Haplotype-based association of the renin-angiotensin-aldosterone system genes polymorphisms with essential hypertension among Han Chinese: the Fangshan study

BACKGROUND: Widely evaluated regarding the genetic make-up of essential hypertension are the renin-angiotensin-aldosterone system (RAAS) genes polymorphisms, whereas results are often not reproducible. METHOD: We thus focused on a large Fangshan population to explore association of thirteen polymorphisms in five genes of RAAS. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism and direct sequencing techniques. Data were analyzed using MDR and Haplo.stats programs. RESULTS: All studied polymorphisms satisfied Hardy-Weinberg equilibrium in controls. Three polymorphisms (AGT M235T, ACE I/D and AT1R A1166C) displayed significant differences in the genotype and allele distributions between patients and controls (P < 0.05). Interaction analysis suggested a six-locus model that can be decomposed into three sets of polymorphisms (TaqI and M235T, A-20C and A-6G, I/D and A2350G) each with nonadditive effects. Logistic regression analysis indicated that TaqI Recessive: crude odds ratio (ORcrude) = 1.47, P = 0.030 and adjusted (ORadjusted) = 1.46, P = 0.050 and I/D (Recessive: ORcrude = 1.40, P = 0.002 and ORadjusted = 1.49, P = 0.002) polymorphisms were significantly and positively associated with the risk of essential hypertension. Under additive and recessive modes of inheritance, similar tendency was observed for M235T polymorphism. Two haplotypes (H6 and H9) were found to significantly reduce essential hypertension risk, whereas after correction only H6 remained significant (OR = 0.25, P = 0.0006). In contrast, haplotype H13 was significantly associated with essential hypertension with a 2.14-2.16-fold increased risk (P < 0.01). Haplotype-phenotype analysis showed significant association of inferred haplotypes with SBP (hap-score = 0.44, simulated P = 0.036). CONCLUSION: Taken together, we demonstrated three two-locus pairs of polymorphisms with synergistic effect out of three genes in RAAS and found significant haplotype-phenotype interaction. Functional studies to confirm or refute these findings are warranted.