약물유전체학 Pharmacogenomics Kangwon National Univ School of Medicine Hee Jae Lee PhD
A : 안녕? 어떻게지내? B : 응, 난요즘혈압이조절이안돼. A : 그래? 난네가고혈압인줄몰랐다. 괜찮니? B : 그리오래되지않았어. 한반개월정도. 우리아버지가혈압이높으셨거든. 형이랑누나들도혈압이높은것같아. A : 나도고혈압때문에병원에다녀. Thiazide 먹어봤니? 내의사는그약을처방해주더라고. 난그것먹고좋아졌어. 가끔은머리가아프지만말이야. B : 이상하네. 실은나도그약먹고있거든. 하지만나한테안듣는것같은데. A : 내쌍둥이동생도처음에는효과가없었다고하더라고. 그런데, 짠음식피하고, 식이요법을한결과혈압이떨어졌다고하던데너도음식조절좀해보지. B : 너도알다시피내가좀신겁게먹고, 야채도많이먹잖니. 게다가몸생각해서운동도열심히한다고. 근데왜나는이약이안듣지?
증상, 진단 : 고혈압요인 처방 유전고염분식사운동부족 항고혈압약물 : 이뇨제 (thiazide) 식이요법운동
약물종류 약물반응이없는군 SSRI ( 항우울제 ) 10-25 % ACE inhibitor ( 항고혈압제 ) 10-30% Beta blocker ( 심혈관질환치료제 ) 15-25% TCA ( 항우울제 ) 20-50% HMGCoA reductase inhibitors ( 고지혈증치료제 ) 30-70% Beta-2 agonist ( 천식치료제 ) 40-70%
약효과가있는거야없는거야? Department of Pharmacology Kangwon National University
생물학적정보의종류 DNA* RNA* Polypeptide* Protein structure Protein function Protein interaction pathways Cellular dynamics Tissue interactions Organism (phenotype) Population dynamics *almost complete knowledge
Gene and Genome ( 유전자와유전체 ) Gene - DNA (1953 yr) Adenine, Guanine, Cytosine, Thymine An antiparallel double helix James Watson & Francis Crick Central Dogma DNA DNA RNA Protein Replication Transcription Translation Department of Pharmacology Kangwon National University
Gene and Genome - Information When, Where, How much, What kind of Department of Pharmacology Kangwon National University
Gene and Genome Chromosome ( 염색체 ) - 46 Chromosome (23 pairs) - about 28,000~35,000 genes Human Genome Project - Sequence 3.1 billion of genetic code - Began in 1990 - Draft in 2001 - Finished in 2003
Gene and Genome Department of Pharmacology Kangwon National University
Many genomes are now sequenced!!! E. coli 4,200 genes sequenced in 1997 mouse ~22,500 genes sequenced in 2005 chimpanzee S. cerevisiae 5,800 genes sequenced in 1997 ~22,500 genes sequenced in 2005 human D. melanogaster 14,000 genes sequenced in 2000 ~22,500 genes sequenced in 2003
Human differences and mutations Polymorphism ( 다형성 ) 집단에서유의적인빈도로둘또는그이상의변이들이존재 alleles ( 대립형질 ), phenotypes, sequence variants, chromosomal structure variants 집단에서빈도가 1% 이상 Department of Pharmacology Kangwon National University
Human differences and mutations Human genetic markers - Blood group (1910-1960) : ~20 (No. of loci) - Electrophoretic mobility variants of serum protein (1960-1975) : ~30 - HLA tissue types (1970- ) : 1 (haplotype) - DNA RFLPs (1975- ) : > 10 5 - DNA VNTRs (minisatellites) (1985- ) : > 10 4 - DNA VNTRs (microsatellites) (1989- ) : > 10 5 - DNA SNPs (1989- ) : > 10 6 Department of Pharmacology Kangwon National University
단일염기다형성 (Single nucleotide polymorphism; SNP) DNA 단일염기 (A,T,C,or G) 변이 Alter regulation of gene expression, mrna processing (splicing, half-life, etc), and protein and enzyme activities.
약물반응과유전학 ( 약물유전학 ) Pharmacogenetics ( 약물유전학 ) 약물반응에대한개인적차이에대하여유전적수준에서연구하는학문
Pharmacogenomics( 약물유전체학 ) 약물에대한개개인의인체의반응을유전체수준에서연구하는학문 proteomics, bioinformatics,microarray 포함 맞춤의약품개발에활용 개인맞춤약물요법
약동학 약물의흡수, 분포, 대사, 배설
약력학 작용부위 ( 수용체 ) 에서의약물작용
약력학 Normal Mutation
Evans and McLeod NEJM 348 (6): 538
약물표적물질의유전자다형성 Evans and McLeod NEJM 348 (6): 538
인종적차이에따른대사효소의활성도 Caucasians Africa Americans Asians NAT2, slow acetylator 40-70% 50-60% 10-15% CYP2D6/null (PM) 6-10% 5% 1% CYP2C19/null (PM) 2% 4%, 18% 12-23% CYP2C9/het/low (PM) 14-37% 0-8% 0-1% beta-2 adrenergic receptor (codon 16) 37% 49% 59& PM : poor metabolizer From Bertilsson (1995); Evans et al., (2001); Mancinelli (2000); Meyer (2000); Wood (2001); Wilson et al., (2001)
Examples of dose adjustments based on PGDx.
In the Future.
Here is my sequence....
개인유전체분석서비스
In the future?
In the future?
In the future? GATACA?