rs699 — AGT M235T

The Blood Pressure Gene That Responds to Training and Salt

Angiotensinogen (AGT) is the precursor protein of the renin-angiotensin system¹¹ renin-angiotensin system
The renin-angiotensin system (RAS) is a hormonal cascade that regulates blood pressure, fluid balance, and electrolyte homeostasis. Renin cleaves AGT to form angiotensin I, which ACE converts to angiotensin II — a potent vasoconstrictor (RAS), one of the body's primary blood pressure control mechanisms. The M235T variant (rs699) changes a methionine to threonine at position 235 of the mature protein, and is one of the most-studied cardiovascular genetic variants with over 300 epidemiological studies and at least 15 meta-analyses published since its discovery in 1992.

The Mechanism

The G allele (coding for threonine at position 235) is associated with 10-30% higher plasma angiotensinogen levels compared to the A allele (methionine). More angiotensinogen means more substrate for renin, leading to increased production of angiotensin II²² angiotensin II
A powerful vasoconstrictor hormone that raises blood pressure by narrowing blood vessels and stimulating aldosterone release, which causes sodium and water retention, the hormone that constricts blood vessels and promotes sodium retention.

The variant is in linkage disequilibrium with a promoter polymorphism (rs5051) that increases AGT gene transcription. Recent research using UK Biobank data suggests the M235T variant may also exert cell-type-specific effects on AGT expression, particularly in the kidney, where local angiotensin II production can independently influence blood pressure.

The Evidence

Blood pressure and hypertension: A meta-analysis of 39 studies³³ meta-analysis of 39 studies
Defined Yilmaz et al. M235T polymorphism in the angiotensinogen gene and cardiovascular disease: An updated meta-analysis. Anatol J Cardiol, 2019 with 9,225 cases and 8,406 controls found the T allele (G on plus strand) associated with cardiovascular disease risk overall (OR 1.16, allelic model). The effect was strongest in East Asian populations (OR 1.46) where the G allele is very common (83%), while Caucasian populations showed no significant association in isolation.

Sodium sensitivity: A large cross-sectional study⁴⁴ large cross-sectional study
Norat et al. Blood pressure and interactions between the angiotensin polymorphism AGT M235T and sodium intake. Am J Clin Nutr, 2008 of 11,384 participants demonstrated that the blood pressure effect of sodium intake approximately doubles in AG and GG carriers compared to AA homozygotes. Carriers of the G allele show the greatest blood pressure reduction when sodium intake is lowered. An earlier intervention trial⁵⁵ earlier intervention trial
Hunt et al. Enhanced blood pressure response to mild sodium reduction in subjects with the 235T variant of the angiotensinogen gene. Hypertension, 1999 confirmed that T235 carriers (G allele) experience significantly greater systolic blood pressure reduction with modest salt restriction.

Exercise response: The HERITAGE Family Study⁶⁶ HERITAGE Family Study
Rankinen et al. AGT M235T and ACE ID polymorphisms and exercise blood pressure in the HERITAGE Family Study. Am J Physiol, 2000 followed 476 sedentary individuals through 20 weeks of endurance training. Men with AA or AG genotypes reduced diastolic blood pressure by 3-4 mmHg at submaximal exercise, while GG homozygotes showed virtually no blood pressure improvement (0.4 mmHg). This suggests GG carriers may need different training strategies to achieve cardiovascular benefits.

Athletic performance: A study of Polish athletes⁷⁷ study of Polish athletes
Zarebska et al. Association of rs699 (M235T) polymorphism in the AGT gene with power but not endurance athlete status. J Strength Cond Res, 2013 found the GG genotype (Thr/Thr) was 2.2 times more common in power athletes than controls and 3.1 times more common than in endurance athletes. The higher angiotensin II levels associated with the G allele may favour power and strength through effects on muscle growth, vasoconstriction, and cardiac hypertrophy.

Practical Implications

The M235T variant has its greatest practical impact through sodium sensitivity. If you carry one or two G alleles, reducing sodium intake to below 2,000 mg/day can meaningfully lower blood pressure. This is especially relevant given that average Western diets contain 3,400-4,000 mg of sodium daily.

For exercise, GG carriers may derive greater cardiovascular benefit from incorporating power and resistance training alongside aerobic exercise, rather than relying solely on endurance training for blood pressure management. Monitoring blood pressure regularly helps track whether your exercise programme and dietary choices are effective for your genotype.

Interactions

The AGT M235T variant interacts with the AGT promoter variant rs5051, which is in strong linkage disequilibrium. The T174M variant (rs4762) in the same gene can compound the effect on angiotensinogen levels. Additionally, an interaction with the ACE insertion/deletion polymorphism has been documented: the HERITAGE study found that GG homozygotes carrying the ACE D allele showed no blood pressure response to endurance training, while other genotype combinations benefited. Population context matters — the G allele frequency ranges from 41% in Europeans to 85% in Africans, so the clinical significance varies substantially across ancestries.