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Mutation of ARHGAP9 in patients with coronary spastic angina

Mikito Takefuji1, Hiroyuki Asano, Kazutaka Mori

  • 1Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Showa-ku, Nagoya, Japan.

Journal of Human Genetics
|November 14, 2009
PubMed

Insights

Genetic variations in ARHGAP9 are linked to coronary artery spasm. A specific ARHGAP9 polymorphism (Ala370Ser) may influence hematopoietic cell infiltration, contributing to endothelial dysfunction and cardiovascular disorders.

Area of Science:

  • Cardiovascular Genetics
  • Molecular Biology
  • Immunology

Background:

  • Coronary artery spasm is a key factor in variant angina and acute coronary syndromes.
  • Rho-family GTPases are implicated in cardiovascular disorders, but their genetic variability's role is understudied.
  • Understanding genetic factors in coronary artery spasm is crucial for disease etiology.

Purpose of the Study:

  • To investigate the association between genetic variability in Rho-family GTPases and their regulators with coronary artery spasm.
  • To identify specific genetic polymorphisms contributing to the development of coronary artery spasm.

Main Methods:

  • A candidate gene analysis was performed on 67 single nucleotide polymorphisms (SNPs) in Rho-family GTPases and regulators.
  • The study included 103 Japanese patients with acetylcholine-induced coronary artery spasm and 102 controls.
  • Functional assays examined the role of ARHGAP9 and its polymorphism in cell migration and adhesion.

Main Results:

  • A significant association was found between the ARHGAP9 (rs11544238, Ala370Ser) polymorphism and coronary artery spasm (odds ratio = 2.67).
  • ARHGAP9 functions as a Rac GTPase-activating protein (RacGAP), negatively regulating cell migration.
  • The Ala370Ser polymorphism reversed the inhibitory effects of ARHGAP9 on cell migration, spreading, and adhesion.

Conclusions:

  • The Ala370Ser polymorphism in the ARHGAP9 gene is associated with coronary artery spasm.
  • ARHGAP9 genetic variations may play a critical role in hematopoietic cell infiltration into the endothelium.
  • This infiltration and subsequent inflammation contribute to endothelial dysfunction and the pathogenesis of coronary artery spasm.

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