rs5186 - GET-Evidence

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Currentness:

rs5186


Short summary

This common noncoding genetic variant has an allele frequency of ~30% and is associated with an increased risk of hypertension. If ~25% of non-carriers have hypertension, Bonnardeaux et al’s data predict ~4% increased risk of hypertension per copy of this variant. This SNP is in the 3’ noncoding region of the AGTR1 transcript (angiotensin II type 1 receptor), also known as AT2R1 or AT1R, which is a target of hypertension drugs.

Variant evidence
Computational
Functional 2

This 3’ UTR site shown to bind miR-155 leading to mRNA degradation. Replacing A with C seems to eliminate or reverse the effect of miR-155 (as does removing the site).

See 17668390, Martin MM et al. 2006 (16675453).

Case/Control 3

p = 0.011

See Bonnardeaux A et al. 1994 (8021009).

Familial

No data found.

 
Clinical importance
Severity 4

Persistent hypertension is one of the risk factors for stroke, myocardial infarction, heart failure and arterial aneurysm, and is a leading cause of chronic kidney failure.

Treatability 4

Effective medicines exist that usually require permanent medication. Weight control and diet can reduce the amount of medication needed.

Penetrance 2

Estimate a ~4% increased attributable risk per allele (see below)

See Bonnardeaux A et al. 1994 (8021009).

 

Impact

Low clinical importance, Likely pathogenic

(The "low clinical importance, likely" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

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Summary of published research, and additional commentary

 

Allele frequency

  • C @ chr3:148459988: 21.5% (985/4584) in EVS
  • C @ chr3:149942677: 19.5% (25/128) in GET-Evidence
  • Frequency shown in summary reports: 21.5% (985/4584)

Publications
 

Bonnardeaux A, Davies E, Jeunemaitre X, Féry I, Charru A, Clauser E, Tiret L, Cambien F, Corvol P, Soubrier F. Angiotensin II type 1 receptor gene polymorphisms in human essential hypertension. Hypertension. 1994 Jul;24(1):63-9. PubMed PMID: 8021009.

This paper refers to rs5186 according to its position relative to the stop codon in mRNA: 1166. Hypertensive patients had onset less than 60 years, diastolic >95 mmHg on 2 consecutive visits OR long-term treatment, family history of <60 years-of-age hypertension in at least one parent and one sibling. These are compared to a normotensive group, which had to have systolic < 140 mm Hg, diastolic <90 mm Hg and no hypertensive treatment.

Genotypes in normotensive group: AA: 153, AC: 121, CC: 24.
Genotypes in hypertensive group: AA: 84, AC: 95, CC: 27.

Counting allele frequencies, using Fisher’s Exact this has p = 0.011. Based on hypertension incidence of ~28%, these allele frequencies predict ~4% increased attributable risk per allele.

van Geel PP, Pinto YM, Zwinderman AH, Henning RH, van Boven AJ, Jukema JW, Bruschke AV, Kastelein JJ, van Gilst WH. Increased risk for ischaemic events is related to combined RAS polymorphism. Heart. 2001 Apr;85(4):458-62. PubMed PMID: 11250978; PubMed Central PMCID: PMC1729671.

 

Kurland L, Melhus H, Karlsson J, Kahan T, Malmqvist K, Ohman KP, Nyström F, Hägg A, Lind L; Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) Trial. Angiotensin converting enzyme gene polymorphism predicts blood pressure response to angiotensin II receptor type 1 antagonist treatment in hypertensive patients. J Hypertens. 2001 Oct;19(10):1783-7. PubMed PMID: 11593098.

 

Lloyd-Jones DM, Evans JC, Levy D. Hypertension in adults across the age spectrum: current outcomes and control in the community. JAMA. 2005 Jul 27;294(4):466-72. PubMed PMID: 16046653.

According to figure 1, incidence of hypertension (Stage 1 + Stage 2) in adults < 60 years of age is 32.0% in men and 23.1% in women.

Martin MM, Lee EJ, Buckenberger JA, Schmittgen TD, Elton TS. MicroRNA-155 regulates human angiotensin II type 1 receptor expression in fibroblasts. J Biol Chem. 2006 Jul 7;281(27):18277-84. Epub 2006 May 4. PubMed PMID: 16675453.

The AGTR1 (called AT1R here) 3’ UTR is shown to bind miR-155 and decrease expression.

