临床药理学药物基因组与个体化医学

Part II：Single nucleotide
polymorphism (SNP)
The biological basis of individualized treatment is single nucleotide polymorphisms（SNPs） ---- Accounting for 90% human genetic variation
Adverse drug reactions (ADRs) are a common cause of morbidity and mortality.
Factors Contributing to Interindividual Variability in Drug Disposition and Action
Anti-metabolic therapy
Percentages of non-responders
40-75%
20-70%
35-75% 10-70%
70% 20-50%
Potential of Pharmacogenomics
All patients with same diagnosis
2
wk.baidu.com
1 Non-responders
Earlier detection of genetic predisposition to disease;
Improve the diagnosis of disease; Improve prediction of drug efficacy or toxicity.
Pharmacogenomics and Pharmacogenetics
A's gene
GCA Ala
1
AGA Arg 23
GAT Asp 4
AAT Asn
5
… T G T Cys
B's gene G C G
编码改变但不 Ala
改变氨基酸序列 1
AGA Arg
23
GAT Asp
AAT Asn
45
… T G T
Cys
C's gene G C A 编码改变使氨 Ala 基酸序列改变 1
and toxic responders
Treat with alternative drug or dose
Responders and patients not predisposed to toxicity
Treat with conventional drug or dose
HGP (Human Genome Project)
Oct 1990 to 2003.
̶ Identify approximately 30000 human genome DNA
̶ Determine composition of the human genome DNA is about 3 billion nucleotides
The Era of Genomic Medicine
and Pharmacogenetics
Pharmaceutical companies adopt “onedrug-fits-all” policy.
Drugs do not work in many people.
More than 90% drugs work only in 30~50% of people.
CYP2C9 gene
CCYYPP22CC99**21
9 Exon 55kb 490 AA
NNoormenazlyemnzaytimc atic acatcivtitvyity
Difference in DNA sequence(SNP)
Difference in
encoding amino acid and protein structure and function
遗传药理学（Pharmacogenetics, PGt) :
− 研究DNA变异如何引起药物反应差异 属于药物基因组学的范畴
药物基因组学 ( Pharmacogenomics, PGx) :
− 研究DNA如何影响药物反应
= 药理学 + 基因组学, 目标:
药物反应的遗传易感性 个体化药物治疗 新医疗模式的变革
导致人类遗传易感性的重要因素
导致人类药物代谢和反应差异的重要因素
C G
SNP
T A
GT突变
野生型
突变型
10q24.2 Chromosome 10
10q24.2
430C>T (Arg144Cys)
5’ G A G G A C CT G T G T T C A A 3’
Glu Asp CAyrgs Val Gln
Outline
➢ Pharmacogenomics and Pharmacogenetics;
➢ Single nucleotide polymorphism (SNP); ➢ Personalized medicine and
Personalized therapy.
Part I：Pharmacogenomics
Percentages of non-responders
Disease
Asthma
Duodenal Ulcer
Hyperlipidemia Hypertension
Solid Cancers Rheumatoid Arthritis
Class
2-adrenergic agents Proton Pump Inhibitors Statins Thiazide diuretics Various drugs
Age Gender Race/ethnicity Nutrition status Co-medications Co-mobidities Lifestyle variables Social factors GENETICS
Interindividual difference
AAA
Lys
23
GAT Asp
AAT Asn
45
… T G T
Cys
SNP forms three genotypes
...C C A T T G A C... …G G T A A C T G...
...C C A T T G A C... …G G T A A C T G...