Association Study Between Polymorphism Of The BHMT And CBS Gene And The Efficacy Of Oral Folate Therapy In Patients With Hyperhomocysteinemia

Hyperhomocysteinemia(HHcy)is a disorder characterized by an abnormal increased level of homocysteine(Hcy)in the blood.Nowadays,the prevalence of HHcy in China is significantly higher than that in western countries.HHcy,an independent risk factor for various cardiovascular diseases(CVD),seriously threatens human health.The prevention and treatment of HHcy is of great public health significance for CVD prevention.There is a consensus that folate is one of the most effective drugs for lowering plasma Hcy levels.Folate have the preventive effect on the occurrence and development of stroke.Most studies only reported the reduction in plasma Hcy levels after long-term folate supplementation but did not assess whether plasma Hcy was reduced to a normal level.Factors affecting plasma Hcy level include age,sex,living habits,liver and kidney function,nutritional factors and genetic factors.In genetic factors,single nucleotide polymorphism(SNP)of folate/Hcy metabolism-related enzymes are research hotspot in recent years.The aim of study is to investigate the effects of gene polymorphisms on the efficacy of folate therapy in HHcy patients.Objective The aim of this study was to evaluate,combining with environmental factors in HHcy patients,the effects of gene polymorphisms in BHMT and CBS gene on the efficacy of oral folate therapy.Methods We utilized a prospective cohort study among the Chinese Han population.All participants were outpatients in treatment at the Department of Neurology at The Fifth Affiliated Hospital of Zhengzhou University in Zhengzhou,the capital of Henan Province in central China,from July to December 2014.Patients were eligible for inclusion if they were diagnosed with HHcy(total plasma Hcy >15?mol/l).All individuals who were enrolled in this study were treated with oral folate(5mg/d)for 90 days.Demographic data(such as age,gender,etc.)and clinical information were obtained at baseline.Fasting plasma Hcy concentrations were measured at baseline.Compliance with oral folate was assessed by phone interview at 45 days and 90 days of follow-up.Plasma Hcy levels were tested at the second follow-up.The patients included in the final analysis were grouped into the treatment success group and treatment failure group based on Hcy levels at the second follow-up(post-treatment Hcy levels).The therapy was effective if patients' Hcy levels decreased to 15?mol/L or less,which put them in the success group.The therapy was unsuccessful if patients' Hcy levels were still >15?mol/l,which put them in the failure group.The analysis of the rs3733890,rs2851391 and rs706209 mutation was performed in triplicate using a matrix-assisted laser desorption/ionization time-of-flight(MALDI-TOF)mass spectrometry platform(MassArray Analyzer;Sequenom,San Diego,CA,USA).Logistic regression analyses were used to explore potential gene-environmental interactions based on additive models.Generalized multifactor dimensionality reduction(GMDR)model was used to analyze multi-factor interactions.Results 1.The plasma Hcy levels at baseline were higher in the success group,compared with that in the failure group(24.28±9.72 vs 20.17±6.36,P<0.001).The changes in the level of plasma Hcy because of folate supplementation in the success groups were obviously greater than that in the failure group(35.63% vs 10.16%,P<0.001).2.Smoking,drinking,diabetes,hypertension,coronary heart disease and dyslipidemia had significant effects on the efficacy of folate therapy,and the cumulative effect of these environmental risk factors would significantly increase the risk of treatment failure in HHcy patients(P<0.001).3.The BHMT rs3733890 and CBS rs706209 genotype distribution presented distinct differences in the two groups.The rs3733890 mutant genotype and allele had significantly increased risk of treatment failure(OR=1.45,95%CI:1.06~1.97;OR=1.38,95%CI:1.09~1.75).Likewise,the rs706209 mutant genotype and allele had significantly increased risk of treatment failure(OR=2.02,95%CI:1.23~3.31;OR=1.27,95%CI:1.01~1.60).The genotype distribution of rs2851391 presented no differences in the two groups(P>0.05).4.The synergistic effects of the BHMT rs3733890 and CBS rs706209 polymorphism with environmental factors(smoking,drinking,diabetes,hypertension,coronary heart disease and dyslipidemia)on the efficacy of oral folate therapy were found(P<0.05,RERI>0).The interaction between CBS rs2851391 polymorphism and environmental factors did not achieve statistical significance.5.There was gene-gene interaction between rs3733890,rs2851391 and rs706209,and HHcy patients who carry three SNPs at the same time had a higher risk of folate treatment failure(OR=2.14,95%CI:1.33~3.43).Smoking,drinking,diabetes,hypertension,coronary heart disease and dyslipidemia,rs3733890,rs2851391 and rs706209 were the optimal models of gene-environment multifactor interactions,which significantly affect the effect of folate intervention in HHcy patients(OR=23.01,95%CI:12.46~42.51).Conclusions 1.The gene polymorphism of BHMT rs3733890 and CBS rs706209 was significantly associated with the efficacy of oral folate therapy for HHcy.2.The interactions between gene polymorphisms of BHMT rs3733890,CBS rs2851391,rs706209 and smoking,drinking,past history would affect the efficacy of oral folate therapy for HHcy.