rs1799998 — CYP11B2 -344C>T

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.