Genetic and Functional Evidence Supports LPAR1 as a Susceptibility Gene for Hypertension
Genetic and Functional Evidence Supports LPAR1 as a Susceptibility Gene for Hypertension
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DOI：
10.1161/hypertensionaha.115.05515
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发表时间：
2015-09
期刊：
影响因子：
8.3
通讯作者：
Ke Xu;Lu Ma;Yang Li-;F. Wang;Gu-Yan Zheng;Zhijun Sun;Feng Jiang;Yundai Chen;Huirong Liu;Aimin Dang;Xi Chen;J. Chun;Xiao-Li Tian
中科院分区：
文献类型：
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作者：
Ke Xu;Lu Ma;Yang Li-;F. Wang;Gu-Yan Zheng;Zhijun Sun;Feng Jiang;Yundai Chen;Huirong Liu;Aimin Dang;Xi Chen;J. Chun;Xiao-Li Tian
原发性高血压是一种受遗传和环境因素影响的复杂疾病，是心血管疾病的主要危险因素。血清溶血磷脂酸与大鼠血压升高相关，溶血磷脂酸与6种受体亚型相互作用。在这项研究中，我们通过对溶血磷脂酸受体LPAR1、LPAR2、LPAR3、LPAR4、LPAR5和LPAR6及其侧边序列编码基因的28个单核苷酸多态性进行基因分型，评估了溶血磷脂酸受体与原发性高血压的遗传关联。研究对象包括3个汉族队列，共2630名患者和3171名对照。我们在LPAR1的3 '侧基因组区域发现了一个与高血压相关的单核苷酸多态性rs531003 （Bonferroni校正P= 1.09×10-5，优势比[95%置信区间]=1.23[1.13-1.33]）。rs531003的风险等位基因C与LPAR1表达增加和高血压易感性相关，特别是在睡眠不足的人群中（P= 4.73×10-5，优势比[95%置信区间]=1.75[1.34-2.28]）。我们进一步证明，在lpar1缺陷小鼠中，睡眠剥夺引起的血压升高和苯肾上腺素诱导的血管收缩都减少了。总之，我们表明LPAR1是人类原发性高血压的一种新的易感基因，并且应激，如睡眠不足，增加了具有危险等位基因的患者对原发性高血压的易感性。
Essential hypertension is a complex disease affected by genetic and environmental factors and serves as a major risk factor for cardiovascular diseases. Serum lysophosphatidic acid correlates with an elevated blood pressure in rats, and lysophosphatidic acid interacts with 6 subtypes of receptors. In this study, we assessed the genetic association of lysophosphatidic acid receptors with essential hypertension by genotyping 28 single-nucleotide polymorphisms from genes encoding for lysophosphatidic acid receptors, LPAR1, LPAR2, LPAR3, LPAR4, LPAR5, and LPAR6 and their flanking sequences, in 3 Han Chinese cohorts consisting of 2630 patients and 3171 controls in total. We identified a single-nucleotide polymorphism, rs531003 in the 3′-flanking genomic region of LPAR1, associated with hypertension (the Bonferroni corrected P=1.09×10–5, odds ratio [95% confidence interval]=1.23 [1.13–1.33]). The risk allele C of rs531003 is associated with the increased expression of LPAR1 and the susceptibility of hypertension, particularly in those with a shortage of sleep (P=4.73×10–5, odds ratio [95% confidence interval]=1.75 [1.34–2.28]). We further demonstrated that blood pressure elevation caused by sleep deprivation and phenylephrine-induced vasoconstriction was both diminished in LPAR1-deficient mice. Together, we show that LPAR1 is a novel susceptibility gene for human essential hypertension and that stress, such as shortage of sleep, increases the susceptibility of patients with risk allele to essential hypertension.