TY - JOUR
T1 - Mutation of ARHGAP9 in patients with coronary spastic angina
AU - Takefuji, Mikito
AU - Asano, Hiroyuki
AU - Mori, Kazutaka
AU - Amano, Mutsuki
AU - Kato, Katsuhiro
AU - Watanabe, Takashi
AU - Morita, Yasuhiro
AU - Katsumi, Akira
AU - Itoh, Toshiki
AU - Takenawa, Tadaomi
AU - Hirashiki, Akihiro
AU - Izawa, Hideo
AU - Nagata, Kozo
AU - Hirayama, Haruo
AU - Takatsu, Fumimaro
AU - Naoe, Tomoki
AU - Yokota, Mitsuhiro
AU - Kaibuchi, Kozo
PY - 2010/1
Y1 - 2010/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/76149096291
UR - https://www.scopus.com/pages/publications/76149096291#tab=citedBy
U2 - 10.1038/jhg.2009.120
DO - 10.1038/jhg.2009.120
M3 - Article
C2 - 19911011
AN - SCOPUS:76149096291
SN - 1434-5161
VL - 55
SP - 42
EP - 49
JO - Journal of Human Genetics
JF - Journal of Human Genetics
IS - 1
ER -