rs4762 — AGT T174M

The Angiotensinogen Variant — Blood Pressure Genetics in the Renin-Angiotensin System

Angiotensinogen (AGT) is the essential precursor protein of the renin-angiotensin system (RAS), the body's primary long-term regulator of blood pressure and fluid balance. The kidney enzyme renin cleaves AGT to produce angiotensin I, which is then converted by ACE to angiotensin II¹¹ angiotensin II
the vasoactive peptide that raises blood pressure by constricting blood vessels and signaling the adrenal glands to release aldosterone. The T174M variant (rs4762) is one of two well-studied missense changes in AGT — alongside [M235T (rs699) | the more frequently studied AGT variant, which is in strong linkage disequilibrium with T174M in many populations] — and both have been investigated for decades as candidates for genetically elevated blood pressure.

The Mechanism

AGT sits on the minus strand of chromosome 1 at position 230,710,231 (GRCh38). The rs4762 G>A change on the plus strand produces a Threonine-to-Methionine substitution at position 198 of the angiotensinogen precursor²² Threonine-to-Methionine substitution at position 198 of the angiotensinogen precursor
also described as T174M in older literature counting from the mature protein after signal peptide cleavage. This amino acid change in the AGT protein is thought to affect its rate of cleavage by renin and its plasma concentration³³ plasma concentration
carriers of the A allele tend to have higher circulating angiotensinogen levels, shifting the equilibrium of the entire RAS toward higher angiotensin II output. Higher angiotensin II drives sustained increases in vascular tone, sodium retention, and — over years — contributes to hypertension and end-organ damage.

The Evidence

The AGT gene's role in hypertension was first established in 1992⁴⁴ first established in 1992
Jeunemaitre et al., "Molecular basis of human hypertension: role of angiotensinogen." Cell 71:169-80, when genetic linkage between AGT variants and hypertension was demonstrated in two large independent family panels. This landmark paper showed that AGT molecular variants were inherited predispositions to essential hypertension and that plasma AGT concentrations differed by genotype.

The cardiovascular consequences of rs4762 were quantified in a 2021 meta-analysis of 7,657 subjects across 11 studies⁵⁵ 2021 meta-analysis of 7,657 subjects across 11 studies
Li et al., "Myocardial Infarction and AGT p.Thr174Met Polymorphism: A Meta-Analysis of 7657 Subjects." Cardiovascular Therapeutics 2021. The A (Met174) allele significantly increased myocardial infarction risk: OR 2.26 (95% CI 1.35–3.77) under the recessive model, OR 1.13 (95% CI 1.02–1.26) under the dominant model, and OR 1.36 (95% CI 1.13–1.64) under the additive model. Effects were strongest in Asian populations; Caucasian subgroup analyses did not reach statistical significance.

Park et al. 2013⁶⁶ Park et al. 2013
"Assessment of two missense polymorphisms (rs4762 and rs699) of the angiotensinogen gene and stroke." Experimental and Therapeutic Medicine 5:343-349 examined 197 stroke patients and 301 controls, finding that the rs4762 A (T allele on coding strand) allele was associated with [intracerebral hemorrhage | 16.2% allele frequency in ICH vs 9.6% in controls, P=0.021] and correlated with worse neurological severity scores. Ischemic stroke was not significantly associated.

In a Mexican cohort of 546 adults with diabetic nephropathy, Vázquez-Moreno et al. 2021⁷⁷ Vázquez-Moreno et al. 2021
"AGT rs4762 is associated with diastolic blood pressure in Mexicans with diabetic nephropathy." Journal of Diabetes and Its Complications 35(3) found that the A allele predicted higher diastolic blood pressure specifically in those with established kidney disease (β=2.84, P=0.026), an important finding because diastolic hypertension drives progression of diabetic nephropathy.

A 2018 study in Han Chinese women⁸⁸ 2018 study in Han Chinese women
Zhou et al., Biomed Res Int 2018, n=156 preeclampsia / 286 controls identified rs4762 as one of seven alleles significantly associated with preeclampsia susceptibility. Notably, a large 2016 meta-analysis of 95 case-control studies⁹⁹ 2016 meta-analysis of 95 case-control studies
Zhang et al., Medical Science Monitor, n=16,646 PE patients / 28,901 controls found no overall significant association of rs4762 with preeclampsia across all ancestries combined, suggesting population-specific effects — consistent with the pattern seen for MI risk.

Practical Implications

The A allele raises circulating angiotensinogen and tips the RAS toward sustained vasoconstriction. For carriers, this is not destiny — the RAS is highly modifiable by both lifestyle and medication. RAS-targeting medications (ACE inhibitors, ARBs) act downstream of AGT and are among the most effective antihypertensives available. Dietary sodium directly amplifies RAS activation: each gram of excess sodium per day substantially raises angiotensin II-driven pressure in those with genetically elevated AGT. Conversely, [low-sodium dietary patterns | below 2,300 mg/day, or ideally 1,500 mg/day for those at elevated cardiovascular risk] are among the most potent non-pharmacological strategies for blunting AGT-mediated pressure elevation.

Interactions

rs4762 is in linkage disequilibrium with rs699 (M235T)¹⁰¹⁰ linkage disequilibrium with rs699 (M235T)
the two variants are often co-inherited and studied as a haplotype block. Haplotype analyses consistently show stronger associations with blood pressure and cardiovascular disease than either SNP alone. The AGT gene also interacts with [rs5186 (AGTR1 A1166C) | the angiotensin II type 1 receptor variant] — when both the AGT signal peptide and the AT1 receptor are variant, the downstream pressor response is amplified. In women, AGT haplotypes interact significantly with hypertension status to modulate coronary artery disease risk, a gene-environment interaction that may partly explain sex-specific cardiovascular risk patterns.