活動

2012年10月31日

下午4時30分

香港中文大學李兆基樓6號講室

陳垣崇教授

陳垣崇教授現任台灣中央研究院生物醫學科學研究所特聘研究員及前任所長和美國杜克大學醫學中心兒科學講座教授。

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3943 7598/ 3943 7455
登記預留座位，請電郵致amyyeung@cuhk.edu.hk

Clinically observed drug toxicity so called adverse drug reactions (ADRs) account for 6-7 % of all hospital admissions and remain a major clinical problem. Pharmacogenomics aims to investigate the genetic basis of inter-individual differences in drug responses, such as efficacy, dose requirements, and adverse events. Research in pharmacogenomics has grown over the past decade, evolving from a candidate-gene approach to genome-wide association studies (GWAS). Genetic variants in genes coding for drug metabolism, drug transport, and more recently human-leukocyte antigens (HLA) have been linked to inter-individual differences in the risk of adverse drug reactions. I will use the following as an example to show that personalized medicine and pharmacogenomics is extremely useful in the right clinical settings.
Stevens-Johnson syndrome (SJS) and the related disease, toxic epidermal necrolysis (TEN), are two of the most serious ADRs. Carbamazepine (CBZ), used primarily in the treatment of epilepsy, neuralgia and bipolar disorder, is the commonest cause of SJS/TEN in Southeast Asian countries. We previously reported that CBZ-induced SJS/TEN in Chinese and many Southeast Asian populations are strongly associated with the human leukocyte antigen (HLA) B*1502. The strong genetic association suggests a direct involvement of HLA in the pathogenesis of drug hypersensitivity and indeed HLA molecule presents an antigenic drug and resulted in clonal expansion and activation of CD8+ cytotoxic T cells have been shown. Pharmacogenomic study also identified an unusual form of granulysin secreted by these cytotoxic T lymphocytes and natural killer cells responsible for the rapid and disseminated keratinocyte death in SJS/TEN. The high sensitivity/specificity of genetic markers provides a plausible basis for developing tests to identify individuals at risk for drug hypersensitivity and indeed a large prospective study has shown that HLA-B*1502 screening before carbamazepine treatment can effectively reduce the incidence of CBZ-induced SJS/TEN. These translational researches demonstrated that preventing drug toxicity by screening people at risk before prescription of a drug is a clinical reality. Application of HLA-B*1502 genotyping as a screening tool for patient taking carbamazepine is now recommended by the Department of Health, Taiwan and by the US FDA.

講座以英語主遘