@article{6125aef03c1645b093d61980c68bca73,
title = "Epidemiologic and Genetic Associations of Erythropoietin With Blood Pressure, Hypertension, and Coronary Artery Disease",
abstract = "While exogenous administration of recombinant erythropoietin has been associated with increased risk of hypertension, coronary artery disease, and mortality, it is not known if endogenous circulating erythropoietin level is associated with coronary artery disease and its risk factors. We measured and analyzed epidemiological and genetic associations of circulating plasma erythropoietin levels in 2 population cohorts, from China (N=4329) and the United States (N=3671). In vitro smooth muscle cell responses and in vivo murine studies of erythropoietin exposure were performed. Erythropoietin levels were positively and linearly associated with blood pressure traits and inversely associated with cholesterol levels and red cell indices. Higher erythropoietin level was associated with higher prevalence of hypertension (odds ratio, 1.20 [95% CI, 1.12-1.29], P=4.41×10-7) and coronary artery disease (odds ratio, 1.16 [95% CI, 1.00-1.34], P=0.046). In a discovery stage genetic association study of erythropoietin 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). Erythropoietin administration, within a physiological range of hematocrit achieved, induced hypertension in vivo and increased contraction of vascular smooth muscle cells in vitro. In conclusion, endogenous circulating erythropoietin level is influenced by common genetic variation and is associated with blood pressure traits, hypertension, and coronary artery disease. Vascular effects of erythropoietin 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.",
keywords = "coronary artery disease, erythropoietin, hypertension, risk factors",
author = "Pengfei Sun and Nitin Kumar and Adrienne Tin and Jing Zhao and Brown, {Michael R.} and Zesen Lin and Yang, {Min Lee} and Qiwen Zheng and Jia Jia and Bielak, {Lawrence F.} and Bing Yu and Eric Boerwinkle and Hunker, {Kristina L.} and Josef Coresh and Chen, {Y. Eugene} and Yong Huo and Kardia, {Sharon L.R.} and Rami Khoriaty and Xiang Zhou and Morrison, {Alanna C.} and Yan Zhang and Ganesh, {Santhi K.}",
note = "Funding Information: The Peking University-University of Michigan Study of Atherosclerosis (PUUMA) cohort genotyping and analyses were supported by the UM-PUHSC Joint Institute for Translational and Clinical Research (grant No: BMU20110177 and BMU20160530). The ARIC (Atherosclerosis Risk in Communities) Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. We thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. Y. Zhang was supported by grants from and Key Laboratory of Molecular Cardiovascular Sciences (Peking University), Ministry of Education; NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides; the Fundamental Research Funds for the Central Universities. S.K. Ganesh was supported by R01HL139672, R01HL122684, R01HL086694, Department of Defense, and the University of Michigan A. Alfred Taubman Institute. N. Kumar was supported by the National Center for Advancing Translational Sciences, NIH, grant No: UL1TR002240. R. Khoriaty was supported by R01HL148333.The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article. Publisher Copyright: {\textcopyright} 2021 American Heart Association, Inc.",
year = "2021",
month = nov,
day = "1",
doi = "10.1161/HYPERTENSIONAHA.121.17597",
language = "English (US)",
volume = "78",
pages = "1555--1566",
journal = "Hypertension",
issn = "0194-911X",
publisher = "Lippincott Williams and Wilkins",
number = "5",
}