ASIC1a polymorphism is associated with temporal lobe epilepsy
Introduction
Epilepsy is one of the most common neurological disorders with a 510⿰ morbidity rate in developed countries (Sander, 2003). Moreover, it accounts for a worldwide illness burden similar to that of breast cancer in women and of lung cancer in men (Kale, 1997). Temporal lobe epilepsy (TLE) is the most common heterogeneous epilepsy syndrome, with both environmental and genetic factors playing a role in its etiology (Stogmann et al., 2002), a feature that is responsible for a majority of the treatment-resistant seizure types. Identifying genetic and pathophysiological pathways involved in epilepsy is critical for the rational design of improved treatments for the one-third of epilepsy patients who do not respond to current medications (Schmidt and Loscher, 2005). Genetic polymorphisms with an impact on expression or function of genes potentially implicated in epilepsy have been found to be associated with TLE. In the last decade some studies have reported associations between common variants in specific genes and sporadic TLE, such as IL-1β, PDYN, GABBR1, and PRNP (Kanemoto et al., 2000, Stogmann et al., 2002, Gambardella et al., 2003, Walz et al., 2003); other new candidate genes might also be associated with TLE. However, the number of alleles and polygenes contributing to the phenotype of TLE is still unknown, and further investigation is needed to clarify the relevance of various genetic polymorphisms to TLE.
Acid-sensing ion channel 1a (ASIC1a; MIM#602866), a ligand-gated cation channel activated by extracellular protons, is widely expressed in the neurons of the peripheral sensory and the central nervous system (Waldmann et al., 1997, Wemmie et al., 2002, Alvarez de la Rosa et al., 2003). It can be activated by low extracellular pH to evoke both transient and sustained inward currents (Waldmann et al., 1997). Regarding the central nervous system, recent in vitro and in vivo data show that the ASIC1a gene may interfere with neuroplasticity and can contribute to synchronized activities underlying epileptic seizures generated in the neocortex and hippocampus (Wemmie et al., 2002, Xiong et al., 2004). In addition, a significant decrease in brain pH during intense neuronal excitation or seizure activity (Ekholm et al., 1995, Chen et al., 2005) suggests that ASIC1a activation might play a role in the generation and maintenance of epileptic seizures. Overall, these findings point to the human ASIC1a gene as a possible TLE susceptibility gene.
In the present study, we investigated the association between the ASIC1a gene variant alleles and TLE in human. A genetic association study was performed for ASIC1a polymorphisms using tagged single-nucleotide polymorphism (SNP) methods.
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Subjects
Informed consent was obtained from each subject and the study was reviewed and approved by the Ethics Committee of Peking Union Medical College Hospital in the People's Republic of China in accordance with the Declaration of Helsinki.
The study consisted of 560 outpatients who visited the Epilepsy Center in Peking Union Medical College Hospital from December 2000 to May 2009. The patients were diagnosed according to the 1989 Classification of Epilepsies and Epileptic Syndromes proposed by the
Results
Direct sequencing confirmed that the genotyping was correct. In this study, genotypic distributions in both patients and controls were in HardyWeinberg equilibrium. There were no significant deviations from HardyWeinberg equilibrium for the three Alu markers within either the patients or the control group (supplementary data Table 1). Comparison of genotype frequencies for the Alu markers between the patient and the control groups (p > 0.05) confirmed that the two cohorts were not significantly
Discussion
In recent years, increasing evidence has indicated that genetic predisposition seems to be an important causal factor in TLE (Ottman, 1989, Briellmann et al., 2001). The difficulty in identifying genes involved in TLE is mainly that TLE is typically a complex disorder in which more than one gene, with or without the influence of acquired factors, act in a multifactorial fashion (Stogmann et al., 2002). To identify genes implicated in complex multi-etiologic diseases such as TLE, association
Acknowledgments
We would like to thank the study participants. We also wish to thank Wayne for critical reading of the manuscript.
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