rs2004776 — AGT

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 haplotypes are in near-complete linkage disequilibrium: if you carry the T allele at rs2004776, you almost certainly carry the other Hap-I variants as well.

A 2026 study by Perla et al.³³ Perla et al.
Effect of Dietary Salt Excess on DNA Methylation and Transcriptional Regulation of Human Angiotensinogen Gene Expression. Am J Hypertension, 2026 found that high dietary salt further amplifies this effect: salt excess causes greater DNA demethylation and stronger transcription factor binding at the AGT promoter in Hap-I (T allele) mice than in Hap-II mice, explaining why rs2004776 T carriers are particularly salt-sensitive.

The Evidence

Mopidevi et al. 2019⁴⁴ 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 individuals⁵⁵ 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, and the effect compounds with other RAAS variants and environmental sodium load.

An independent study of 2,881 East African participants⁶⁶ 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

The rs2004776 T allele raises blood pressure primarily through two mechanisms: higher baseline AGT/angiotensin II production, and amplified AGT upregulation in response to dietary sodium. Both of these are actionable. Reducing dietary sodium is effective for the overall population, but the Hap-I haplotype data indicate T carriers get a disproportionate benefit from sodium restriction because the gene-environment interaction that amplifies their RAAS activity is blunted when salt intake is low.

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

rs2004776 is in near-complete linkage disequilibrium with three other Hap-I variants in AGT intron I (rs2493134 at +507) and the promoter (−217A and −6A SNPs, including rs5051). These variants act together to drive higher AGT transcription — the combination, not any single variant, defines the Hap-I pro-hypertensive phenotype.

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.