Study On The Relationship Between Polymorphisms Of ACE, SLC6A2 Genes And Essential Hypertension Complicated By Heart Failure

Objective: To investigat the association between polymorphisms of the norepinephrine transporter gene(solute carrier family 6, member 2; SLC6A2 promoter 3 ) angiotensin converting enzyme(ACE) gene insertion/deletion and essential hypertension complicated by heart failure.Methods: We collected EH-HF group of 176 subjects with NYHAⅢ-Ⅳfunctional class, and matched EH group with normal functional class and control subjects controlling for individual age±4, gender and geography. SLC6A2 gene-promoter3-G/C, ACE gene-I/D polymorphisms were determined with the use of Polymerase Chain Reaction-Restriction Fragment Length Polymorphism methods,and polymorphic frequencies were compared in patients with EH-HF, EH group and control. Information about prior exposure to various potential risk factors was also obtained. Chi-square test was used to compare difference of genotypes distribution among three groups. The Hardy-Weinberg equilibrium was tested by Chi-square test of goodness of fit. Odds ratios for these comparisons of dangerous factors were calculated by Binary and Multinomial Logistic Regression.Results: 1. Both ACE-I/D and SLC6A2-promoter3 polymorphism exhibited a nonsignificant difference by the Hardy-Weinberg equilibrium in control. 2. Chi-square test showed significant difference for SLC6A2-AA, AG and GG genotypes distribution in the three groups(χ2=17.063,P<0.001), and then Partitions ofχ2 method indicated that SLC6A2-AG/GG genotype frequencies in EH-HF group(41.48%) were significantly higher than those in EH group(26.70%)and Control group(22.16%) (χ2=7.937,P=0.005). The constituent ratio of ACE-II, ID, DD genotype was significantly different in the three groups(χ2=19.858,P=0.001), and then Partitions ofχ2 method showed that ACE–DD genotype frequencies in EH-HF group(26.14%) were significantly higher than those in EH group(12.50%)and Control group(22.16%)(χ2=17.897,P<0.001). The 2 gene conjoint Analysis indicated significant difference of combined genotype frequencies in the three groups (χ2=34.604 , P < 0.001), furthermore, and Partitions ofχ2 method showed that DD+AG/GG genotype frequencies in EH-HF group(11.36%) were significantly higher than those in EH group(3.41%)and Control group(1.70%)(χ2=17.532,P<0.001).3. Multinomial logistic-regression Analysis indicated that Smoke, High blood sugar, Kidney hypofunction, Blood Pressure Levels, ACE-DD genotype, SLC6A2-AG/GG genotype and combined DD+AG/GG genotype were risk factors for EH-HF with the reference category of EH. The odds ratios(OR) of the SLC6A2-AG/GG genotype vs AA and ACE-DD genotype vs II/ID for EH-HF were 1.905 (95%CI: 1.138-3.188,P=0.014) and 1.908 (95%CI: 1.009-3.609,P=0.047) after adjusting other confounding factors, respectively. If II/ID+AA genotype was made reference frame(OR=1), maximal OR was significantly found after adjustment: OR for DD+AG/GG genotype vs the other was 3.446 (95%CI: 1.195-9.940). It is suggested that the cooperation of two genes was significantly associated with hypertension complicated with heart failure.Conclusion: SLC6A2-GG/AG, ACE-DD and DD+AG/GG genotype may be the independent risk factors of hypertensive patients with heart failure。DD+AG/GG genotype are significantly associated with EH-HF and have the highest risk in EH-HF,and may be one of the genes that contribute to EH-HF in Chinese. It suggests that ACE and SLC6A2 gene have synergistic action in the pathogenesis of EH-HF.