CpG Methylation Signature Define Human Temporal Lobe Epilepsy and Predict Drug-Resistant

Abstract

Background: Temporal lobe epilepsy (TLE) is the most common focal epilepsy syndrome in adults and frequently develops drug resistance. Aberrant DNA methylation implicated in underlying epileptogenesis and progression mechanisms of epilepsy has gained considerable attention. A substantial number of studies have investigated the value of peripheral DNA methylation signature as molecular biomarker for diagnosis or prognosis. However, to date, methylation biomarkers for TLE diagnosis and pharmacoresistance prediction have not been explored. Methods: We initially conducted genome-wide DNA methylation profiling in TLE patients; then selected candidate CpGs in training cohort and validated those CpGs in another independent cohort by employing machine learning algorithms. Furthermore, a nomogram comprising DNA methylation and clinicopathological data was generated to predict the drug-response in the entire patient cohort. Lastly, bioinformatics analysis for CpGassociated genes was performed using Ingenuity Pathway Analysis. Findings: After screening and validation, eight CpGs were identified for diagnostic biomarker with an area under the curve (AUC) of 0.81, six CpGs for drug-resistant prediction biomarker with an AUC of 0.79. The nomogram for drug-resistant prediction comprised methylation risk score, disease course, seizure frequency, and hippocampal sclerosis,with AUC as high as 0.96. Bioinformatics analysis indicated drug-response related CpGs corresponding genes closely related to DNA methylation. Interpretation: This study introduced a methodological framework to screen and validate CpG methylation biomarker, and demonstrates the ability to use machine learning as a potential clinical tool for epilepsy diagnosis and drug-resistant prediction after more comprehensive validation. Funding Statement: This study was supported financially by Omics-based precision medicine of epilepsy being entrusted by Key Research Project of the Ministry of Science and Technology of China(No. 2016YFC0904400), and the National Natural Science Foundation of China (No.81671299 to BX, No.81671300 to LLL and No.81701182 to YJF), and the Science and Technology Department Funds of Hunan Province Key Project(No.2016JC2057 to BX and No.2018JJ3822 to HYL)and Independent Exploration and Innovation project for postgraduate of Central South University(No. 2018zzts248 to WBX). Declaration of Interests: The authors stated: None declared. Ethics Approval Statement: Written informed consent was obtained from all enrolled participants. Study was conducted in accordance with the guideline for the research involving human, and approved by the Ethics Committee of Central South University, Xiangya School of Medicine and the affiliated Xiangya Hospital.