rs4762 — AGT T174M

Missense variant in angiotensinogen that increases AGT protein levels and raises risk of hypertension, myocardial infarction, and stroke, with stronger effects in Asian populations

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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] — 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 type 2 diabetes, 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.

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

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.

Genotype Interpretations

What each possible genotype means for this variant.

GG Normal AGT Normal

Common angiotensinogen genotype with typical blood pressure regulation

You carry two copies of the G (reference) allele at rs4762. This is the most common genotype globally — about 77% of people share it. Your angiotensinogen protein is the standard threonine form, and this variant does not increase your risk of hypertension or cardiovascular disease.

AG AGT Heterozygous Intermediate

One copy of the risk allele modestly increases angiotensinogen activity and blood pressure risk

The additive OR of 1.36 from the 2021 meta-analysis (PMID 34025779) applies per allele — heterozygous carriers have one dose of the effect, homozygous carriers two. The clinical relevance depends heavily on your overall cardiovascular risk profile.

AA AGT Homozygous Risk High Risk

Two copies of the risk allele elevate angiotensinogen levels and increase cardiovascular risk

Homozygous AA carriers produce angiotensinogen protein with the methionine substitution at both alleles, leading to persistently higher circulating AGT and greater angiotensin II-driven vasoconstriction. The 2021 meta-analysis (PMID 34025779) found OR 2.26 (95% CI 1.35–3.77) for MI under the recessive model, and OR 2.20 (95% CI 1.33–3.62) under the codominant model — meaning AA individuals face roughly double the myocardial infarction risk of GG carriers attributable to this locus. The association with intracerebral hemorrhage (PMID 23251296) suggests that chronic AGT-driven hypertension may stress the cerebrovascular vasculature over time, increasing hemorrhagic stroke risk. Diastolic blood pressure appears particularly sensitive to AA status in those with co-existing metabolic disease such as diabetic nephropathy (PMID 33423909).

Importantly, the RAS is highly drug-targetable: ACE inhibitors and ARBs work specifically on the AGT → angiotensin II → AT1 receptor axis that this variant amplifies. If medication is indicated, RAS-targeting agents are the mechanistically best-matched choice for your genotype.