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

McDonough, Caitrin W.a; Burbage, Sarah E.a; Duarte, Julio D.b; Gong, Yana; Langaee, Taimour Y.a; Turner, Stephen T.c; Gums, John G.d; Chapman, Arlene B.e; Bailey, Kent R.f; Beitelshees, Amber L.g; Boerwinkle, Erich; Pepine, Carl J.i; Cooper-DeHoff, Rhonda M.a,i; Johnson, Julie A.a,i

doi: 10.1097/HJH.0b013e32835e2a71
ORIGINAL PAPERS: Genetic aspects

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.

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aDepartment of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, University of Florida, College of Pharmacy, Gainesville, Florida

bDepartment of Pharmacy Practice, University of Illinois at Chicago, Chicago, Illinois

cDivision of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota

dDepartment of Community Health and Family Medicine, University of Florida, College of Medicine, Gainesville, Florida

eThe Renal Division, Department of Medicine, Emory University, Atlanta, Georgia

fDivision of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota

gDivision of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland, Baltimore, Maryland

hHuman Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas

iDivision of Cardiovascular Medicine, Department of Medicine, University of Florida, Gainesville, Florida, USA

Correspondence to Julie A. Johnson, Pharm.D, Department of Pharmacotherapy and Translational Research, University of Florida, 1600 SW Archer Rd - Room PG-22, Box 100486, Gainesville, FL, 32610-0486, USA. Tel: +1 352 273 6007; fax: +1 352 273 6485; e-mail:

Abbreviations: PEAR, Pharmacogenomic Evaluation of Antihypertensive Responses; INVEST, International Verapamil SR Trandolapril Study; MI, myocardial infarction; ENaC, Epithelial sodium channel; NEDD4L, Neural precursor cell expressed developmentally down-regulated 4 like; NORDIL, Nordic Diltiazem Study; BP, blood pressure; HCTZ, hydrochlorothiazide; CCB, calcium channel blocker; INVEST-GENES, INVEST Genetic Substudy; HWE, Hardy–Weinberg Equilibrium; OR, odds ratio; CI, confidence Interval

Received 11 September, 2012

Revised 1 November, 2012

Accepted 20 December, 2012

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© 2013 Lippincott Williams & Wilkins, Inc.