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

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

Abstract

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.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adipogenesis / genetics
  • African Americans / genetics*
  • Antihypertensive Agents / administration & dosage
  • Antihypertensive Agents / adverse effects*
  • Antihypertensive Agents / therapeutic use
  • Blood Glucose / analysis
  • Calcium-Binding Proteins
  • Genome-Wide Association Study
  • Humans
  • Hydrochlorothiazide / administration & dosage
  • Hydrochlorothiazide / adverse effects*
  • Hydrochlorothiazide / therapeutic use
  • Hypertension / drug therapy*
  • Hypertension / genetics
  • Hypertension / metabolism
  • Lipid Metabolism / genetics*
  • Nerve Tissue Proteins / genetics*
  • Triglycerides / blood

Substances

  • Antihypertensive Agents
  • Blood Glucose
  • Calcium-Binding Proteins
  • NELL1 protein, human
  • Nerve Tissue Proteins
  • Triglycerides
  • Hydrochlorothiazide