Genetic variance in nitric oxide synthase and endothelin genes among children with and without endothelial dysfunction

J Transl Med. 2013 Sep 25;11:227. doi: 10.1186/1479-5876-11-227.

Abstract

Background: The presence of endothelial dysfunction (ED) constitutes an early risk factor for cardiovascular disease (CVD) in children. Nitric oxide (NO) and endothelin (EDN) are generated in endothelial cells and are critical regulators of vascular function, with ED resulting from an imbalance between these two molecules. We hypothesized that genetic variants in NO synthase and EDN isoforms and its receptors (EDNRA and EDNRB) may account for a proportion of the risk for ED in developing children.

Methods: Consecutive children (ages 5-10 years) were prospectively recruited from the community. Time to peak post-occlusive reperfusion (Tmax) was considered as the indicator of either normal endothelial function (NEF; Tmax < 45 sec) or ED (Tmax ≥ 45 sec). Lipid profiles, high sensitivity C-reactive protein (hsCRP), fasting glucose and insulin were assayed using ELISA. Genomic DNA from peripheral blood was extracted and genotyped for NOS1 (209 SNPs), NOS2 (122 SNPs), NOS3 (50 SNPs), EDN1 (43 SNPs), EDN2 (48 SNPs), EDN3 (14 SNPs), EDNRA (27 SNPs), and EDNRB (23 SNPs) using a custom SNPs array. Linkage disequilibrium was analyzed using Haploview version 4.2 software.

Results: The relative frequencies of SNPs were evaluated in 122 children, 84 with NEF and 38 with ED. The frequencies of NOS1 (11 SNPs), and EDN1 (2 SNPs) were differentially distributed between NEF vs. ED, and no significant differences emerged for all other genes. Significant SNPs for NOS1 and EDN1 SNPs were further validated with RT-PCR.

Conclusions: Genetic variants in the NOS1 and EDN1 genes appear to account for important components of the variance in endothelial function, particularly when concurrent risk factors such as obesity exist. Thus, analysis of genotype-phenotype interactions in children at risk for ED will be critical for more accurate formulation of categorical CVD risk estimates.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Child
  • Child, Preschool
  • Cohort Studies
  • Demography
  • Endothelins / genetics*
  • Endothelium, Vascular / metabolism*
  • Endothelium, Vascular / physiopathology*
  • Female
  • Gene Expression Regulation
  • Gene Frequency / genetics
  • Genetic Association Studies
  • Haplotypes / genetics
  • Humans
  • Linkage Disequilibrium / genetics
  • Male
  • Nitric Oxide Synthase / genetics*
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics*
  • Reproducibility of Results
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Endothelins
  • Nitric Oxide Synthase