Abstract Body (Do not enter title and authors here): Background: The renin angiotensin aldosterone system (RAAS) is crucial for circulatory homeostasis and multiple cardiovascular diseases. Despite research on key RAAS components, resulting in multiple therapeutics, the role of angiotensinogen, the sole substrate, remains less understood. We sought to elucidate the relationship between circulating angiotensinogen levels and single nucleotide polymorphisms (SNPs) in a multi-ethnic cohort study.

Methods: Genome-wide association analyses of plasma angiotensinogen levels were conducted in 4,899 MESA participants (self-identified as White, n=1,868; Hispanic, n=1,115; Black, n=1,283; and Chinese, n=633). Plasma angiotensinogen levels were measured at the baseline using an enzyme-linked immunoassay. Linear models were adjusted for age, sex, comorbidities, and sex hormones, along with top principal components to account for population structure. Furthermore, we conducted conditional analysis identifying SNPs meeting genome-wide significance for population-specific associations conditioned on the lead SNP in each race/ethnicity.

Results: We identified 115 SNPs associated with angiotensinogen levels (p< 5×10⁻⁸), including the lead SNP rs4762 (Thr174Met) in exon 2 (β=-0.159, p=1.51E^-100) and SNP rs5050 (A-20C) in the promoter region (β=-0.109, p=2.26E^-69) within the AGT gene. Strong Linkage Disequilibrium [LD (r²>0.8)] was observed between rs4762 and rs35837081 for White, Black, and Hispanic ethnicities. Conversely, this level of LD was noted between rs4762 and rs3789657 specifically within Chinese. The LD between rs4762 and rs5050 was higher for White (r²=0.65), followed by Chinese (r²=0.56), Hispanic (r²=0.55), and Black (r²=0.29). Conditioned on rs4762 in the White population, we identified four secondary signals associated with angiotensinogen including rs2493151 (β=0.053, p=4.08E^-9), implicated in transcription factor binding. Measured angiotensinogen levels were 9.7%, 12.8%, and 17.3% lower in Black, Hispanic, and Chinese, respectively, compared to White participants.

Conclusions: These findings extend angiotensinogen research, highlighting the SNPs rs4762 and rs5050 as the key variants associated with angiotensinogen levels, both previously linked to hypertension.