Association of variants in NEDD4L with blood pressure response and adverse cardiovascular outcomes in hypertensive patients treated with thiazide diuretics

• Type of Material: Article
• Authors: Caitrin W. McDonough, University of Florida; Sarah E. Burbage, University of Florida; Julio D. Duarte, University of Illinois; Yan Gong, University of Florida; Taimour Y. Langaee, University of Florida; Stephen T. Turner, Mayo Clinic; John G. Gums, University of Florida; Arlene B Chapman, Emory University; Kent R. Bailey, Mayo Clinic; Amber L. Beitelshees, University of Maryland; Eric Boerwinkle, University of Texas Houston; Carl J. Pepine, University of Florida; Rhonda M. Cooper-DeHoff, University of Florida; Julie A. Johnson, University of Florida
• Language: English
• Date: 2013-04-01
• Publisher: Lippincott, Williams & Wilkins
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 Lippincott Williams & Wilkins, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1097/HJH.0b013e32835e2a71
• Title of Journal or Parent Work: Journal of Hypertension
• ISSN: 0263-6352
• Volume: 31
• Issue: 4
• Start Page: 698
• End Page: 704
• Grant/Funding Information: PEAR was also supported by funds from the Mayo Foundation.; The INVEST trial and Genetics substudy were supported by grants from BASF Pharma and Abbott Laboratories, and the University of Florida Opportunity Fund.; PEAR was supported by the National Institute of Health Pharmacogenetics Research Network grant U01-GM074492 and the National Center for Advancing Translational Sciences under the award number UL1 TR000064 (University of Florida); UL1 TR000454 (Emory University) and UL1 TR000135 (Mayo Clinic).; C.W.M. is supported by the UF Nephrology Training Grant T32 DK007518.; A.L.B. is supported by K23HL091120.
• Keywords: Peripheral Vascular Disease; Cardiovascular System & Cardiology; Life Sciences & Biomedicine; epithelial sodium channel; International Verapamil SR Trandolapril Study; GENETIC-VARIATION; Pharmacogenomic Evaluation of Antihypertensive Responses; COMMON; hypertension; Science & Technology; EPITHELIAL SODIUM-CHANNEL; pharmacogenetics; neural precursor cell expressed developmentally down-regulated 4 like; DISEASE
• Research Categories: Biology, Genetics; Health Sciences, Medicine and Surgery

Abstract

OBJECTIVE:: Single-nucleotide polymorphisms (SNPs) in NEDD4L may influence the ability of the NEDD4L protein to reduce epithelial sodium channel expression. A variant in NEDD4L, rs4149601, was associated with antihypertensive response and cardiovascular outcomes during treatment with thiazide diuretics and β-blockers in a Swedish population. We sought to further evaluate associations between NEDD4L polymorphisms, blood pressure response and cardiovascular outcomes with thiazide diuretics and β-blockers. METHODS:: Four SNPs, rs4149601, rs292449, rs1008899 and rs75982813, were genotyped in 767 patients from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) clinical trial and association was assessed with blood pressure response to hydrochlorothiazide and atenolol. One SNP, rs4149601, was also genotyped in 1345 patients from the International Verapmil SR Trandolapril Study (INVEST), and association was examined with adverse cardiovascular outcomes relative to hydrochlorothiazide treatment. RESULTS:: Significant associations or trends were found between rs4149601, rs292449, rs75982813 and rs1008899 and decreases in blood pressure in whites on hydrochlorothiazide, and a significant association was observed with increasing copies of the GC rs4149601-rs292449 haplotype and greater blood pressure response to hydrochlorothiazide in whites (P = 0.0006 and 0.006, SBP and DBP, respectively). Significant associations were also seen with rs4149601 and an increased risk for adverse cardiovascular outcomes in whites not treated with hydrochlorothiazide [P = 0.022, odds ratio (95% confidence interval) = 10.65 (1.18-96.25)]. CONCLUSION:: NEDD4L rs4149601, rs292449 and rs75982813 may be predictors for blood pressure response to hydrochlorothiazide in whites, and NEDD4L rs4149601 may be a predictor for adverse cardiovascular outcomes in whites not treated with hydrochlorothiazide.