Transethnic meta-analysis suggests genetic variation in the HEME pathway influences potassium response in patients treated with hydrochlorothiazide.

TitleTransethnic meta-analysis suggests genetic variation in the HEME pathway influences potassium response in patients treated with hydrochlorothiazide.
Publication TypeJournal Article
Year of Publication2015
AuthorsDel-Aguila, JL, Cooper-Dehoff, RM, Chapman, AB, Gums, JG, Beitelshees, AL, Bailey, K, Turner, ST, Johnson, JA, Boerwinkle, E
JournalPharmacogenomics J
Volume15
Issue2
Pagination153-7
Date Published2015 Apr
ISSN1473-1150
KeywordsAfrican Americans, Antihypertensive Agents, Bayes Theorem, Carrier Proteins, Cation Transport Proteins, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 8, European Continental Ancestry Group, Female, Genome-Wide Association Study, Heme, Hemeproteins, Humans, Hydrochlorothiazide, Hypertension, Hypokalemia, Male, Middle Aged, Mitochondrial Proteins, Polymorphism, Single Nucleotide, Potassium
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.

DOI10.1038/tpj.2014.46
Alternate JournalPharmacogenomics J.
PubMed ID25201287
PubMed Central IDPMC4362777
Grant ListM01 RR00039 / RR / NCRR NIH HHS / United States
HL53335 / HL / NHLBI NIH HHS / United States
M01 RR000082 / RR / NCRR NIH HHS / United States
UL1 RR029890 / RR / NCRR NIH HHS / United States
U01 GM074492 / GM / NIGMS NIH HHS / United States
M01 RR000039 / RR / NCRR NIH HHS / United States
HL74735 / HL / NHLBI NIH HHS / United States
UL1 TR001427 / TR / NCATS NIH HHS / United States
UL1 TR000454 / TR / NCATS NIH HHS / United States
R01 HL074735 / HL / NHLBI NIH HHS / United States
UL1 RR024150 / RR / NCRR NIH HHS / United States
M01 RR00082 / RR / NCRR NIH HHS / United States
UL1 RR025008 / RR / NCRR NIH HHS / United States