Pharmacogenetic Predisposition of Anticonvulsants Hypersensitivity( I )

Aromatic anticonvulsants, such as carbamazepine (CBZ), phenytoin (PHT), and phenobarbital (PB) are common prescribed first-line drugs for the treatment of seizure. However, they are commonly to induce hypersensitivity reactions which are the most important concern in clinics, and hinder the physicians from prescribing the aromatic anticonvulsants. The clinical manifestations of anticonvulsants-induced hypersensitivity reactions range from mild maculopapular eruption (MPE), to severe drug hypersensitivity syndrome (HSS, also known as drug rash with eosinophilia and systemic symptoms (DRESS)), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). According to the records of Taiwan Drug Relief Foundation, aromatic anticonvulsants are the major causes for drug compensation. We carried out translation research for drug hypersensitivity which was thought as unpredicted. We found the strong association between HLA-B*1502 and CBZ-induced SJS/TEN, leading to the relabel of the drug information of CBZ by FDA of US and TFDA of the department of health of Taiwan in year 2007. According to the application of our successful translational research, the incidence of CBZ-SJS/TEN decreased dramatically in Taiwan in the recent years. However, the screening of HLA-B*1502 is only useful for the prevention of CBZ-induced SJS/TEN, but not for CBZ-induced MPE/DRSSS. Oxcarbazepine (OXC) has been more commonly used in clinics to replace CBZ, however, OXC can also induce MPE, DRESS, SJS or TEN. The genetic determinates for aniticonvulsants, including OXC, PHT and PB are unclear. Our preliminary results revealed that the genetic susceptibility of anticonvulsants-induced hypersensitivity reactions is not only linked to HLA, but also associates with other genetic factors, such as genes involved in drug metabolism. This project aims to apply a comprehensive genomic approach to elucidate the genomic determinants of the aromatic anticonvulsants induced hypersensitivity reactions. We will use our established drug hypersensitivity database and collaborate with the international team from Germany and France (Regi-SCAR consortium) to compare the interethnic differences. The follows are the specific aims of this project. 1: To perform the genome-wide association study (GWAS) and SNP fine mapping to analyze the candidate genes/region(s) of CBZ, OXC, PHT or PB-induced hypersensitivity reactions. 2: To apply exome sequencing by exome SNP chips to investigate the genomic determinants of hypersensitivity reactions caused by CBZ, OXC, PHT or PB. 3: To apply next generation sequencing (NGS) to identify the rare variants of hypersensitivity reactions caused by CBZ, OXC, PHT or PB. We anticipate that this project will uncover the genetic determinates of aromatic anticonvulsants-induced hypersensitivity reactions, including MPE, DRESS, SJS and TEN. This project has much potential to develop genetic tests for the use in clinics to decrease the incidence of anticonvulsants hypersensitivity. Our translational research will be advantage for the progress of personalized medication.

Project ID:PC10109-0131
External Project ID:NSC101-2321-B182-008