Mutation of ARHGAP9 in patients with coronary spastic angina
Mutation of ARHGAP9 in patients with coronary spastic angina
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DOI：
10.1038/jhg.2009.120
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发表时间：
2010-01-01
影响因子：
3.5
通讯作者：
Kaibuchi, Kozo
中科院分区：
文献类型：
--
作者：
Takefuji, Mikito;Asano, Hiroyuki;Kaibuchi, Kozo
冠状动脉痉挛在变异型心绞痛等急性冠状动脉综合征的发病中起重要作用。在心血管疾病中已观察到Rho家族GTP酶的异常激活，但Rho家族GTP酶的遗传变异性在心血管疾病中的功能仍有待评估。我们研究了冠状动脉痉挛中Rho家族GTPases及其调节因子的遗传变异性。我们对103例乙酰胆碱诱导的冠状动脉痉挛的无关日本患者和102例无乙酰胆碱诱导的冠状动脉痉挛的对照日本受试者进行了Rho家族GTPases及其调节因子中67个氨基酸取代单核苷酸多态性的综合候选基因分析。我们注意到ARHGAP 9单核苷酸多态性（rs 11544238，Ala 370 Ser）与冠状动脉痉挛相关（优势比=2.67）。我们发现ARHGAP 9使Rac失活为RacGAP，并且在造血细胞中强烈检测到ARHGAP 9的mRNA水平。ARHGAP 9负调节细胞迁移。Ala 370 Ser多态性抵消了ARHGAP 9减少的细胞迁移，扩散和粘附。ARHGAP 9基因Ala 370 Ser多态性与冠状动脉痉挛相关这些数据表明，ARHGAP 9的多态性在造血细胞向内皮细胞的浸润和导致内皮功能障碍的炎症中具有关键功能。Journal of Human Genetics（2010）55，42-49; doi：10.1038/jhg.2009.120; 2009年11月13日在线发表
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. Journal of Human Genetics (2010) 55, 42-49; doi: 10.1038/jhg.2009.120; published online 13 November 2009