NEXN is a novel susceptibility gene for coronary artery disease in Han Chinese

PLoS One. 2013 Dec 11;8(12):e82135. doi: 10.1371/journal.pone.0082135. eCollection 2013.

Abstract

Coronary artery disease (CAD) is the leading cause of death and disability in the world. Genome-wide association studies have implicated the importance of the genetic contribution of vascular smooth muscle cells (VSMCs) function in CAD susceptibility. The aberrant phenotypic modulation of VSMC is responsible for the pathological vascular intima hyperplasia that is the hallmark for atherosclerotic morphology. NEXN is a muscle-specific F-actin binding protein and is regulated by inflammatory cytokines in VSMCs. Whether NEXN contributes to human vascular disorders is still unknown. In this study, we genotyped 5 SNPs, tagging all of the 17 common SNPs within 54 kilobases (kb) covering NEXN gene and its flanking region, in 1883 patients with CAD and 1973 healthy individuals from Han Chinese, and identified one SNP, rs1780050, which was strongly associated with CAD trait. The Bonferroni corrected P-value was 7.65×10(-5). The odds ratio (95% confidence interval) was 1.23 (1.12-1.36) with statistical power of 0.994. Functional analysis showed that NEXN promotes VSMC to a contractile phenotype in vitro and inhibits balloon-injury induced neointima formation in vivo. Further eQTL analysis demonstrated that the risk allele T of rs1780050 is associated with decreased expression of NEXN, thus contributing to a higher risk of CAD susceptibility in the population. This is, to our knowledge, the first study to identify NEXN as a novel CAD susceptibility gene with both genetic and functional evidence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Angioplasty, Balloon
  • Animals
  • Asian People
  • China
  • Coronary Artery Disease / genetics*
  • Coronary Artery Disease / physiopathology
  • Ethnicity / genetics*
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Humans
  • Male
  • Microfilament Proteins / genetics*
  • Middle Aged
  • Muscle, Smooth, Vascular / metabolism
  • Muscle, Smooth, Vascular / pathology
  • Myocardial Contraction
  • Myocytes, Smooth Muscle / metabolism
  • Myocytes, Smooth Muscle / pathology
  • Neointima / pathology
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Reproducibility of Results
  • Risk Factors

Substances

  • Microfilament Proteins
  • NEXN protein, human

Grants and funding

This study was supported by grants from the National Natural Science Foundation of China (NSFC Grant No. 81170097) and the National Basic Research Program of the Chinese Ministry of Science and Technology (973 Grant No. 2013CB530700). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.