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PubMed PMID: 17668390

The authors note that this is an experimentally-supported target of microRNA and also contains a SNP. They created a luciferase reporter construct containing the 3’ UTR from AGTR1. In the presence of microRNA-155, the expression of the luciferase containing the 1166A allele is somewhat reduced (p = 0.019). Replacing A with C appears to reverse the effect slightly increasing expression (authors claim no effect, but one is visible in figure 2 and they fail to analyze the p-value comparing 0nM and 20nM for 1166C), as does deleting this region. There is a p-value of 0.0085 for the difference between luciferase measurements for 10nM miR-155 condition on A allele vs. C allele.

Genomes
 

hu011C57 - CGI sample GS01669-DNA_B05 from PGP sample 86486261
het C @ chr3:148459988

 

hu034DB1 - CGI sample GS00253-DNA_A02_200_37
hom C @ chr3:148459988

 

hu04FD18 - CGI sample GS00253-DNA_F01_200_37
hom C @ chr3:148459988

 

hu0D879F - CGI sample GS00253-DNA_G01_200_37
het C @ chr3:148459988

 

 

hu241DEA - CGI sample GS01175-DNA_D05 from PGP sample 1205491
het C @ chr3:148459988

 

hu2D6140 - CGI sample GS01173-DNA_F06 from PGP sample 64191565
het C @ chr3:148459988

 

hu342A08 - CGI sample GS01175-DNA_B05 from PGP sample 83494370
het C @ chr3:148459988

 

hu3CAB43 - CGI sample GS01175-DNA_D03 from PGP sample 27486199
hom C @ chr3:148459988

 

hu4040B8 - CGI sample GS01175-DNA_D01 from PGP sample 31286272
het C @ chr3:148459988

 

hu4339C0 - CGI sample GS01175-DNA_H01 from PGP sample 94797469
het C @ chr3:148459988

 

hu44DCFF - CGI sample GS01669-DNA_C07 from PGP sample 74521372
het C @ chr3:148459988

 

hu604D39 - CGI sample GS00253-DNA_B02_200_37
het C @ chr3:148459988

 

hu72A81D - CGI sample GS01173-DNA_C02 from PGP sample 10366372
het C @ chr3:148459988

 

hu92C40A - CGI sample GS01175-DNA_G03 from PGP sample 92527586
het C @ chr3:148459988

 

hu9385BA - CGI sample GS00253-DNA_E01_200_37
het C @ chr3:148459988

 

huA0E089 - CGI sample GS01175-DNA_B04 from PGP sample 88590671
het C @ chr3:148459988

 

huAE6220 - CGI sample GS00253-DNA_H01_200_37
het C @ chr3:148459988

 

huB1FD55 - CGI sample GS01173-DNA_B07 from PGP sample 61499538
het C @ chr3:148459988

 

huBEDA0B - CGI sample GS00253-DNA_C01_200_37
hom C @ chr3:148459988

 

huC30901 - CGI sample GS00253-DNA_B01_200_37
het C @ chr3:148459988

 

GS07357 - var-GS07357-1100-36-ASM
het C @ chr3:149942678

 

GS18526 - var-GS18526-1100-36-ASM
het C @ chr3:149942678

 

GS19648 - var-GS19648-1100-36-ASM
het C @ chr3:149942678

 

GS19649 - var-GS19649-1100-36-ASM
het C @ chr3:149942678

 

GS19669 - var-GS19669-1100-36-ASM
het C @ chr3:149942678

 

GS19735 - var-GS19735-1100-36-ASM
het C @ chr3:149942678

 

GS20502 - var-GS20502-1100-36-ASM
het C @ chr3:149942678

 

GS20509 - var-GS20509-1100-36-ASM
het C @ chr3:149942678

 

Other external references
 

    dbSNP
  • rs5186
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PharmGKB
  • [Hypertension]
    AGTR1:1166A, but not AGTR1:1166C, is down-regulated by microRNA MIRN155 in vitro. This may explain the reported association of the C allele with hypertension.
    www.ncbi.nlm.nih.gov/pubmed/17668390
  • [atenolol; losartan]
    Angiotensin II type 1 receptor polymorphism AGTR1:1166A>C was not related to the response to antihypertensives in the SILVHIA study of 86 white hypertensive patients.
    www.ncbi.nlm.nih.gov/pubmed/11593098
  • [Coronary Artery Disease]
    [pravastatin]
    In the REGRESS study of 885 Dutch male patients with stable coronary artery disease, patients who carried both the ACE:I/D DD genotype and AGTR1:116A>C CC genotype had significantly more ischaemic events during the two year follow up than those carrying other genotype combinations.
    www.ncbi.nlm.nih.gov/pubmed/11250978

Other in silico analyses
 

  • GET-Evidence autoscore = 1

Edit history
 

Gene search

"GENE" or "GENE A123C":

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