Mutation of ARHGAP9 in patients with coronary spastic angina

• Published in: Journal of human genetics Vol. 55; no. 1; pp. 42 - 49
• Main Authors: Takefuji, Mikito, Asano, Hiroyuki, Mori, Kazutaka, Amano, Mutsuki, Kato, Katsuhiro, Watanabe, Takashi, Morita, Yasuhiro, Katsumi, Akira, Itoh, Toshiki, Takenawa, Tadaomi, Hirashiki, Akihiro, Izawa, Hideo, Nagata, Kozo, Hirayama, Haruo, Takatsu, Fumimaro, Naoe, Tomoki, Yokota, Mitsuhiro, Kaibuchi, Kozo
• Format: Journal Article
• Language: English
• Published: England 01.01.2010
• Subjects: Acetylcholine - administration & dosage; Angina Pectoris, Variant - genetics; Angina Pectoris, Variant - physiopathology; Coronary Angiography; Coronary Vasospasm - chemically induced; Coronary Vasospasm - genetics; Coronary Vasospasm - physiopathology; Female; Genetic Predisposition to Disease; GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - metabolism; HeLa Cells; Humans; Japan; Jurkat Cells; Male; Mutation; Polymorphism, Single Nucleotide; Japan
• ISSN: 1434-5161; 1435-232X
• DOI: 10.1038/jhg.2009.120

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.