Mutation of ARHGAP9 in patients with coronary spastic angina

J Hum Genet. 2010 Jan;55(1):42-9. doi: 10.1038/jhg.2009.120. Epub 2009 Nov 13.

Abstract

Coronary artery spasm has an important function in the etiology of variant angina and other acute coronary syndromes. Abnormal activation of Rho-family GTPases has been observed in cardiovascular disorders, but the function of genetic variability in Rho-family GTPases remains to be evaluated in cardiovascular disorders. We examined the genetic variability of Rho-family GTPases and their regulators in coronary artery spasm. We performed a comprehensive candidate gene analysis of 67 single nucleotide polymorphisms with amino-acid substitution in Rho-family GTPases and their regulators in 103 unrelated Japanese patients with acetylcholine-induced coronary artery spasm and 102 control Japanese subjects without acetylcholine-induced coronary artery spasm. We noted an association of the single nucleotide polymorphism of ARHGAP9 (rs11544238, Ala370Ser) with coronary artery spasm (odds ratio =2.67). We found that ARHGAP9 inactivated Rac as RacGAP and that the mRNA level of ARHGAP9 was strongly detected in hematopoietic cells. ARHGAP9 negatively regulated cell migration. The Ala370Ser polymorphism counteracted ARHGAP9-reduced cell migration, spreading and adhesion. The Ala370Ser polymorphism in the ARHGAP9 gene is associated with coronary artery spasm. These data suggest that the polymorphism of ARHGAP9 has a critical function in the infiltration of hematopoietic cells into the endothelium and inflammation leading to endothelial dysfunction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / administration & dosage
  • Angina Pectoris, Variant / genetics
  • Angina Pectoris, Variant / physiopathology
  • Coronary Angiography
  • Coronary Vasospasm / chemically induced
  • Coronary Vasospasm / genetics*
  • Coronary Vasospasm / physiopathology
  • Female
  • GTPase-Activating Proteins / genetics*
  • GTPase-Activating Proteins / metabolism
  • Genetic Predisposition to Disease*
  • HeLa Cells
  • Humans
  • Japan
  • Jurkat Cells
  • Male
  • Mutation*
  • Polymorphism, Single Nucleotide

Substances

  • ARHGAP9 protein, human
  • GTPase-Activating Proteins
  • Acetylcholine