Lidani Karita C F, Tomar Shubham, Mousavi Hossein, Buscaglia Robert, Michael Kirolos, Landry Alexander P, Dupuis Leonie, Michos Erin D, Morgan Erin S, Guo Xiuqing, Yao Jie, Lin Henry J, Rotter Jerome I, Post Wendy S, Tsimikas Sotirios, Trainor Patrick J, DeFilippis Andrew P
Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, New Mexico.
J Hypertens. 2025 Sep 1;43(9):1500-1509. doi: 10.1097/HJH.0000000000004080. Epub 2025 Jun 23.
The renin angiotensin aldosterone system plays a key role in circulatory homeostasis. We sought to identify genetic determinants of measured plasma angiotensinogen levels and subsequently evaluate the association of these single nucleotide polymorphisms (SNPs) with blood pressure (BP) and hypertension in a multiethnic population.
Genome-wide association study (GWAS) of plasma angiotensinogen levels, measured using an enzyme-linked immunoassay, was conducted in 4899 Multi-Ethnic Study of Atherosclerosis (MESA) participants (self-identified as White, n = 1865; Hispanic, n = 1113; Black, n = 1224; and Chinese, n = 629). Linear and logistic models examined the association between SNPs with angiotensinogen and hypertension, respectively. Mediation analysis evaluated the effect of angiotensinogen on BP/hypertension through the top SNPs identified by GWAS.
In the analysis utilizing all participants, 115 SNPs were associated with angiotensinogen ( P < 5 × 10 -8 ), including lead SNP rs4762(G>A) in exon 2 ( P = 1.51E -100 ) and rs5050(T>G) in the promoter region ( P = 2.26E -69 ) of the AGT gene. Race/ethnic-specific analyses identified rs4762(G>A) as the lead SNP for White and Hispanic participants, whereas Black and Chinese participants had rs5050(T>G) and rs16852311(G>C), respectively. Both rs4762(G>A) and rs5050(T>G) indirectly increased systolic BP, diastolic BP, and the odds of hypertension through its effect of increasing angiotensinogen.
Our findings demonstrate racial/ethnic differences in genetic effects on angiotensinogen levels across multiple SNPs. AGT rs4762(G>A) and rs5050(T>G) impact BP and hypertension through a mediated effect via angiotensinogen, though opposing direct effects may mask the overall association.
肾素血管紧张素醛固酮系统在循环稳态中起关键作用。我们试图确定实测血浆血管紧张素原水平的遗传决定因素，并随后在多民族人群中评估这些单核苷酸多态性（SNP）与血压（BP）和高血压的关联。
对4899名动脉粥样硬化多民族研究（MESA）参与者（自我认定为白人，n = 1865；西班牙裔，n = 1113；黑人，n = 1224；中国人，n = 629）进行了血浆血管紧张素原水平的全基因组关联研究（GWAS），采用酶联免疫吸附测定法进行测量。线性和逻辑模型分别检验了SNP与血管紧张素原和高血压之间的关联。中介分析通过GWAS确定的顶级SNP评估血管紧张素原对血压/高血压的影响。
在对所有参与者的分析中，115个SNP与血管紧张素原相关（P < 5×10 -8），包括AGT基因外显子2中的主要SNP rs4762（G>A）（P = 1.51E -100）和启动子区域中的rs5050（T>G）（P = 2.26E -69）。种族/民族特异性分析确定rs4762（G>A）为白人和西班牙裔参与者的主要SNP，而黑人和中国参与者分别有rs5050（T>G）和rs16852311（G>C）。rs4762（G>A）和rs5050（T>G）均通过增加血管紧张素原的作用间接增加收缩压、舒张压和高血压几率。
我们的研究结果表明，多个SNP对血管紧张素原水平的遗传效应存在种族/民族差异。AGT rs4762（G>A）和rs5050（T>G）通过血管紧张素原的介导作用影响血压和高血压，尽管相反的直接作用可能掩盖总体关联。
