Relation Between The Gene Polymorphisms Of Homocysteine Metabolic Enzymes And The Efficacy Of Oral Folic Acid In The Treatment Of Hyperhomocysteinemia

Hyperhomocysteinaemia(HHcy) is a risk factor for many diseases such as cardio-cerebrovascular diseases, diabetes, hepatorenal diseases and mental diseases,which has attracted increasing attention. A growing number of studies show that plasma homocysteine(Hcy) can be used as independent judgment of cardio-cerebrovascular diseases, and has higher application value when compared with the traditional indicators. In the methods for the prevention of HHcy, the supplement of vitamin B group is the most economic and effective, such as the folic acid. Studies found that after the treatment, the Hcy levels of some people declined,some people were still higher than normal level, eventhough they were in the same area and had the same diet habit. The relationship between the gene polymophisms of the related metabolic enzymes and the Hcy levels has been a hot research topic in recent years, but the relationship between the genetic background and the efficacy of folic acid in the treatment of HHcy has not been studied. This study is to combine the environmental factors and gentic factors to discuss the causes of the failure of folic acid therapy.ObjectiveTo study the efficacy of oral folic acid in reducing the Hcy levels, to explore the influence of the MTRR, MTR and CBS gene polymorphisms on the efficacy of oral folic acid in the treament of HHcy, and to analyze the gene-gene and gene-enviroment interactions on the efficacy.MethodsUsing the method of prospective study, the patients(Hcy≥15μmol/L) were recruited to enter the queue from the fifth affiliated hospital of Zhengzhou university between July and December in 2014 and were treated with folic acid(5mg/d) for three months. After the treatment, their plasma Hcy levels were followed up. Subjects were divided into success group(Hcy<15μmol/L) and failure group(Hcy≥15μmol/L).After extracting the whole blood genomic DNA of the subjects, the genotypes of the SNPs of MTRR gene(rs1801394, rs162036 and rs1532268), MTR gene(rs1805087)and CBS gene(rs706209, rs2851391) were identified by the Mass Array system.Under the condition of meeting Hardy-Weinberg equilibrium, the distribution characteristics of the six sites’ genotypes and alleles were analyzed between the two groups. The unconditional logistic regression was used to estimate the coarse OR, the adjusted OR and the corresponding 95% confidence intervals(95%CI). The t test was used to compare the difference of plasma Hcy levels among the genotypes of related locis. Gene-gene interactions and gene-environment interactions were evaluated using multifactor dimensionality reduction(MDR) model.Results1. Oral folic acid reduced Hcy level by 23.13%. The rs1801394 GA genotype(OR=2.69,95%CI:1.85-3.92), GG genotype(OR=2.71,95%CI:1.36-5.42),(GA+GG)genotype(OR=2.69,95%CI:1.87-3.87) and G allele(OR=1.89,95%CI:1.48-2.41)could increase the risk of the failure of folic acid therapy in the treatment of HHcy.The rs162036 GA genotype(OR=0.55,95%CI:0.36-0.82),(GA+GG) genotype(OR=0.63,95%CI:0.43-0.93) could reduce the risk of the failure of folic acid therapy.The rs706209 CT genotype(OR=2.06,95%CI:1.16-3.67), TT genotype(OR=2.05,95%CI:1.14-3.67),(CT+TT) genotype(OR=2.06,95%CI:1.17-3.56) and T allele(OR=1.27,95%CI:1.01-1.60) could increase the risk of the failure of folic acid therapy. The rs1532268, rs1805097, rs2851391 were not associated with the efficacy of folic acid therapy.2. The baseline Hcy levels of rs1801394(GA+GG) genotype were higher than rs1801394 AA genotype. The gentypes of rs162036 and rs706209 were not associated with the baseline Hcy levels.3. Haplotype AG(rs1801394-rs162036) could increase the risk of the failure of folic acid therapy in the treatment of HHcy(OR=0.66,95%CI:0.48-0.91), Haplotype GA(rs1801394-rs162036) could reduce the risk of the failure of folic acid therapy in the treatment of HHcy(OR=1.68,95%CI:1.31-2.15).4. The gene-gene interactions reported that the best model was the combination of rs1801394 and rs162036(OR=2.98,95%CI:2.16-4.11). The result of gene-environment interactions showed that the best model consisted of rs1801394,rs162036 and coronary heart disease, which had the greatest inpact on inventionIXX(OR=4.84,95%CI: 3.44-6.80).Conclusions1. The rs1801394, rs162036 and rs706209 on the gene of homocysteine metabolic enzymes can influence the efficacy of oral folic acid in the treatment of HHcy.2. Haplotypes(rs1801394-rs162036) are associated with the efficacy of folic acid therapy.3. There are significantly gene-gene interactions between rs1801394 and rs162036, and significantly gene-environment interactions between the two locis and coronary heart disease on the efficacy of folic acid therapy.