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Author Notes:

Corresponding Author: E Boerwinkle; Human Genetics Center, University of Texas Health Science Center at Houston, 6901 Bertner, Houston, TX 77030, USA. Email: eric.boarwinkle@uth.tmc.edu

We acknowledge and thank the valuable contributions of the study participants, study physicians, support staff and the technical assistance: Zhiying Wang, Megan Grove, Jodie Van De Rostyne, Jeremy Palbicki, Robert Tarrell and Prabin Thapa.

The authors declare no conflict of interest.


Research Funding:

The GERA study was supported by NIH grants HL74735, HL53335, and the Mayo Foundation.

The PEAR study was supported by a grant from the National Institutes of Health (Bethesda, MD, USA), grant U01 GM074492, funded as part of the Pharmacogenetics Research Network.

This work was also supported by the following grants from the NIH National Center for Research Resources: grant M01 RR00082 and UL1 RR029890 to the University of Florida, grants UL1 RR025008 and M01 RR00039 to Emory University, and UL1 RR024150 to Mayo Clinic.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Genetics & Heredity
  • Pharmacology & Pharmacy
  • pharmacogenomics
  • NELL1
  • hydrochlorothiazide
  • hyperglycemia
  • hypertriglyceridemia
  • GENE
  • RISK

Genome-wide association analyses suggest NELL1 influences adverse metabolic response to HCTZ in African Americans


Journal Title:

Pharmacogenomics Journal


Volume 14, Number 1


, Pages 35-40

Type of Work:

Article | Final Publisher PDF


Hydrochlorothiazide (HCTZ) is one of the most widely prescribed antihypertensive medications. Although it is well known that HCTZ is associated with hyperglycemia and hypertriglyceridemia, the mechanisms underlying these adverse effects are not well understood. We performed a genome-wide association study and meta-analysis of the change in fasting plasma glucose and triglycerides in response to HCTZ from two different clinical trials: the Pharmacogenomic Evaluation of Antihypertensive Responses and the Genetic Epidemiology of Responses to Antihypertensive studies. Two single-nucleotide polymorphisms (rs12279250 and rs4319515 (r 2 =0.73)), located at 11p15.1 in the NELL1 gene, achieved genome-wide significance for association with change in fasting plasma triglycerides in African Americans, whereby each variant allele was associated with a 28 mg dl -1 increase in the change in triglycerides. NELL1 encodes a cytoplasmic protein that contains epidermal growth factor-like repeats and has been shown to represses adipogenic differentiation. These findings may represent a novel mechanism underlying HCTZ-induced adverse metabolic effects.

Copyright information:

© 2014 Macmillan Publishers Limited

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported License (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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