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From SNPedia

Geno Mag Summary
(G;G) 0 normal
(G;T) 2 1.8x increased risk for high blood pressure
(T;T) 2.1 1.8x increased risk for high blood pressure
ReferenceGRCh38 38.1/141
is asnp
is mentioned by
dbSNP (classic)rs4961
1000 genomesrs4961
GWAS Ctlgrs4961
Max Magnitude2.1
? (G;G) (G;T) (T;T) 28

rs4961 is a variation in the adducin 1 ADD1 gene, encoding a change from a glycine to a tryptophan, so it is also known as G460W or Gly460Trp.

Originally, a study of 477 Italian patients indicated that carriers of one or two rs4961(T) alleles were at 1.8x increased risk for hypertension (CI: 1.32-2.43). This study also indicated that carriers of the risk (T) allele responded better to diuretics and sodium-restricted diets, in that they tended to lower their blood pressure by ~10 mmHg points compared to rs4961(G;G) homozygotes similarly treated.[PMID 9149697]

Subsequent studies have tended to confirm this association, and to extend it to risk for heart disease. They also have tended to confirm that risk allele carriers respond better to therapy.

In a study of ~2200 Belgian patients, rs4961(T) carriers were generally at 2-3 fold higher rik for cardiovascular mortality and morbidity.[PMID 16043664]

In a study of ~1000 hypertensives followed for 10 years, rs4961(T) carriers responded better to low-dose diuretic therapy, as seen by a lower (almost halved) risk of combined myocardial infarction or stroke than if other antihypertensive therapies were used to achieve the same reduction in blood pressure.[PMID 11926892]

A SNP in another adducin gene, adducin 3 ADD3, may modify the risk of carrying an rs4961 risk allele. Carriers of an rs4961(T) allele who are also rs3731566(G;G) homozygotes have higher systolic and diastolic blood pressure, by about 8 mmHg, compared to if they have another rs3731566 genotype.[PMID 15716695]

This SNP is also cited in US patent 10,465,246 (2019), where one of the claims is prescribing a hydrochlorothiazide to a patient as a first line therapy (for high blood pressure), without a beta blocker and without a vasodilator, if the patient carries a rs4961(T).

rs4961 is in strong linkage with rs4963 (also known as S586C), another ADD1 gene SNP.

[PMID 19927152] Accumulation of common polymorphisms is associated with development of hypertension: a 12-year follow-up from the Ohasama study

[PMID 19960031] Lack of association between alpha-adducin G460W polymorphism and hypertension: evidence from a case-control study and a meta-analysis

[PMID 20145305] Association between α-adducin gene polymorphism (Gly460Trp) and genetic predisposition to salt sensitivity: a meta-analysis

[PMID 19838659OA-icon.png] alpha- and beta-Adducin polymorphisms affect podocyte proteins and proteinuria in rodents and decline of renal function in human IgA nephropathy

[PMID 21291465] The association of genetic polymorphisms with cerebral palsy: a meta-analysis

[PMID 21339657] Angiotensin-converting enzyme (rs4646994) and ? ADDUCIN (rs4961) gene polymorphisms' study in primary spontaneous intracerebral hemorrhage


Risk Rs4961(T;T)
Alt Rs4961(T;T)
Reference Rs4961(G;G)
Significance Other
Disease Hypertension furosemide and spironolactone response - Efficacy
Variation info
Gene ADD1
CLNDBN Hypertension, salt-sensitive essential, susceptibility to furosemide and spironolactone response - Efficacy
Reversed 0
HGVS NC_000004.11:g.2906707G>T
CLNSRC OMIM Allelic Variant PharmGKB Clinical Annotation UniProtKB (protein)
CLNACC RCV000019936.2, RCV000211330.1,

[PMID 18279468OA-icon.png] Ten renin-angiotensin system-related gene polymorphisms in maximally treated Canadian Caucasian patients with heart failure.

[PMID 18398333OA-icon.png] Relationships among endogenous ouabain, alpha-adducin polymorphisms and renal sodium handling in primary hypertension.

[PMID 18513389OA-icon.png] New application of intelligent agents in sporadic amyotrophic lateral sclerosis identifies unexpected specific genetic background.

[PMID 18660489] Multiple genetic variants along candidate pathways influence plasma high-density lipoprotein cholesterol concentrations.

[PMID 18787518] Arterial properties in relation to genetic variations in the adducin subunits in a white population.

[PMID 19131662OA-icon.png] A meta-analysis of candidate gene polymorphisms and ischemic stroke in 6 study populations: association of lymphotoxin-alpha in nonhypertensive patients.

[PMID 19199261] [Association of the polymorphisms of sodium transport related genes with essential hypertension].

[PMID 19263529OA-icon.png] Genetic risk factors in recurrent venous thromboembolism: A multilocus, population-based, prospective approach.

[PMID 19330901OA-icon.png] Association of 77 polymorphisms in 52 candidate genes with blood pressure progression and incident hypertension: the Women's Genome Health Study.

[PMID 19379518OA-icon.png] Development of a fingerprinting panel using medically relevant polymorphisms.

[PMID 19559392OA-icon.png] A candidate gene association study of 77 polymorphisms in migraine.

[PMID 19574959OA-icon.png] Novel genetic variants in the alpha-adducin and guanine nucleotide binding protein beta-polypeptide 3 genes and salt sensitivity of blood pressure.

[PMID 20565774OA-icon.png] Population based allele frequencies of disease associated polymorphisms in the Personalized Medicine Research Project.

[PMID 21194526] A study of ACE and ADD1 polymorphism in ischemic and hemorrhagic stroke.

[PMID 22198647] Do ACE (rs4646994) and alphaADDUCIN (rs4961) gene polymorphisms predict the recurrence of hypertensive intracerebral hemorrhage?

[PMID 23122309] The relationship between polymorphisms at 17 gene sites and hypertension among the Aboriginal Tibetan people

[PMID 22810272] Computational study of ADD1 gene polymorphism associated with hypertension.

[PMID 27480094] Association of interactions between dietary salt consumption and hypertension-susceptibility genetic polymorphisms with blood pressure among Japanese male workers.

[PMID 26387843] Gene and dietary calcium interaction effects on brachial-ankle pulse wave velocity.

[PMID 29550988] Genetic variants conferring susceptibility to gastroschisis: a phenomenon restricted to the interaction with the environment?