rs1799998 — CYP11B2 -344C>T

Promoter variant in aldosterone synthase increasing CYP11B2 transcription, associated with elevated aldosterone, higher blood pressure, and sodium-sensitive left ventricular hypertrophy

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CYP11B2 -344C>T — The Aldosterone Volume Knob

The CYP11B2 gene11 CYP11B2 gene
encodes aldosterone synthase, the enzyme catalyzing the final three steps of aldosterone biosynthesis in the adrenal cortex. Aldosterone is the body's primary mineralocorticoid hormone — it controls sodium retention, potassium excretion, and blood pressure by acting on the kidneys' collecting ducts. The rs1799998 variant (-344C>T) sits in the promoter region of CYP11B2 at a binding site for steroidogenic factor-1 (SF-1)22 steroidogenic factor-1 (SF-1)
a transcription factor that drives expression of steroid-synthesizing enzymes including CYP11B2. Depending on which allele you carry, your adrenal glands may be genetically primed to produce more aldosterone throughout your life.

Important note on allele notation: Published literature uses coding-strand notation (C and T alleles). Because CYP11B2 is on the minus strand, genome files report the complementary plus-strand alleles: A corresponds to the T allele described in papers (the higher-expression allele), and G corresponds to the C allele. All genotypes in this profile use plus-strand notation.

The Mechanism

The -344 position in the CYP11B2 promoter sits within the SF-1 binding site33 SF-1 binding site
SF-1, encoded by NR5A1, is a master regulator of adrenal steroidogenic gene expression. The T allele (A on plus strand) alters the binding affinity of this site, shifting the regulatory landscape toward enhanced transcriptional output.

CYP11B2 exists within a haplotype block containing three linked promoter variants. The haplotype containing -344T (haplotype-I) shows measurably greater CYP11B2 expression — demonstrated in transgenic mice carrying the human gene with haplotype-I, which produced 2.2-fold higher mRNA in adrenals and 1.54-fold higher expression in kidneys compared to haplotype-II (-344C) mice. Critically, haplotype-I mice developed a 7 mmHg higher baseline blood pressure, and under high-salt diet, failed to appropriately suppress aldosterone — driving further blood pressure elevation — while haplotype-II mice showed normal salt-induced RAAS suppression.

The Evidence

In a multi-ethnic study of 1,313 participants, the TT genotype was associated with 14% higher plasma aldosterone levels and 3.7 mmHg higher systolic / 2.1 mmHg higher diastolic blood pressure compared to CC carriers44 the TT genotype was associated with 14% higher plasma aldosterone levels and 3.7 mmHg higher systolic / 2.1 mmHg higher diastolic blood pressure compared to CC carriers, after adjustment for age, sex, and ethnicity. The T allele was also over-represented in individuals with elevated aldosterone-to-renin ratios.

In an Egyptian cohort, the T allele was significantly more frequent in hypertensive patients (OR 2.51; 95% CI 1.3–3.5; P=0.002)55 the T allele was significantly more frequent in hypertensive patients (OR 2.51; 95% CI 1.3–3.5; P=0.002). The TT genotype was specifically associated with greater left ventricular mass index (LVMI), suggesting that the elevated aldosterone drives not just blood pressure but also cardiac remodeling.

For cardiac structure, the -344 C/T polymorphism is associated with left ventricular structure in arterial hypertension66 the -344 C/T polymorphism is associated with left ventricular structure in arterial hypertension, with different patterns by genotype: CC carriers tend toward eccentric LVH, while a strong correlation between LV mass and urinary sodium excretion was observed specifically in CC and intron-2-conversion carriers77 CC and intron-2-conversion carriers, suggesting the sodium-LV mass link operates through different mechanisms by genotype.

The SILVHIA trial found a striking pharmacogenomic signal: TT carriers showed -21 mmHg systolic BP reduction with irbesartan, versus 0 mmHg for CC carriers88 TT carriers showed -21 mmHg systolic BP reduction with irbesartan, versus 0 mmHg for CC carriers, suggesting the T allele's excess aldosterone production creates greater suppressibility by AT1 receptor blockade. A Chinese study found CC+CT carriers responded better to valsartan (4.7 mmHg greater SBP reduction), illustrating that drug-response findings vary by population.

