Mutation of ARHGAP9 in patients with coronary spastic angina

Mikito Takefuji, Hiroyuki Asano, Kazutaka Mori, Mutsuki Amano, Katsuhiro Kato, Takashi Watanabe, Yasuhiro Morita, Akira Katsumi, Toshiki Itoh, Tadaomi Takenawa, Akihiro Hirashiki, Hideo Izawa, Kozo Nagata, Haruo Hirayama, Fumimaro Takatsu, Tomoki Naoe, Mitsuhiro Yokota, Kozo Kaibuchi

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)42-49
Number of pages8
JournalJournal of Human Genetics
Volume55
Issue number1
DOIs
Publication statusPublished - 01-01-2010

Fingerprint

Muscle Spasticity
Spasm
Coronary Vessels
rho GTP-Binding Proteins
Mutation
Acetylcholine
Cell Movement
Single Nucleotide Polymorphism
Inborn Genetic Diseases
Genetic Association Studies
Amino Acid Substitution
Acute Coronary Syndrome
Cell Adhesion
Endothelium
Odds Ratio
Inflammation
Messenger RNA
Genes

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Takefuji, M., Asano, H., Mori, K., Amano, M., Kato, K., Watanabe, T., ... Kaibuchi, K. (2010). Mutation of ARHGAP9 in patients with coronary spastic angina. Journal of Human Genetics, 55(1), 42-49. https://doi.org/10.1038/jhg.2009.120
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. / Mutation of ARHGAP9 in patients with coronary spastic angina. In: Journal of Human Genetics. 2010 ; Vol. 55, No. 1. pp. 42-49.
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Takefuji, M, Asano, H, Mori, K, Amano, M, Kato, K, Watanabe, T, Morita, Y, Katsumi, A, Itoh, T, Takenawa, T, Hirashiki, A, Izawa, H, Nagata, K, Hirayama, H, Takatsu, F, Naoe, T, Yokota, M & Kaibuchi, K 2010, 'Mutation of ARHGAP9 in patients with coronary spastic angina', Journal of Human Genetics, vol. 55, no. 1, pp. 42-49. https://doi.org/10.1038/jhg.2009.120

Mutation of ARHGAP9 in patients with coronary spastic angina. / 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.

In: Journal of Human Genetics, Vol. 55, No. 1, 01.01.2010, p. 42-49.

Research output: Contribution to journalArticle

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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 - 2010/1/1

Y1 - 2010/1/1

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.

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Takefuji M, Asano H, Mori K, Amano M, Kato K, Watanabe T et al. Mutation of ARHGAP9 in patients with coronary spastic angina. Journal of Human Genetics. 2010 Jan 1;55(1):42-49. https://doi.org/10.1038/jhg.2009.120