The Role Of Methylation Of Folate Metabolism-Related Gene In The Efficacy Of Oral Folate Therapy In Patients With Hyperhomocysteinemia

Folate supplementation is the first-line therapy for hyperhomocysteinaemia?HHcy?.Up to 40%of HHcy patients do not benefit from folate therapy.Folate metabolism is a complex metabolic network involving many enzymes.Besides affecting the metabolism of homocysteine?Hcy?,folate metabolism is also closely related to DNA methylation.As one of the most common epigenetic mechanisms,DNA methylation can make up for the defect of genetic factors.Although,several investigations have demonstrated that DNA methylation of BHMT and MTHFR in folate metabolic network is associated with Hcy concentrations,the relationship linking DNA methylation and the efficacy of folate therapy remain unknown.It is necessary to further explore the role of methylation in the efficacy of folate therapy in HHcy patients.ObjectiveCombining with the environmental and genetic factors in the efficacy of folate therapy.To estimate the association between the methylation levels of BHMT and MTHFR with the efficacy of folate therapy,and to explore what role can DNA methylation play in the efficacy of folate therapy.MethodsAll participants were outpatients at the Department of Neurology in the Fifth Afiliated Hospital of Zhengzhou University from July to December in 2014.All patients were given oral folate?5mg/d?for 90 days.According to the plasma Hcy concentrations were obtained at the day 90,patients were then divided into success group?Hcy<15?mol/L?and failure group?Hcy?15?mol/L?,respectively.299 individuals were recruited by extreme sampling approach and DNA methylation level was examined using High-throughput sequencing.To explore the role of DNA methylation in the efficacy of folate therapy by three causal models:?1?Independent associations model,?2?Interaction model,and?3?Mediation model.Results1.There were statistically significant differences in the distribution of levels of baseline Hcy level,body mass index?BMI?,total cholesterol?TC?,low-density lipoprotein cholesterol?LDL-C?,vitamin B12,and the distribution of diabetes,hypertension,stroke and coronary heart disease?CHD?between the success group and failure group?P<0.05?.2.After 90 days of folate intervention,the change of Hcy level in success group?40.10%?was higher than failure group?10.18%?.Hypertension,stroke,CHD,and genetic variation had significant effects on the efficacy of folate therapy?P<0.05?.3.Independent associations analysis showed that DNA methylation of BHMT and BHMT₁ was associated with the efficacy of folate therapy?P<0.05?,OR?95%CI?were 0.576?0.360-0.921?and 0.577?0.361-0.924?.There was no significant association between MTHFR methylation and the efficacy of folate therapy?P>0.05?.4.Interaction analysis showed that there was no interaction between BHMT methylation with environmental or genetic factors,but presented the interaction between MTHFR methylation and CHD,and the RERI was 6.370?1.449-11.292?.There was an interaction between MTHFR hyper-methylation with rs1801133 polymorphism in dominant genetic model?P<0.05?.5.Mediation analysis showed that the methylation of BHMT and BHMT₁ mediate 34.84%?P=0.03?and 33.06%?P=0.044?of the effect of rs3733890 on the efficacy of folate therapy,respectively.Conclusions1.DNA methylation level of BHMT was associated with the efficacy of folate therapy.2.DNA methylation level of MTHFR would affect the efficacy of folate therapy according to the interaction with environment and genetic factors3.DNA methylation levle of BHMT proportional mediates the effects of polymorphisms on the efficacy of folate therapy.