One large multi-ethnic U.S. study (n=3,452) found no association with blood pressure, plasma aldosterone, or LV mass99 found no association with blood pressure, plasma aldosterone, or LV mass, highlighting genuine heterogeneity in the literature — likely driven by differences in dietary sodium, comorbidities, population genetic backgrounds, and LD patterns.

Practical Actions

The most actionable implication of the -344T/A genotype is salt sensitivity of blood pressure. Even without confirmed hypertension, carriers of one or two A alleles (particularly AA homozygotes) have a biological predisposition toward aldosterone-mediated sodium retention. Reducing dietary sodium blunts the aldosterone-driven pathway at its source.

If you have hypertension and carry the AA genotype, AT1 receptor blockers (irbesartan, valsartan) may offer superior blood pressure reduction by blocking the downstream effects of elevated aldosterone. Discuss this pharmacogenomic data with your physician when selecting antihypertensive therapy.

Interactions

CYP11B2 rs1799998 functions within the renin-angiotensin-aldosterone system (RAAS) pathway alongside AGTR1 rs5186 (A1166C), which affects angiotensin II receptor expression, and AGT rs699 (M268T), which influences angiotensinogen levels. Published studies have found interactive effects between CYP11B2 -344T and ACE insertion/deletion on atrial fibrillation risk and T2DM susceptibility. Individuals carrying multiple RAAS-sensitizing variants across CYP11B2, AGTR1, and AGT may have additive blood pressure effects beyond any single variant, with the CYP11B2 AA + AGTR1 CC combination representing the highest sodium-sensitive hypertension burden within this pathway.

Drug Interactions

irbesartan dose_adjustment literature
valsartan dose_adjustment literature

Genotype Interpretations

What each possible genotype means for this variant.

GG Standard Aldosterone Output Normal

Normal CYP11B2 promoter activity and typical aldosterone regulation

You carry two copies of the G allele at this position, which corresponds to the C allele (-344C) in the CYP11B2 promoter as described in published literature. This is the lower-expression haplotype: your adrenal glands are not genetically primed toward excess aldosterone synthesis. About 18% of people globally share this genotype, with higher frequency in European populations (~20%) and lower in African (~4%). Your aldosterone regulation is expected to follow the typical pattern in response to sodium intake and RAAS signaling.

AG Elevated Aldosterone Tendency Intermediate

One copy of the higher-expression allele; moderately increased aldosterone tendency

The AG heterozygous genotype produces an intermediate phenotype for aldosterone synthesis capacity. The multi-ethnic study by Davies et al. (PMID 15361760) showed a linear trend across CC-CT-TT genotypes for plasma aldosterone and blood pressure, with CT carriers at an intermediate level. This suggests that even one copy of the A (T) allele shifts aldosterone output upward, though not as dramatically as two copies.

Your blood pressure response to dietary sodium may be somewhat greater than GG carriers. Importantly, if you develop hypertension, your genotype may influence which antihypertensive class works best — AT1 receptor blockers showed differential efficacy by genotype in the SILVHIA trial.

AA High Aldosterone Producer High Risk

Two copies of the higher-expression allele; genetically predisposed to elevated aldosterone and sodium-sensitive blood pressure

The AA (TT) genotype creates a genetically sustained tendency toward higher aldosterone secretion throughout life. Aldosterone acts on the kidneys to retain sodium and excrete potassium; chronically elevated levels lead to volume expansion, vascular stiffness, and direct cardiac fibrotic effects. Left ventricular hypertrophy seen in TT carriers may result from both hemodynamic loading (higher blood pressure) and direct aldosterone-driven myocardial fibrosis.

The pharmacogenomic signal is clinically important: in the SILVHIA trial, TT carriers showed 21 mmHg systolic reduction with irbesartan compared to essentially no benefit in CC carriers. This suggests the elevated aldosterone production in AA individuals creates greater suppressibility via angiotensin II blockade — the upstream signal driving the excess synthesis is removed.

One large U.S. study (n=3,452) found no association with blood pressure or aldosterone, underscoring that this SNP is a risk modifier, not a deterministic variant. Environmental factors — particularly dietary sodium intake — appear to modulate how much the genotype manifests clinically. This makes dietary sodium reduction especially high-yield for AA carriers.