Epidemiologic and Genetic Associations of Erythropoietin With Blood Pressure, Hypertension, and Coronary Artery Disease.
Epidemiologic and Genetic Associations of Erythropoietin With Blood Pressure, Hypertension, and Coronary Artery Disease.
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DOI：
10.1161/hypertensionaha.121.17597
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发表时间：
2021-11
期刊：
影响因子：
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通讯作者：
Ganesh SK
中科院分区：
文献类型：
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作者：
Sun P;Kumar N;Tin A;Zhao J;Brown MR;Lin Z;Yang ML;Zheng Q;Jia J;Bielak LF;Yu B;Boerwinkle E;Hunker KL;Coresh J;Chen YE;Huo Y;Kardia SLR;Khoriaty R;Zhou X;Morrison AC;Zhang Y;Ganesh SK
虽然外源性施用重组促红细胞生成素 (EPO) 与高血压、冠状动脉疾病 (CAD) 和死亡率增加的风险相关，但内源性循环 EPO 水平是否与 CAD 及其危险因素相关尚不清楚。我们测量并分析了来自中国 (N=4,329) 和美国 (N=3,671) 两个人群队列中循环血浆 EPO 水平的流行病学和遗传关联。进行了 EPO 暴露的体外平滑肌细胞反应和体内小鼠研究。 EPO 水平与血压特征呈正相关且线性相关，与胆固醇水平和红细胞指数呈负相关。 EPO水平较高与高血压（OR=1.20，95%CI：1.12-1.29，P=4.41×10−7）和CAD（OR=1.16，95%CI：1.00-1.34，P=0.046）患病率较高相关。在EPO水平的发现阶段遗传关联研究中，我们鉴定了先前报道的6号染色体上的一个位点（靠近HBS1L-MYB的rs7776054，P=4.86×10−25）和4号染色体上的一个新位点（靠近PDGFRA-KIT的rs172629，P=2.1×10−8），该位点是独立复制的。对发现和复制遗传关联结果的荟萃分析确定了 22 号染色体上的一个位点（TMPRSS6 附近的 rs855791，P=3.60×10−9）。在血细胞比容的生理范围内施用EPO可诱导体内高血压并增加体外血管平滑肌细胞的收缩。总之，内源性循环 EPO 水平受常见遗传变异的影响，并且与血压特征、高血压和 CAD 相关。体外和体内证明的 EPO 的血管作用支持了新发现的高血压和心血管风险机制，对临床红细胞生成支持具有潜在影响。
While exogenous administration of recombinant erythropoietin (EPO) has been associated with increased risk of hypertension, coronary artery disease (CAD), and mortality, it is not known if endogenous circulating EPO level is associated with CAD and its risk factors. We measured and analyzed epidemiologic and genetic associations of circulating plasma EPO levels in two population cohorts, from China (N=4,329) and the United States (N=3,671). In vitro smooth muscle cell responses and in vivo murine studies of EPO exposure were performed. EPO levels were positively and linearly associated with blood pressure traits, and inversely associated with cholesterol levels and red cell indices. Higher EPO level was associated with higher prevalence of hypertension (OR=1.20, 95%CI:1.12–1.29, P=4.41×10−7) and CAD (OR=1.16, 95%CI:1.00–1.34, P=0.046). In a discovery stage genetic association study of EPO level, we identified a previously reported locus on chromosome 6 (rs7776054 near HBS1L-MYB, P=4.86×10−25) and a new locus on chromosome 4 (rs172629 near PDGFRA-KIT, P=2.1×10−8) which was independently replicated. Meta-analysis of discovery and replication genetic association results identified a locus on chromosome 22 (rs855791 near TMPRSS6, P=3.60×10−9). EPO administration within a physiologic range of hematocrit induced hypertension in vivo and increased contraction of vascular smooth muscle cells in vitro. In conclusion, endogenous circulating EPO level is influenced by common genetic variation, and is associated with blood pressure traits, hypertension, and CAD. Vascular effects of EPO demonstrated in vitro and in vivo support a newly discovered mechanism of hypertension and cardiovascular risk with potential implications for erythropoietic support in the clinic.