The Blood Pressure Gene That Responds to Training and Salt
Angiotensinogen (AGT) is the precursor protein of the
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 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 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 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 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 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 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.
All Genotypes
Normal angiotensinogen levels with standard sodium sensitivity
You carry two copies of the ancestral methionine allele at AGT M235T. Your angiotensinogen levels are in the lower-normal range, which is associated with standard blood pressure regulation. About 30% of the global population and roughly 35% of people of European descent share this genotype. Your blood pressure is less sensitive to sodium intake compared to carriers of the G allele.
Moderately elevated angiotensinogen with increased sodium sensitivity
You carry one copy of the threonine variant at AGT M235T. This is the most common genotype globally, shared by about 49% of the population. Your angiotensinogen levels are moderately elevated (roughly 10-20% above baseline), and your blood pressure responds more strongly to sodium intake than AA homozygotes. In population studies, the blood pressure effect of sodium approximately doubles compared to the AA genotype.
Highest angiotensinogen levels with pronounced sodium sensitivity and blunted endurance training response
You carry two copies of the threonine variant at AGT M235T. About 21% of the global population shares this genotype, though it is much more common in East Asian (approximately 69%) and African (approximately 72%) populations than in Europeans (approximately 17%). Your plasma angiotensinogen levels are elevated by 20-30%, which increases angiotensin II production and makes your blood pressure notably more responsive to sodium intake. Research also suggests that endurance training alone may be less effective at lowering your blood pressure.