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Pharmacogenomics J. 2014 Feb;14(1):35-40. doi: 10.1038/tpj.2013.3. Epub 2013 Feb 12.

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

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Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, USA.
Division of Endocrinology, Diabetes and Nutrition, University of Maryland, Baltimore, MD, USA.
Department of Pharmacotherapy and Translational Research and Division of Cardiovascular Medicine, Colleges of Pharmacy and Medicine, University of Florida, Gainesville, FL, USA.
Renal Division, Emory University School of Medicine, Atlanta, GA, USA.
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.
1] Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, USA [2] Human Genome Sequencing Center at Baylor College of Medicine, Houston, TX, USA.


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.

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