rs4961
badMag 3.5This is a variant in the ADD1 gene that changes a glycine to an tryptophan.
Key Literature Trait Associations
Salt-Sensitive Blood Pressure
Alpha-adducin (ADD1) influences how kidney cells reabsorb sodium. The rs4961 variant (Gly460Trp) increases sodium reabsorption efficiency, meaning T allele carriers retain more sodium on a high-salt diet — salt-sensitive hypertension. A meta-analysis found an overall OR of 1.40 (95% CI 0.96–2.04) that did not reach statistical significance in the overall population, but was significant in the Asian subgroup (OR 1.33, p=0.02). People with this variant may benefit more from a low-sodium diet or diuretic medications for blood pressure management.
Hypertension
The ADD1 rs4961 Trp460 (T) allele has been associated with essential hypertension, particularly in East Asian populations. A large meta-analysis of 33 studies (n=40,432) found significant associations in Asians across dominant and allele models (p<0.0001), though not robustly in the overall population due to heterogeneity. An earlier meta-analysis of 15 studies (n=10,133) found no significant association in either Asians or Caucasians. The discrepancy likely reflects differences in study inclusion and statistical models. The overall evidence supports a modest, population-specific effect primarily in East Asians.
Antihypertensive drug response
The ADD1 Trp460 (T) allele has been proposed as a pharmacogenomic marker for thiazide diuretic response, based on its role in renal sodium reabsorption. A meta-analysis of 4 studies (n=1,001) found significant differences in blood pressure reduction between Gly/Gly and Trp-allele carriers on hydrochlorothiazide (standardized difference in means 2.78, 95% CI 0.56–4.99 for GlyGly vs GlyTrp). However, the GENRES trial (n=208) found the Trp allele did not predict better hydrochlorothiazide response in Finnish men. A small study (n=87) found Trp allele carriers combined with ACE I allele had the greatest response (−12.7 vs −3.4 mmHg). Findings remain inconsistent and no clinical pharmacogenomic guideline currently recommends rs4961 testing.
▶ClinVar annotation
Hypertension, salt-sensitive essential, susceptibility to; hydrochlorothiazide response - Efficacy
View on ClinVar →▶Research that mentions this SNP (4)
▶Genetic variants conferring susceptibility to gastroschisis: a phenomenon restricted to the interaction with the environment?Meta-analysisN=434Victor M. Salinas-Torres et al.(2018)· Pediatric Surgery International
This systematic review analyzed genetic associations with gastroschisis from 1980-2017, identifying 14 SNPs from 10 genes associated with crude risk and 30 SNPs from 14 genes with stratified risk. Four SNPs showed significant associations: rs4961 (ADD1, p=0.023), rs5443 (GNB3, p=0.002), rs1042713 (ADRB2, p=0.007), and rs1042714 (ADRB2, p=0.006). The findings suggest genetic susceptibility in gastroschisis is not restricted to gene-environment interactions, with blood pressure regulation genes playing a significant role in vascular disruption pathogenesis.
▶α- and β-Adducin polymorphisms affect podocyte proteins and proteinuria in rodents and decline of renal function in human IgA nephropathyAssociationN=328Mara Ferrandi et al.(2010)· Journal of Molecular Medicine
This study demonstrates that α- and β-adducin polymorphisms affect podocyte protein expression and proteinuria in rodent models and are associated with the rate of renal function decline in human IgA nephropathy patients. The ADD2 1797T variant (rs4984) showed significant association with GFR decline (β=-4.66, p=0.0043), with significant interaction with ADD1 460Trp (rs4961, p=0.0174). Targeted deletion of β-adducin in mice reduced proteinuria and increased podocyte protein expression, while introduction of the polymorphic MHS β-adducin locus in normotensive rats caused early reduction in podocyte proteins, glomerular lesions, and proteinuria.
▶Polymorphisms in the GNB3 and ADD1 genes and blood pressure in a Chinese populationAssociationN=2,746Shufeng Chen et al.(2010)· Human Genetics
A study of 2,746 Han Chinese participants from 636 families examined associations between 12 SNPs in GNB3 and ADD1 genes and blood pressure (SBP, DBP, MAP). The GNB3 SNP rs4963516 showed significant association with diastolic blood pressure and mean arterial pressure, with CC homozygotes having 2.35 mmHg higher DBP (P=0.0002) and 2.45 mmHg higher MAP (P=0.0004) compared to A allele carriers, suggesting a role for GNB3 in blood pressure regulation in Chinese populations.
▶Diuretic Therapy, the α-Adducin Gene Variant, and the Risk of Myocardial Infarction or Stroke in Persons With Treated HypertensionMethodsN=5,126Psaty BM et al.(2002)· JAMA
This is a study design and baseline characteristics paper for a nested case-control pharmacogenetic study of antihypertensive drug treatment. The study recruited 5,126 participants (794 myocardial infarction cases, 4,997 controls) through Dutch community pharmacies to assess whether specific genetic polymorphisms in renin-angiotensin system genes (AGT, ACE, AGTR1), alpha-adducin (ADD1), and other cardiovascular-related genes (GNB3, NOS3) modify the effect of antihypertensive drugs on myocardial infarction risk. The paper presents recruitment methodology, participant baseline characteristics, and selected genetic polymorphisms for analysis rather than association results.
Gene information from NCBI Gene. Variant classifications from ClinVar.
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