Genome-wide association study of angiotensinogen levels and key single nucleotide polymorphism associations with blood pressure

Karita C F Lidani; Shubham Tomar; Hossein Mousavi; Robert Buscaglia; Kirolos Michael; Alexander P Landry; Leonie Dupuis; Erin D Michos; Erin S Morgan; Xiuqing Guo; Jie Yao; Henry J Lin; Jerome I Rotter; Wendy S Post; Sotirios Tsimikas; Patrick J Trainor; Andrew P Defilippis

doi:10.1097/HJH.0000000000004080

Genome-wide association study of angiotensinogen levels and key single nucleotide polymorphism associations with blood pressure

J Hypertens. 2025 Jun 23. doi: 10.1097/HJH.0000000000004080. Online ahead of print.

Authors

Karita C F Lidani¹, Shubham Tomar¹, Hossein Mousavi², Robert Buscaglia³, Kirolos Michael^{1

4}, Alexander P Landry¹, Leonie Dupuis¹, Erin D Michos⁵, Erin S Morgan⁶, Xiuqing Guo⁷, Jie Yao⁷, Henry J Lin⁷, Jerome I Rotter⁷, Wendy S Post⁵, Sotirios Tsimikas^{6

8}, Patrick J Trainor¹, Andrew P Defilippis¹

Affiliations

¹ Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
² Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, New Mexico.
³ Department of Mathematics and Statistics, Northern Arizona University, Flagstaff, Arizona.
⁴ Meharry Medical College, Nashville, Tennessee.
⁵ Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
⁶ Ionis Pharmaceuticals, Carlsbad.
⁷ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance.
⁸ Division of Cardiovascular Medicine, University of California-San Diego, La Jolla, California, USA.

PMID: 40552363
DOI: 10.1097/HJH.0000000000004080

Abstract

Objective: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: AGT; ASO; GWAS; MESA; Multi-Ethnic Study of Atherosclerosis; RAAS; SNP; angiotensinogen; angiotensinogen gene; antisense oligonucleotide; genome wide association study; hypertension; renin–angiotensin–aldosterone system; siRNA; single nucleotide polymorphism; small interfering RNA.