rs2004776 — AGT

Intronic regulatory variant in angiotensinogen intron I that enhances HNF3β transcription factor binding, increases AGT expression, and raises blood pressure by 12–13 mmHg in transgenic models

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The AGT Regulatory Switch — How an Intronic Variant Turns Up Your Blood Pressure Set Point

Angiotensinogen (AGT) is the only known substrate for renin, the enzyme that initiates the renin-angiotensin-aldosterone system11 renin-angiotensin-aldosterone system
The RAAS is a hormonal cascade that controls blood pressure and fluid balance. Renin cleaves AGT to form angiotensin I, which ACE converts to the potent vasoconstrictor angiotensin II. Angiotensin II constricts blood vessels and drives aldosterone-mediated sodium retention. (RAAS), the body's primary long-term blood pressure regulator. The more AGT your liver produces, the more substrate is available for renin — and the more angiotensin II gets generated, narrowing blood vessels and promoting sodium retention.

rs2004776 sits in intron I of the AGT gene at chromosomal position 230,712,956 (GRCh38) on chromosome 1. The AGT gene runs on the minus (coding) strand, so the plus-strand T allele corresponds to an A in coding-strand notation at position +1164 of intron I. It does not change the AGT protein sequence, but it changes how much AGT protein your liver makes — with meaningful consequences for blood pressure.

The Mechanism

The +1164 position in intron I overlaps a binding motif for HNF3β22 HNF3β
Hepatocyte nuclear factor 3β (also known as FOXA2), a liver-enriched transcription factor that regulates expression of many metabolic and secreted proteins, including angiotensinogen.. Electrophoretic mobility shift assays (EMSA) show that the T allele (coding-strand A) creates a sequence with stronger HNF3β homology and binds more avidly to nuclear extracts than the C allele. This stronger transcription factor binding translates into higher AGT mRNA levels in the liver and higher plasma angiotensinogen concentrations — more substrate for the RAAS, and ultimately more angiotensin II.

rs2004776 is one of four variants that define the pro-hypertensive Hap-I haplotype (along with promoter variants at −217 and −6, and an intron I variant at +507/rs2493134).

The Evidence

Mopidevi et al. 201933 Mopidevi et al. 2019
A polymorphism in intron I of the human angiotensinogen gene affects binding by HNF3 and hAGT expression and increases blood pressure in mice. J Biol Chem, 2019 demonstrated the mechanistic link directly. Transgenic mice expressing the human Hap-I haplotype (T allele at rs2004776) showed systolic blood pressure approximately 12–13 mmHg higher than mice expressing Hap-II (C allele), with correspondingly elevated plasma AGT and angiotensin II levels. The paper also noted the human association was confirmed in a dataset of approximately 1 million subjects.

In humans, a meta-analysis of 86,588 individuals44 meta-analysis of 86,588 individuals
Johnson et al. Association of hypertension drug target genes with blood pressure and hypertension in 86,588 individuals. Nat Genet, 2011 from the CHARGE consortium, Global BPgen Consortium, and Women's Genome Health Study found rs2004776 among the strongest validated AGT associations: the T allele was associated with systolic blood pressure (beta = 0.42 mmHg per allele, SE = 0.09, p = 3.8×10⁻⁶) and diastolic blood pressure (beta = 0.32 mmHg, SE = 0.06, p = 5.0×10⁻⁸), reaching genome-wide significance. The per-allele effect is modest in isolation, but two T alleles double it.

An independent study of 2,881 East African participants55 2,881 East African participants
Kayima et al. Association of genetic variation with blood pressure traits among East Africans. Clin Genet, 2017 confirmed rs2004776 associations with both systolic and diastolic blood pressure, validating the association across ancestries. The T allele frequency is highest in East Asians (56%) and Africans (42%), versus 23% in Europeans, making it a particularly relevant variant for non-European populations.

Practical Implications

Blood pressure monitoring is valuable for anyone with the T allele — it provides real-time feedback on whether dietary and lifestyle interventions are translating into lower pressures. For TT homozygotes, who carry two copies of the pro-hypertensive haplotype, the aggregate effect is approximately additive, warranting closer attention to RAAS-relevant lifestyle factors and earlier engagement with clinical care if pressures trend upward.

Interactions

The better-known AGT coding variant rs699 (M235T) is also associated with blood pressure and plasma AGT levels, and may be in partial LD with the Hap-I haplotype depending on ancestry. Carriers of both T allele at rs2004776 and G allele at rs699 may have additive upward pressure on RAAS activation. The compound interaction has not been independently established in intervention studies — see rs699 for the M235T-specific evidence on sodium sensitivity and exercise response.

Nutrient Interactions

sodium altered_metabolism
potassium increased_need

Genotype Interpretations

What each possible genotype means for this variant.

CC Normal

Standard angiotensinogen expression and baseline RAAS activity

You carry two copies of the C allele at rs2004776 — the Hap-II haplotype that produces normal levels of angiotensinogen in the liver. About 57% of the global population and approximately 59% of Europeans share this genotype. Your intrinsic RAAS activity is at population baseline. No specific action is needed based on this variant alone.

CT Intermediate

One copy of the hypertensive haplotype; moderately elevated angiotensinogen expression

The T allele creates stronger HNF3β binding at the +1164 position in AGT intron I, promoting higher AGT transcription in the liver. Because you carry only one T allele, your AGT production is intermediate between CC and TT genotypes.

The T allele frequency is 56% in East Asians and 42% in Africans, so CT genotype is common in those ancestries. Population-specific effects appear real: the East African GWAS confirmed blood pressure associations with this variant independently of European cohort data.

TT High

Two copies of the hypertensive haplotype; highest angiotensinogen expression

Transgenic mouse data using the human Hap-I haplotype (T/T at rs2004776) demonstrated systolic blood pressure approximately 12–13 mmHg higher than Hap-II mice, with measurably elevated plasma angiotensin II. In humans, the T allele was the strongest validated AGT association in an 86,588-person meta-analysis (p=5.0×10⁻⁸ for diastolic BP), and confirmed in East African cohorts.

Potassium intake is especially important for this genotype. Higher angiotensin II drives aldosterone-mediated sodium retention; potassium promotes renal sodium excretion and directly counteracts the aldosterone signal.