rs3755351 — ADD2

Intronic variant in beta-adducin modulating renal Na+/K+-ATPase trafficking and sodium reabsorption, associated with hypertension susceptibility in a Japanese GWAS

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ADD2 rs3755351 — Beta-Adducin and the Renal Sodium Set Point

Beta-adducin11 Beta-adducin
encoded by ADD2, one of three adducin subunit genes (ADD1, ADD2, ADD3) is a cytoskeletal protein that heterodimerizes with alpha-adducin to regulate the cortical actin network beneath the plasma membrane of renal tubular epithelial cells. The adducin complex controls how efficiently the sodium-potassium pump (Na+/K+-ATPase) is recycled to and from the cell surface — a mechanism that sets the kidney's baseline rate of sodium reabsorption and, by extension, blood pressure. The intronic variant rs3755351 emerged from the first large-scale Japanese hypertension GWAS as the single SNP with the strongest statistical signal in the entire genome-wide screen.

The Mechanism

In renal proximal tubule cells, adducin anchors Na+/K+-ATPase pumps to the clathrin-mediated endocytic machinery. Normal constitutive endocytosis22 Normal constitutive endocytosis
the baseline recycling of membrane proteins into the cell interior continuously removes a proportion of Na+/K+-ATPase from the cell surface, limiting how much sodium the kidney retakes from the filtrate. Hypertension-associated adducin variants reduce this constitutive endocytosis, keeping more pumps at the membrane and increasing sodium reabsorption — a subtle but persistent upward shift in the blood pressure set point.

rs3755351 lies within an intron of ADD2. Because ADD2 produces multiple splicing isoforms33 splicing isoforms
different mRNA transcripts from the same gene by including or excluding different exon segments with distinct expression levels in kidney and brain, intronic variants can alter splice-site strength, exon inclusion rates, or regulatory element binding — changing effective ADD2 protein levels in the tissues where blood pressure is set. The precise molecular consequence of rs3755351 has not been characterized at the protein level; its biological plausibility rests on the well-established role of adducin in renal sodium handling and the convergent evidence from the Milan hypertensive rat model.

The Evidence

Kato et al. 200844 Kato et al. 2008 performed a three-tiered genome-wide association study in Japanese subjects (up to 619 hypertensive and 1,406 normotensive individuals in the final tier) and found rs3755351 carried the lowest p-value of all 75 candidate SNPs selected from an initial screen of 80,795 markers (combined p = 1.7×10⁻⁵). The authors explicitly noted that ADD2 was "nominated" as a susceptibility gene for hypertension, pending independent replication.

Mechanistic support comes from cell biology. Torielli et al. 200855 Torielli et al. 2008 demonstrated in renal epithelial cell lines that alpha-adducin mutations reduce constitutive Na+/K+-ATPase endocytosis and that adducin associates directly with clathrin-coated vesicles involved in pump internalization. Bianchi 200566 Bianchi 2005 reviewed the full translational chain from Milan hypertensive rats (which carry adducin mutations) to human association data, describing how adducin polymorphisms increase tubular sodium reabsorption and proposing pharmacogenomic targeting of this pathway with diuretics.

A replication attempt in an African-Brazilian quilombo population77 African-Brazilian quilombo population (652 individuals from 97 families) found no significant individual association of rs3755351 with blood pressure. This population-specific null result, combined with the absence of any GWAS Catalog registration for rs3755351, means the hypertension association remains a single-study nomination with limited independent confirmation.

Evidence level is therefore emerging: mechanistically credible, with one genome-wide signal in a specific ancestry group and no large cross-ancestry meta-analytic validation.

Practical Implications

Because rs3755351 is an intronic variant in ADD2 without established clinical utility, carriers of the T allele cannot currently receive guideline-supported medication adjustments based on this SNP alone. The actionable guidance centers on monitoring blood pressure trends and understanding that sodium handling is a core determinant of blood pressure in individuals with adducin pathway variants.

The well-studied alpha-adducin variant rs4961 (ADD1 G460W) has clearer pharmacogenomic data linking adducin carrier status to enhanced thiazide diuretic responsiveness. Carriers of ADD2 rs3755351 risk alleles may share an underlying sodium-retaining physiology that has implications for the same class of antihypertensives, but this is inferential rather than directly demonstrated.

Limiting dietary sodium is the most evidence-supported intervention for sodium-sensitive hypertension, and adducin pathway variants are the best-characterized molecular basis of sodium sensitivity identified through GWAS.

Interactions

ADD2 encodes beta-adducin, which obligately functions as a heterodimer with alpha-adducin (rs4961, ADD1). The ADD1 G460W variant (Trp allele of rs4961) has been independently associated with hypertension and specifically with enhanced blood pressure response to thiazide diuretics in multiple cohorts. Carriers of risk alleles at both ADD1 and ADD2 may have additive impairment of renal Na+/K+-ATPase regulation. The Milan hypertensive rat model, which provided the original mechanistic framework, carries mutations in both alpha- and beta-adducin subunits, suggesting that compound genotypes across ADD1 and ADD2 may have stronger combined effects on sodium reabsorption than either variant alone.

Genotype Interpretations

What each possible genotype means for this variant.

GG Normal

Common genotype with standard renal sodium handling

You carry two copies of the reference G allele at rs3755351 in the ADD2 gene. This is the most common genotype globally (approximately 44% of people) and in European populations. Your beta-adducin protein is produced from the standard ADD2 transcript architecture, and renal sodium handling follows the typical pattern without the elevated Na+/K+-ATPase surface density associated with the T allele in the index GWAS.

GT Intermediate

One copy of the hypertension-associated T allele; moderately elevated sodium retention signal

The T allele at rs3755351 lies within an intron of ADD2, which encodes beta-adducin — the obligate dimerization partner of alpha-adducin in renal tubular cells. Adducin variants are the best-characterized genetic basis of sodium-sensitive hypertension. The intronic location suggests the T allele may alter ADD2 splicing or expression in kidney tissue, though the specific molecular mechanism has not been characterized in cell-based experiments. Mechanistically, reduced adducin-mediated endocytosis of Na+/K+-ATPase pumps increases tubular sodium reabsorption, raising the blood pressure set point — an effect documented for alpha-adducin variants in renal cell culture and the Milan hypertensive rat model. Whether this specific intronic T allele replicates in large, independent cohorts remains to be established.

TT High Risk

Two copies of the hypertension-associated T allele; highest sodium-retention risk in this gene

Beta-adducin (ADD2) and alpha-adducin (ADD1) form the adducin heterodimer that anchors Na+/K+-ATPase pumps to the renal tubular cell membrane via clathrin-coated endocytic machinery. Mutations that reduce constitutive pump endocytosis increase the density of active Na+/K+-ATPase at the membrane, driving higher sodium reabsorption in the proximal tubule. The result is a persistently elevated blood pressure set point — the defining feature of sodium-sensitive hypertension. The rs3755351 intronic T allele likely acts on ADD2 expression or splicing; kidney and brain are the tissues with highest ADD2 expression, both relevant to blood pressure control. Importantly, the ADD1 G460W variant (rs4961) has established pharmacogenomic data showing enhanced thiazide diuretic response in adducin variant carriers, and the adducin heterodimer biology means ADD2 variants may share this therapeutic relevance, though direct evidence for rs3755351 TT carriers and diuretic response is absent.