INTRODUCTION TO

PHARMACOGENETICS &
PERSONALIZED THERAPY
 Personalized Medicine
• Medicine is personal:
– We are all different.
– Some of our differences translate into how we react to drugs
as individuals.
– This is why personalized medicine is important to
everyone.
• Why does someone need twice the standard dose to
be effective?
• Why does this drug work for you but not me?
• Why do I have side-effects and you don’t?
• Why do some people get cancer and others don’t?
The Goal of Personalized Medicine
• The Right Dose of
• The Right Drug for
• The Right Indication for
• The Right Patient at
• The Right Time.
 Pharmacogenetics &
Pharmacogenomics
• Pharmacogenetics: Study of variability in drug
response determined by single genes.
🡪 study of individual gene-drug interactions, usually
one or two genes that have dominant effect on a drug
response (SIMPLE relationship)
• Pharmacogenomics: Study of variability in drug
response determined by multiple genes within the
genome.
🡪 study of genomic influence on drug response, often
using high-throughput data (sequencing, SNP chip,
expression, proteomics - COMPLEX interactions)
People react differently to drugs
Toxic responders
Non-responders
“One size does not fit all …” Responders

Patients with drug toxicity

Genotyping
Patients with non-response
to drug therapy

Patient population
with same disease Patients with normal response
to drug therapy
phenotype
 The aim of pharmacogenetics
• To make ‘personalized medicine’ as applicable
to various patient groups.
 Potential causes of variability in drug effects

• Pathogenesis and the severity of the disease being treated.

• Drug interactions from concomitant treatments (plasma
protein binding, metabolism)
• Individual’s age, gender, lifestyle (including environmental
factors), behavior, nutritional state, renal and liver
function, and concomitant illnesses.
• Genetic variation
HUMAN GENOME PROJECT
GENOME
HUMAN CHROMOSOMES
 GENES
▪ Genes are small sections of DNA within the genome
that code for proteins.
▪The purpose of genes is to store information.
▪Each gene contains the information required to build
specific proteins needed in an organism.
▪The human genome contains 20,687 protein-coding
genes
▪Genes come in different forms, called alleles
 GENES
▪In humans, alleles of particular genes come in pairs,
one on each chromosome.
If the alleles of a particular gene are the same, the
organism is described as homozygous for that
gene.
If they are different the organism is described as
heterozygous for that gene.
 GENES
▪An individual’s phenotype is determined by the
combination of alleles.
▪For example, for a gene that determines eye colour
there may be several different alleles. One allele may
result in blue eyes, while another might result in
brown eyes. The final colour of the individual’s eyes
will depend on which alleles they have and how they
interact.
▪The characteristic associated with a certain allele can
sometimes be dominant or recessive
 ĐỘT BIẾN PHỔ QUÁT Ở BỘ GEN NGƯỜI

Hai dạng đột biến phổ quát ở bộ gen người:

1. Đột biến lớn: Copy number variation
2. Đột biến nhỏ:
COPY NUMBER VARIATION (VARIANTS)

Autism (microdeletion),
Schizophrenia
(microduplication) on
16p11.2
CHROMOSOME
MUTATION
POINT MUTATION
SINGLE NUCLEOTIDE POLYMORPHISM
PHARMACOGENETICS POLYMORPHISM
 Polymorphism and pharmacogenetics facts

• Humans share about 99.9% sequence identity. The

other 0.1% are mostly SNPs.
• SNPs are the most common polymorphism type and
occur about every 1000 bases.
• SNPs can be silent—99% of them are not in coding
regions and not in genes and thus cause harmless,
harmful, latent changes.
• Genetic polymorphisms are one of the most important
factors that may contribute to ethnic sensitivity of a drug.
 Polymorphism and pharmacogenetics facts

• FDA recommends for following guidelines relating to

“ethnically sensitive situations” for some drugs and
suggests solutions that may control such ethnic
sensitivity in the context of therapeutic applications and
study designs.
• FDA has been working to improve pharmacogenetics
technologies in the development, regulation and use of
medications and revise drug labels in terms of
pharmacogenetic biomarkers in oncology area.
BỘ GEN NGƯỜI & ĐÁP ỨNG THUỐC
Single Nucleotide Polymorphism (SNP)
The major consequence of pharmacogenetic
polymorphisms in drug-metabolizing enzymes is
concentration-dependent toxicity resulting from
impaired drug clearance. In certain cases,
reduced
conversion of prodrug to therapeutically active
compounds is also of clinical importance
HLA-B*1502 in Chinese induces Steven-Johnson
Sd while taking Carbamazepine; HLA-B*5701
induced hypersensitive reaction to abacavir
(alternative Nevirapine)
 Interplay of genetic variability in
molecules of drug metabolism and elimination versus
pharmacodynamic structures.
ẢNH HƯỞNG EPIGENETICS TRÊN
PHENOTYPE
 PHƯƠNG THỨC HOẠT ĐỘNG CỦA
EPIGENETICS

1. DNA methylation.
2. Histone modification.
DNA methylation
Histon modification
CÁC YẾU TỐ GENE
ẢNH HƯỞNG ĐẾN
DƯỢC LỰC HỌC
RECEPTOR POLYMORPHISM
CONSEQUENCE OF POINT MUTATION
RECEPTOR POLYMORPHISM
ĐỘT BiẾN ĐiỂM TẠO TÍNH ĐA HÌNH TRÊN THỤ THỂ BETA 1

Đột biến sai nghĩa ở vị trí aa 389 tạo phiên bản Glycine 389
đáp ứng đảo ngược (inverse antagonist) so với phiên bản
Arginine 389 khi gắn kết với Carvedilol
CÁC YẾU TỐ GENE ẢNH HƯỞNG ĐẾN
DƯỢC ĐỘNG HỌC
 BiỂU HiỆN GEN CỦA CÁC YẾU TÔ
CHUYỂN VẬN THUỐC

DRUG
TRANSPORTERS
EXPRESSION IN
HUMAN
HAI GIAI ĐOẠN CHUYỂN HOÁ THUỐC
MEN CHUYỂN HOÁ THUỐC KHÔNG PHẢI LÀ P450
 β-
glucoronidase

Serotonine-N-acetyltransfer
ase
 ACETYLCHOLINESTERASE

Tryptophan-84
Phenylalanine-3
30
Glutamic-199
 Catechol-O-methyltransferas
e (COMT)
Monoamine oxidase A
(MAO)
https://www.pharmvar.org/genes
Ứ NG DỤNG TRÊN LÂM SÀNG
GENOTYPE-BASED DOSING
Effect of Metabolic Rate on Drug
Dosage

© 2006 American Medical Association. All rights reserved

AmpliChip CYP450 test
AmpliChip CYP450 test: from determined genotype,
predicted phenotype to optimized drug dose
Molecular diagnostics of pharmacogenomic traits
CẢM ƠN SỰ QUAN TÂM THEO DÕI