Jin Jing-Ji, Nakura Jun, Wu Zhihong, Yamamoto Miyuki, Abe Michiko, Chen Yusen, Tabara Yasuharu, Yamamoto Yoshikuni, Igase Michiya, Bo Xiao, Kohara Katsuhiko, Miki Tetsuro
Department of Geriatric Medicine, School of Medicine, Ehime University, Onsen-gun, Ehime, Japan.
Hypertens Res. 2003 Jul;26(7):547-52. doi: 10.1291/hypres.26.547.
The renin-angiotensin system plays an important role in blood pressure regulation by influencing salt-water homeostasis and vascular tone. Angiotensin II, the major biologically active component of this system, exerts its effect via two pharmacologically distinct subtypes of angiotensin II receptors, the angiotensin II type 1 receptor (AT1-R) and the angiotensin II type 2 receptor (AT2-R). Thus, the AT2-R gene may be involved in hypertension. Accordingly, our objective was to examine whether polymorphisms of the AT2-R gene are involved in hypertension. The entire AT2-R gene including the promoter region was screened to find polymorphisms. As a result, two novel single nucleotide polymorphisms (SNPs), A1818T in intron 2 and G4303A in exon 3, as well as two known SNPs, A1675G in intron 1 and C4599A in exon 3, were identified. These four SNPs had similar allele frequencies, and the A1675G and C4599A polymorphisms were in almost complete linkage disequilibrium. Because the AT2-R gene is located on the X chromosome, we analyzed the possible association between the C4599A polymorphism and hypertension in men and in women separately in two large Japanese populations. This analysis showed that the C4599A polymorphism was associated with hypertension in women (p=0.0058), but not in men. Moreover, this female-specific association was pronounced in premenopausal women. The female-specific association may be helpful in conducting further molecular and biological studies on the relationship among sex, the renin-angiotensin system, and hypertension.
肾素-血管紧张素系统通过影响水盐平衡和血管张力在血压调节中发挥重要作用。血管紧张素II是该系统的主要生物活性成分，它通过两种药理学上不同的血管紧张素II受体亚型发挥作用，即血管紧张素II 1型受体（AT1-R）和血管紧张素II 2型受体（AT2-R）。因此，AT2-R基因可能与高血压有关。相应地，我们的目的是研究AT2-R基因的多态性是否与高血压有关。对包括启动子区域在内的整个AT2-R基因进行筛选以寻找多态性。结果，鉴定出两个新的单核苷酸多态性（SNP），即内含子2中的A1818T和外显子3中的G4303A，以及两个已知的SNP，即内含子1中的A1675G和外显子3中的C4599A。这四个SNP具有相似的等位基因频率，并且A1675G和C4599A多态性几乎完全处于连锁不平衡状态。由于AT2-R基因位于X染色体上，我们在两个大型日本人群中分别分析了男性和女性中C4599A多态性与高血压之间的可能关联。该分析表明，C4599A多态性与女性高血压相关（p = 0.0058），但与男性无关。此外，这种女性特异性关联在绝经前女性中更为明显。这种女性特异性关联可能有助于对性别、肾素-血管紧张素系统和高血压之间的关系进行进一步的分子和生物学研究。
