Pharmacogenetics of Drug-Induced Side Effects

Transcription

1 Pharmacogenetics of Drug-Induced Side Effects Hui - Ching Huang Department of Pharmacy, Yuli Hospital DOH Department of Pharmacology, Tzu Chi University April 20, 2013

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4 Brief history of HGP 1953: DNA structure discovered, the double helix 1977: Sanger sequencing technique developed 1985: US DOE initiated the concept 1988: Human Genome project initiated 1990: US Congress approved the $3 billion, 15-year program led by NIH 1995: Influenza genome sequenced (5Mb) 1998: High throughput sequencing machine developed. Celera established, the commercial industry joined the race 2000: Drosophila genome sequenced (180Mb) 2001: Human genome rough draft published (2.91Bb) 2003: Human genome completed (50 years after the discovery of the DNA structure)

5 What do we know? Human Genome ~ 35,000 human genes: ~ 26,000 genes are annotated (Av. 27Kb/gene) 42% don t have known functions ~ 6,000 diseases caused by single gene: only ~500 are linked Multiple genes diseases are still largely unknown Over 8 million SNPs are discovered:

6 Response rates of patients to a major drug for a selected group of therapeutic areas Therapeutic area Efficacy rate (%) Alzheimer s Analgesics (Cox-2) Asthma Cardiac arrhythmias Depression (SSRI) Diabetes HCV Incontinence Migraine (acute) Migraine (prophylaxis) Oncology Osteoporosis Rheumatoid arthritis Schizophrenia Trends in Molecular Medicine 2001; 7:

7 Why genetics The reasons why a patient might or might not respond to a drug or suffer an adverse event misdosing (42%) drug-drug interactions drug allergies medication error genetic factors (50%)

8 Pharmacogenetics Pharmacogenetics is a research field encompassing the analysis of gene variants that are associated with the variability of drug response and adverse drug reactions. This field has grown rapidly within recent two decades and it is anticipated that genotyping could be used to personalize drug treatment for vast numbers of subjects, ultimately increasing the efficacy of drugs and decreasing the cost of drug treatment.

9 Pharmacogenomics Pharmacogenomics The molecular study of genetic factors that determine drug efficacy and toxicity Examines an individual's genetic inheritance affects the body's response to drugs A Trend in Post Genome Era for Personalized Medicine

10 Medical Care in the 20 th Century DISEASE DOMINANT PATHOLOGY DIAGNOSIS THERAPY One Size Fit All! Not Personalized

11 Medical Care in the 21 th Century PREDISPOSING FACTORS DISEASE DOMINANT PATHOLOGY Public Health Education PREVENTION Diagnosis Prognosis Therapy Customized! Personalized

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15 Single nucleotide polymorphisms ( SNPs) SNPs (pronounced snips ), are the most common type of genetic variation among people. Each SNP represents a difference in a single DNA building block, called a nucleotide. SNPs can act as biological markers, helping scientists locate genes that are associated with disease.

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18 drug-hla story Expressing the HLA-B*1502 allele exposes patients of Asian origin to a and 36-fold higher risk of SJS to carbamazepine and phenytoin, respectively.

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20 HLA-B HLA (human leukocyte antigen) is the human version of the major histocompatibility complex (MHC), a gene family that occurs in many species. The HLA complex helps the immune system distinguish the body's own proteins from proteins made by foreign invaders. If the immune system recognizes the peptides as foreign (such as viral or bacterial peptides), it responds by destroying the infected cell. The HLA-B gene is located on the short (p) arm of chromosome 6 at position 21.3, from base pair 31,429,845 to base pair 31,432,923.

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25 The incidence of Stevens-Johnson syndrome (SJS) Han Chinese (8 per million) Caucasian (2-3 per million). Carbamazepine (CBZ), a drug commonly prescribed for the treatment of seizures, is the drug most commonly associated with SJS in Asians (25-33% of cases), whereas only 5-6% of Caucasian SJS cases are caused by it.

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