Associations between genetic variation in one-carbon metabolism and leukocyte DNA methylation in valproate-treated patients with epilepsy.
Valproate (VPA) as a first-line antiepileptic drug is useful for the most types of epileptic seizure treatment. Previous studies observed that VPA influenced one-carbon metabolism (OCM), consequently, DNA methylation. However, other individual genetic variations, as well as VPA, modify DNA methylation.



In this study, we investigated associations between genetic variations in OCM and leukocyte DNA methylation in VPA-treated patients with epilepsy.



This was a cross-sectional study of 101 epileptic patients who underwent VPA monotherapy and 68 healthy controls. All subjects were measured OCM-related nutrients (folate, homocysteine and vitamin B12), and DNA methylation of specific regions were analyzed. Furthermore, we examined the associations between genetic variations in OCM and DNA methylation levels in epileptic patients.



VPA-treated patients with epilepsy exhibited both higher serum homocysteine and vitaminB12 levels and lower folate levels relative to controls (P = 0.018, P = 0.003, P < 0.001 respectively), the methylation level of the MTHFR amplicon was significantly lower in the VPA group compared with those in the controls (P = 0.043). VPA-treated epileptic patients carrying the T-allele of methylenetetrahydrofolate reductase (MTHFR) c.677C>T showed higher serum Hcy levels than those observed in the 677CC group (P < 0.01). Epileptic patients who carried G-allele of methionine synthase (MTR) c.2756A>G showed significantly lower MTHFR amplicon methylation levels compared to carriers of the wild-type MTR 2756AA genotype (P = 0.028).



Our study provided evidence that the MTR c.2756A>G polymorphism is associated with MTHFR amplicon hypomethylation in VPA-treated patients with epilepsy.
Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China.
Guanzhong
G
Ni
Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China.
Jiaming
J
Qin
Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China.
Ziyi
Z
Chen
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong Province, China.
Hongliang
H
Li
Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China.
Jueqian
J
Zhou
Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong Province, China.
Min
M
Huang
Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, China. Electronic address: lmzhou56@163.com.
Liemin
L
Zhou
D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000627:therapeutic use*; D016022:Case-Control Studies; D019175:DNA Methylation / Q000235:genetics*; D004827:Epilepsy / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics; D005260:Female; D006801:Humans; D007962:Leukocytes / Q000737:chemistry; D008297:Male; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D014635:Valproic Acid / Q000627:therapeutic use*; D055815:Young Adult
D000927:Anticonvulsants; D014635:Valproic Acid; D008780:Methyltransferases
DNA methylation; Epilepsy; One-carbon metabolism; Single nucleotide polymorphism; Valproate