A propensity score-based case-control study of renin-angiotensin system gene polymorphisms and diastolic heart failure.

Angiotensin II plays an important role in diastolic heart failure (DHF). However, genetic studies of DHF are scarce in the literature. We hypothesized that RAS genes might be the susceptible genes for DHF and conducted a propensity score-based case-control study to prove this hypothesis. A total of 666 subjects (285 diagnosed with DHF confirmed by echocardiography and 381 without diastolic dysfunction) were recruited. Genotyped were: the angiotensin-converting enzyme (ACE) gene insertion/deletion polymorphism; the T174M, M235T, G-6A, A-20C, G-152A and G-217A polymorphisms of the angiotensinogen (AGT) gene; and the A1166C polymorphisms of the angiotensin II type I receptor (AT1R) gene. Propensity scores (PS) were used to find patients with and without DHF with equalized characteristics. We also assembled another set of PS matched groups for all characteristics except left ventricular mass (LVM) to detect the genetic association with DHF through the effect of left ventricular hypertrophy. PS matched 210 patients with DHF to 210 without. In a single-locus analysis, the odds ratios (ORs) for DHF were significant with the ACE DD genotype (OR=1.30, 95% CI=1.13-1.49, permuted P=0.003) and the AT1R 1166 CC genotype (OR=2.61, 95% CI=1.52-4.45, permuted P<0.001). Significant gene-gene interaction between the two genes was also detected. However, the ACE gene effect was diminished if LVM was not controlled in the propensity scores. We concluded that genetic variants in the RAS genes may determine individual risk to develop DHF through different pathways. Concomitant presence of ACE DD and AT1R 1166 CC genotypes synergistically increased the predisposition to DHF.