Renin-Angiotensin System Gene Polymorphisms and Diastolic Heart Failure

Objectives: We analysis the renin-angiotensin system(RAS) genes and determine the association between single locus RAS genes polymorphisms, and multilocus AGT gene polymorphisms and gene-gene interaction with diastolic heart failure(DHF).
Background: DHF refers to an abnormality of diastolic distensibility, filling, or relaxation of the left ventricle. Pathology leading to DHF include impaired relaxation, increased passive stiffness, endocardial and pericardial disorders, microvacular flow and neurohormonal regulation. Among them, the association of RAS system and diastolic dysfunction are already established. There are many reports demonstrating the association of RAS system genes polymorphisms with congestive heart failure, but to what extent they affect DHF remains uncertain. We hypothesized that RAS gene might be the susceptible gene for DHF and conducted a case-control study with this regard.
Method: The definition of DHF is according to guidelines from the ACC and AHA which include typical symptoms and signs of heart failure, normal left ventricle(LV) ejection fraction, evidence of LV impaired relaxation under echocardiography. Exclusion criteria include coronary artery disease, significant valvular heart disease, cardiomyopathy, pericardial disease and renal insufficiency. A total of 148 patients with DHF and 148 controls were included. The controls were matched to cases on a 1-to-1 basis with regard to age, gender, diabetes mellitus, hypertension. The ACE gene insertion/deletion polymorphism, the T174M, M235T, G-6A, A-20C, G-152A and G-217A polymorphisms of the angiotensinogen gene and the A1166C polymorphisms of the angiotensin II type I receptor gene were genotyped. Differences in allele frequencies and genotype distributions between the DHF and control group patients were compared using the χ2 test or the Fisher exact test. Mutilocus haplotypes analysis and gene-gene interaction analysis were performed by composite haplotype method of Zaykin et al.
Results In single-locus analysis, ACE gene DD genotype, the angiotensin II type I receptor A1166C gene CC genotype were significantly associated with higher incidence of DHF. The odds ratio for DHF were 2.37 (95% CI 1.33 to 4.22, p=0.003) with ACE DD genotype, 4.44 (95% CI 1.81 to 10.9, p=0.001) with 1166CC plus 1166AC genotype. In addition, two angiotensinogen gene haplotype frequencies (GAAATC, AGAGCC) were significantly different between DHF group and the controls. There were obvious gene-gene interaction between ACE I/D and AGT A-20C, T174M in determing DHF.
Conclusions This study confirmed an association of RAS gene polymorphisms with DHF. ACE DD and AT1R 1166 AC/CC genotypes conferred risk for DHF. We first demonstrate that AGT haplotype is associated with DHF.