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AT1R (Angiotensin II Type 1 Receptor) :

DEFECT: An A to C transversion at position 1166 of the 3'untranslated region of the AT1R gene.

FREQUENCY: 17% of Caucasians of European descent have the AT1R CC genotype.

MODE OF ACTION: The Angiotensin II Type 1 Receptor (AT1R) is a major component of the renin-angiotensin system which regulates blood pressure. The AT1R binds Angiotensin II, a potent regulator of cardiovascular homeostasis.

ASSOCIATED RISK: The C allele is more prevalent in hypertensive patients.

METHOD OF DETECTION: Allele-specific PCR.

POSSIBLE CLINICAL UTILITY: Hypertensive individuals and those presenting with coronary artery disease should be tested for this polymorphism.

References:

1. Anvari A, Turel Z, Schmidt A, Yilmaz N, Mayer G, Huber K, Schuster E, Gottsauner-Wolf M.; Angiotensin-converting enzyme and angiotensin II receptor 1 polymorphism in coronary disease and malignant ventricular arrhythmias. Cardiovasc Res 1999 Sep;43(4):879-83

This is the first report investingating the association between the ACE and AT1 receptor gene polymorphisms and malignant ventricular arrhythmias. The risk of malignant ventricular arrhythmias was associated with the combination of ACE D and AT1 C allele. Among CAD patients with malignant ventricular arrhythmias and treated with an implantable cardioverter defibrillator (ICD), the prevalence of ACE DD genotype and the AT1 CC genotype was found to be significantly higher (19% versus 10%, p < 0.0001) than in CAD patients without malignant ventricular arrhythmias (controls). The risk for malignant ventricular arrhythmias was associated with the combination of ACE D and AT1 C alleles (odds-ratio: 2.4, 95% confidence interval 1.41 to 3.94, p < 0.001). Because of available pharmacological inhibitors, the researchers suggest that these results may have clinical implications for the prevention of sudden cardiac death.

2. Alvarez R, Reguero JR, Batalla A, Iglesias-Cubero G, Cortina A, Alvarez V, Coto E.; Angiotensin-converting enzyme and angiotensin II receptor 1 polymorphisms: association with early coronary disease. Cardiovasc Res 1998 Nov;40(2):375-9

The researchers found a synergistic contribution of ACE and AT1R polymorphisms to the risk of coronary artery disease. Among patients with the AT1R CC genotype, there was a higher prevalence of the ACE DD allelle, with an odds ratio of 5.32. In addition, among the AT1R CC patients, 13% of the hypertensives and 75% of the normotensives were DD (p = 0.014). This gene-gene interaction could have clinical implications. Approximately 2% of individuals in our population are CC + DD, and the genotyping of both polymorphisms could identify those with a high relative risk for coronary artery disease.

3. Tiret L, Bonnardeaux A, Poirier O, Ricard S, Marques-Vidal P, Evans A, Arveiler D, Luc G, Kee F, Ducimetiere P, et al; Synergistic effects of angiotensin-converting enzyme and angiotensin-II type 1 receptor gene polymorphisms on risk of myocardial infarction. Lancet 1994 Oct 1;344(8927):910-3

The researchers found a significant interaction between ACE (I/D) and AT1R (A/C) gene polymorphisms. The odds ratio for myocardial infarction associated with the ACE DD genotype was 1.05 for subjects without the AT1R C allele, 1.52 in AC heterozygotes, and 3.95 in CC homozygotes. Among patients defined as low risk, the interaction was even stronger. The odds ratio for ACE DD patients are 1.64 if they are AT1R AA, 7.03 for AC heterozygotes and 13.3 for CC homozygotes.

4. Bonnardeaux A, Davies E, Jeunemaitre X, Fery 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

The researchers have identified five polymorphisms (T573-->C, A1062-->G, A1166-->C,
G1517-->T, and A1878-->G) in the 3' untranslated region of the AT1R gene. However, no mutations that alter the encoded amino acid sequence were detected. A significant increase in allelic frequency of C1166 was found in hypertensive subjects (P < .01). These findings are compatible with a common variant of the AT1 receptor imparting a small effect on blood pressure.

5. Amant C, Hamon M, Bauters C, Richard F, Helbecque N, McFadden EP, Escudero X, Lablanche JM, Amouyel P, Bertrand ME.; The angiotensin II type 1 receptor gene polymorphism is associated with coronary artery vasoconstriction. J Am Coll Cardiol 1997 Mar 1;29(3):486-90

The AT1 receptor gene polymorphism is associated with coronary vasomotion in humans. Among 140 patients with normal coronary arteries, coronary vasomotion was assessed with quantitative coronary angiography. The patients carrying the AT1 receptor CC genotype was found to have significantly greater vasoconstriction in distal coronary vessels (p < 0.009).

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