEME pathway influencing hydrochlorothiazide-induced renal potassium loss.
authors.affiliation: Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Del-Aguila
authors.affiliation: Department of Pharmacotherapy and Translational Research and Division of Cardiovascular Medicine and Center for Pharmacogenomics, University of Florida, Gainesville, FL, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Cooper-DeHoff
authors.affiliation: Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: A B
authors.initials: AB
authors.lastname: Chapman
authors.affiliation: Department of Pharmacotherapy and Translational Research and Division of Cardiovascular Medicine and Center for Pharmacogenomics, University of Florida, Gainesville, FL, USA.
authors.forename: J G
authors.initials: JG
authors.lastname: Gums
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Beitelshees
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.
authors.forename: K
authors.initials: K
authors.lastname: Bailey
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.
authors.forename: S T
authors.initials: ST
authors.lastname: Turner
authors.affiliation: Department of Pharmacotherapy and Translational Research and Division of Cardiovascular Medicine and Center for Pharmacogenomics, University of Florida, Gainesville, FL, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Johnson
authors.affiliation: 1] Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, TX, USA [2] Human Genome Sequencing Center at Baylor College of Medicine, Houston, TX, USA.
authors.forename: E
authors.initials: E
authors.lastname: Boerwinkle
mesh_terms: D001741:Black or African American / Q000235:genetics; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001499:Bayes Theorem; D002352:Carrier Proteins / Q000235:genetics*; D027682:Cation Transport Proteins / Q000235:genetics; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods; D006418:Heme / Q000235:genetics*; D000081062:Heme-Binding Proteins; D006420:Hemeproteins / Q000235:genetics*; D006801:Humans; D006852:Hydrochlorothiazide / Q000378:metabolism / Q000627:therapeutic use*; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D007008:Hypokalemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011188:Potassium / Q000378:metabolism*; D044465:White People / Q000235:genetics
chemical_list: D000959:Antihypertensive Agents; D002352:Carrier Proteins; D027682:Cation Transport Proteins; C000631029:HEBP1 protein, human; D000081062:Heme-Binding Proteins; D006420:Hemeproteins; D024101:Mitochondrial Proteins; C561492:Slc25a37 protein, human; D006852:Hydrochlorothiazide; D006418:Heme; D011188:Potassium