Promoter Variants of the ADAM10 Gene and Their Roles in Temporal Lobe Epilepsy.

Hua Tao,Jianghao Zhao,Ying Chen,Lifen Yao,Haihong Zhou,Yujie Cai,Lili Cui,Zhonghua Ma,Fuhai Sun,Xu Zhou,Bin Zhao,Shu Zhao,Yanyan Chen,Keshen Li

doi:10.3389/fneur.2016.00108

Abstract

Previous evidence has indicated that downregulated ADAM10 gives rise to epileptic seizures in Alzheimer’s disease, and this study investigated the association of ADAM10 with temporal lobe epilepsy (TLE) from a genetic perspective. A total of 496 TLE patients and 528 healthy individuals were enrolled and genotyped for ADAM10 promoter variants (rs653765 G > A and rs514049 A > C). The alleles, genotypes, and haplotypes were then compared with clarify the association of these variants with TLE and their impacts upon age at onset, initial seizure types before treatments, and responses to drug treatments. In cohorts I, II, and I + II, the frequencies of the A allele and AA genotype at rs514049 were consistently increased in the cases compared with the controls (p = 0.020 and p = 0.009; p = 0.008 and p = 0.009; p = 0.000 and p = 0.000; q = 0.003 and q = 0.002, respectively). In contrast, the frequency of the AC haplotype (rs653765–rs514049) decreased in cohorts I + II (p = 0.013). Further analyses of the TLE patients indicated that the AA genotype functioned as a predisposing factor to drug-resistant TLE and the AC haplotype as a protective factor against generalized tonic–clonic seizures (GTCS) and drug-resistant TLE. This study is the first to demonstrate an association of the ADAM10 promoter variants with TLE. In particular, the AA genotype and AC haplotype showed their effects upon GTCS and drug-resistant TLE.

Highlights

The past decades have witnessed great efforts to investigate temporal lobe epilepsy (TLE), but its pathogenesis remains unclear [1]
We first observed the roles of the promoter variants in TLE: the A allele and the AA genotype at rs514049 were associated with predisposition to TLE, whereas the AC haplotype exerted protective effects against TLE
Further analyses of the TLE patients indicated that the AA genotype functioned as a predisposing factor to drug-resistant TLE and the AC haplotype as a protective factor against generalized tonic–clonic seizures (GTCS) and drug-resistant TLE

Summary

Introduction

The past decades have witnessed great efforts to investigate temporal lobe epilepsy (TLE), but its pathogenesis remains unclear [1]. Some brain diseases are associated with increased risks of seizures, especially Alzheimer’s disease (AD), with a 6- to 10-fold risk of developing seizures [2,3,4,5,6,7,8]. The levels of ADAM10 decrease in the pyramidal cell layers of the rat hippocampus after status epilepticus [12] and in the brain tissues of AD patients [13]. After the gene encoding ADAM10 was knocked out in mice, the expression level of ADAM10 was downregulated in the brain cortex; this was accompanied by repetitive seizures [14], which indicate that insufficient expression of ADAM10 could represent a potential etiology of epileptic seizures in AD patients. ADAM10 should play a protective role against epileptic activities

Methods

Results

Conclusion