Genetic Variants Influencing Plasma Renin Activity in Hypertensive Patients From the PEAR Study (Pharmacogenomic Evaluation of Antihypertensive Responses).

TitleGenetic Variants Influencing Plasma Renin Activity in Hypertensive Patients From the PEAR Study (Pharmacogenomic Evaluation of Antihypertensive Responses).
Publication TypeJournal Article
Year of Publication2018
AuthorsMcDonough, CW, Magvanjav, O, Sá, ACC, Rouby, NMEl, Dave, C, Deitchman, AN, Kawaguchi-Suzuki, M, Mei, W, Shen, Y, Singh, RShankar Pr, Solayman, M, Bailey, KR, Boerwinkle, E, Chapman, AB, Gums, JG, Webb, A, Scherer, SE, Sadee, W, Turner, ST, Cooper-Dehoff, RM, Gong, Y, Johnson, JA
JournalCirc Genom Precis Med
Date Published2018 04
KeywordsAdolescent, Adult, Aged, Antihypertensive Agents, Atenolol, Blood Pressure, Genome-Wide Association Study, Humans, Hydrochlorothiazide, Hypertension, Male, Middle Aged, Pharmacogenomic Variants, Polymorphism, Single Nucleotide, Prospective Studies, Renin, Treatment Outcome, United States, Young Adult

BACKGROUND: Plasma renin is an important regulator of blood pressure (BP). Plasma renin activity (PRA) has been shown to correlate with variability in BP response to antihypertensive agents. We conducted a genome-wide association study to identify single-nucleotide polymorphisms (SNPs) associated with baseline PRA using data from the PEAR study (Pharmacogenomic Evaluation of Antihypertensive Responses).

METHODS: Multiple linear regression analysis was performed in 461 whites and 297 blacks using an additive model, adjusting for age, sex, and ancestry-specific principal components. Top SNPs were prioritized by testing the expected direction of association for BP response to atenolol and hydrochlorothiazide. Top regions from the BP response prioritization were tested for functional evidence through differences in gene expression by genotype using RNA sequencing data. Regions with functional evidence were assessed for replication with baseline PRA in an independent study (PEAR-2).

RESULTS: Our top SNP rs3784921 was in the gene region. The G allele of rs3784921 was associated with higher baseline PRA (β=0.47; =2.09×10) and smaller systolic BP reduction in response to hydrochlorothiazide (β=2.97; 1-sided =0.006). In addition, expression differed by rs3784921 genotype (=0.007), and rs1802409, a proxy SNP for rs3784921 (=0.98-1.00), replicated in PEAR-2 (β=0.15; 1-sided =0.038). Additional SNPs associated with baseline PRA that passed BP response prioritization were in/near the genes and CONCLUSIONS: We identified multiple regions associated with baseline PRA that were prioritized through BP response signals to 2 mechanistically different antihypertensive drugs.

CLINICAL TRIAL REGISTRATION: URL: Unique identifier: NCT00246519.

Alternate JournalCirc Genom Precis Med
PubMed ID29650764
PubMed Central IDPMC5901893
Grant ListL30 HL115706 / HL / NHLBI NIH HHS / United States
UL1 TR000064 / TR / NCATS NIH HHS / United States
U01 GM074492 / GM / NIGMS NIH HHS / United States
T32 HL083810 / HL / NHLBI NIH HHS / United States
T32 DK104721 / DK / NIDDK NIH HHS / United States
UL1 TR001427 / TR / NCATS NIH HHS / United States
UL1 TR000135 / TR / NCATS NIH HHS / United States
UL1 TR000454 / TR / NCATS NIH HHS / United States
UL1 TR002378 / TR / NCATS NIH HHS / United States
KL2 TR001429 / TR / NCATS NIH HHS / United States

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