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Angiotensin II type 1 receptor gene polymorphisms in patients with cardiac hypertrophy
A Ishanov1, H Okamoto, M Watanabe
1Department of Cardiovascular Medicine, Hokkaido University, School of Medicine, Sapporo, Japan.
Insights
The angiotensin II type 1 receptor (AGT1R) A1166C gene variant does not directly cause left ventricular hypertrophy (LVH) or hypertrophic cardiomyopathy (HCM). However, combined with the ACE D allele, it increases the risk for family history of HCM in relatives without manifesting the disease.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Hypertension Research
Background:
- Arterial hypertension-induced chronic mechanical stress is a key driver of left ventricular hypertrophy (LVH).
- The renin-angiotensin system (RAS) influences cardiac hypertrophy, partly independent of systemic blood pressure.
- Angiotensin converting enzyme (ACE) is upregulated in cardiac hypertrophy and heart failure.
Purpose of the Study:
- To investigate the role of angiotensin II type 1 receptor (AGT1R) A1166C gene polymorphisms in the development of left ventricular hypertrophy (LVH).
- To examine the interaction between AGT1R A1166C and ACE I/D polymorphisms in relation to LVH and hypertrophic cardiomyopathy (HCM).
Main Methods:
- Genotyping of AGT1R A1166C and ACE I/D polymorphisms in patients with hypertensive LVH, HCM patients, HCM relatives, and healthy controls.
- Statistical analysis including chi-squared tests and odds ratio calculations to assess allele frequencies and gene-gene interactions.
Main Results:
- The C allele frequency of AGT1R A1166C was higher in hypertensive LVH and HCM relatives compared to HCM patients, but not significantly different from healthy controls.
- A significant interaction was observed between ACE D allele and AGT1R C allele in HCM relatives, increasing the odds of a family history of HCM.
- The AGT1R A1166C variant alone did not appear to contribute to cardiac hypertrophy in hypertensive LVH or HCM.
Conclusions:
- The AGT1R A1166C gene polymorphism is not a direct contributor to cardiac hypertrophy in hypertensive LVH and HCM.
- Combined carriage of ACE D and AGT1R C alleles is associated with an increased risk for family history of HCM in asymptomatic relatives.
- Genetic variations within the RAS pathway, particularly interactions between ACE and AGT1R, play a complex role in the predisposition to cardiac hypertrophy and HCM.
Abstract:
Chronic mechanical stress of the heart secondary to arterial hypertension is a primary cause of left ventricular hypertrophy (LVH). The renin-angiotensin system (RAS) plays an important role in the cardiovascular system, regulating the expression of cardiac hypertrophy, in part, independent of the effects of systemic hypertension. A major component of RAS is angiotensin converting enzyme (ACE), which is upregulated in pressure overload-induced cardiac hypertrophy as well as heart failure. In a recent study, we found that the T allele of the M235T polymorphism of the angiotensinogen gene in sporadic hypertrophic cardiomyopathy (HCM) patients is associated with LVH. The present study was designed to assess the contribution of the polymorphisms of the angiotensin II type 1 receptor (AGT1R A1166C) genes on development of left ventricular hypertrophy. Patients with hypertensive LVH and relatives of HCM without manifesting the disease, showed higher C allele frequency compared to patients with HCM (11.3% vs 4.2%, chi 2 = 5.3, p < 0.05 and 10.5% vs 4.2%, chi 2 = 5.3, p < 0.05, respectively), but healthy controls did not (11.3% vs 7.5%, chi 2 = 1.42, NS and 10.5% vs 7.5%, chi 2 = 1.2, NS). The strong interaction between ACE I/D and AGT1R A1166C gene polymorphisms has been found in groups of relatives of HCM patients; odds ratio associated with ACE D allele was significant in subjects carrying the AGT1R C allele (OR = 7.3, 95% CI 1.6-33.1; chi 2 = 7.9, p < 0.02) compared with healthy subjects. We conclude that the molecular variant of the AGT1R A1166C gene is not contributing to the development of cardiac hypertrophy in hypertensive LVH and HCM patients, whereas carriers of both C and D alleles had a four-fold increase in the odds ratio for family history of HCM without manifesting the disease.