Analysis The Efficacy Of Folic Acid Therapy For Hyperhomocysteinemia Patients And The Effect Of The Folate Metabolism-related Gene Polymorphysimson On The Efficacy

At present, the prevalence of Hyperhomocysteinemia(HHcy) in China was high and is closely related to the development of various diseases such as coronary artery disease(CAD), stroke, peripheral vascular diseases and adverse pregnancy outcome, which has serious impact on human health. Folic acid is one of the most effective drugs that can lower the plasma Hcy levels, which can reduce Hcy level by 20%-30%. Many studies have been conducted to explore the decrease in plasma Hcy levels after folic acid supplementation. However, few studies reported the effective rate defined as percentage of patients achieved normal plasma Hcy levels after folic acid therapy. Therefor, this study analyzed the effective rate of folic acid treatment for HHcy and explored the effect of gene factor and environment factor on its efficacy. ObjectiveTo analyze the effective rate of folic acid for the treatment of HHcy and to explore the impact of plasma baseline homocysteine(Hcy) levels, the compliance of oral folic acid and the folate metabolism-related gene polymorphysims on its efficacy. Also, to explore the effect of gene-gene and gene-environment interaction on its efficacy. MethodHHcy patients who were measured plasma Hcy levels in the fifth affiliated hospital of Zhengzhou University from July to December 2014 were selected as subjects. The subjects were treated with oral folic acid(5mg/d) for ninety days. The first and second phone interview was respectively conducted in the medium-term of folic acid treatment at 45 days and the end of treatment at 90 days. During the period of therapy, patients were urged to follow doctor’s advice and determine plasma Hcy levels after folic acid treatment. According to the post-treatment Hcy levels, we analysis the effective rate of folic acid for the treatment of HHcy. And subjects were divided into the success group with Hcy < 15μmol/L and the failure group with Hcy ≥ 15μmol/L. We selected 11 SNPs in MTHFR gene, MTHRD gene, MTR gene and MTRR gene. These SNPs were genotyped by the time of flight Mass spectrometry(Mass Array system) of Sequenom Company. Unconditioned logistic regression was conducted to analyze the association between 11 SNPs with the efficacy of folic acid therapy for HHcy. SHEsis software online was used to estimate haplotype. Multi-factor dimensionality reduction(MDR) software was used to evaluate gen-gen and gene-environment interaction. Result1. The effective rate of folic acid therapy for HHcy was 56.41% and the average of Hcy levels decreased by 28.05%. The effective rate of folic acid therapy in mild Hcy elevated group and intermediate Hcy elevated group were 61.34% and 27.78%, respectively(P<0.05). The effective rates among patients with good and general compliance of oral folic acid were 65.29% and 35.18%, respectively(P<0.05).2. MTHFR rs1801133 CT genotype, TT genotype and T allele, rs1801131 AC genotype, CC genotype and C allele, MTRR rs1801394 GA genotype, GG genotype and G allele and rs162306 AG genotype and AG/GG genotype were associated with the efficacy of folic acid therapy for HHcy(P<0.05). No association was seen between other SNPs and the efficacy of folic acid therapy for HHcy.3. Both haplotype CA, CC and TA(MTHFR rs1801133-rs1801131) were associated withthe efficacy of folic acid therapy for HHcy [OR(95%CI) =0.69(0.53, 0.89), 0.60(0.43, 0.88) and 1.72(1.36, 2.16)]. Both haplotype AG and GA(MTRR rs1801394-rs162036) were associated withthe efficacy of folic acid therapy for HHcy [OR(95%CI) =0.66(0.48, 0.91), 1.68(1.31, 2.15)].4. The optimal model of gene-gene interaction was two factors interaction model included rs1801133 and rs1801394. As the two factors existed, the risk of failure of folic acid treatment for HHcy was 2.65 times higher than the low risk population. The optimal model of gene-environment interaction was three factors interaction model included history of hypertension, history of coronary heart disease and rs1801133. As the three factors existed, the risk of failure of folic acid treatment for HHcy was 6.88 times higher than the low risk population. Conclusion1. Folic acid supplementation can effectively decrease Hcy level. However, almost half of HHcy patients failed to reach the normal range. High basic Hcy level and general compliance with oral folic acid are associated with lower effective rate.2. MTHFR rs1801133 CT genotype, TT genotype and T allele and MTRR rs1801394 AG genotype, GG genotype and G allele can increase the risk of the failure of folic acid treatment for HHcy. MTHFR rs1801131 AC genotype, CC genotype and C allele and MTRR rs162036 AG genotype and AG+GG genotype can reduce the risk.3. Both haplotype CA, CC(MTHFR rs1801133-rs1801131) and haplotype AG(MTRR rs1801394-rs162036) can reduce the risk of the failure of folic acid treatment for HHcy. Both haplotype TA(MTHFR rs1801133-rs1801131) and haplotype GA(MTRR rs1801394-rs162036) can increase the risk of the failure of folic acid treatment for HHcy.4. There was a significantly interaction among rs180133 and rs1801394 in the efficacy of folic acid therapy for HHcy. The interaction among rs180133, coronary heart disease and hypertensive was also found.