title: Mutation of ARHGAP9 in patients with coronary spastic angina.
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.
authors.affiliation: Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Showa-ku, Nagoya, Japan.
authors.forename: Mikito
authors.initials: M
authors.lastname: Takefuji
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Asano
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Mori
authors.forename: Mutsuki
authors.initials: M
authors.lastname: Amano
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Kato
authors.forename: Takashi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Morita
authors.forename: Akira
authors.initials: A
authors.lastname: Katsumi
authors.forename: Toshiki
authors.initials: T
authors.lastname: Itoh
authors.forename: Tadaomi
authors.initials: T
authors.lastname: Takenawa
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hirashiki
authors.forename: Hideo
authors.initials: H
authors.lastname: Izawa
authors.forename: Kozo
authors.initials: K
authors.lastname: Nagata
authors.forename: Haruo
authors.initials: H
authors.lastname: Hirayama
authors.forename: Fumimaro
authors.initials: F
authors.lastname: Takatsu
authors.forename: Tomoki
authors.initials: T
authors.lastname: Naoe
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yokota
authors.forename: Kozo
authors.initials: K
authors.lastname: Kaibuchi
mesh_terms: D000109:Acetylcholine / Q000008:administration & dosage; D000788:Angina Pectoris, Variant / Q000235:genetics / Q000503:physiopathology; D017023:Coronary Angiography; D003329:Coronary Vasospasm / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006367:HeLa Cells; D006801:Humans; D007564:Japan; D019169:Jurkat Cells; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide
chemical_list: C431580:ARHGAP9 protein, human; D020690:GTPase-Activating Proteins; D000109:Acetylcholine