Pharmacogenomic in

asthma treatment
 Pharmacogenomics

DRUG
DRUG DRUG
METABOLIZING
TARGETS TRANSPORTERS
ENZYMES

PHARMACODYNAMICS PHARMACOKINETICS

Variability in
Efficacy/Toxicity
Johnson JA. Trends in Genetics 2003: 660-666
 Site of polymorphisms
Genetic variations can influence the activity of, or have an
effect on the expression of, the following types of proteins
Phase I Cytochromes P450
metabolizing
enzymes
Phase II UGTs, GSTs, SULTs, MTs, EHs, NATs
metabolizing
enzymes
Drug Influx transporters: PGPs
transporters Efflux transporters: OATPs (organic anion transport
proteins), OCTPs (organic cation transport proteins).
Drug receptors Class 1 receptors : ligand-controlled ion channels
Class 2 receptors : G-protein coupled receptors
Receptors regulating gene expression
G-proteins i.e. GNAS1, GNB3
 Effects on Pharmacokinetics and Pharmacodynamics

PharmGKB (www.pharmgkb.org)
 Definition of asthma

Asthma is a heterogeneous disease, usually characterized by

chronic airway inflammation. It is defined by the history of
respiratory symptoms such as wheeze, shortness of breath,
chest tightness and cough that vary over time and in
intensity, together with variable expiratory airflow limitation

[GINA 2016]
 Definition of asthma

Working definition for asthma:

Asthma is a chronic inflammatory disorder of the airways in
which many cells and cellular elements play a role: in
particular, mast cells, eosinophils, T lymphocytes,
macrophages, and epithelial cells.
In susceptible individuals, this inflammation causes recurrent
episodes of coughing (particularly at night or early in the
morning), wheezing, breathlessness, and chest tightness.
These episodes are usually associated with widespread but
variable airflow obstruction that is often reversible either
spontaneously or with treatment

NAEPP (National Asthma Education and Prevention Program), 2007; GINA, 2011
 Patofisiologi

Inflammation
Bronchoconstriction
Mucus
hypersecretion
hyperresponsiveness

http://www.laucke.com.au/health/images/asthma.jpg
 Pharmacological therapy

Reliever/acute Controller/maintenance

merelaksasi otot polos bronkus mengatasi inflamasi dan

dan mengatasi mencegah gejala asma (harus
bronkokonstriksi dipakai secara rutin)

short-acting 2-agonists Corticosteroids inhalation

inhalation (salbutamol, terbutalin) (beclomethasone dipropionate ,
budesonide, fluticasone, etc)
Systemic corticosteroids
Long-acting 2-agonists inhalation
Anticholinergics (ipratropium
(salmeterol, formoterol)
bromide)
cromolyn sodium/nedocromil
Epinefrin injection
leukotriene modifiers
Aminofilin injection
Imunomodulator (anti-IgE)
 The facts......

Despite the availability of several classes of asthma

medications and their overall effectiveness, a significant
portion of patients fail to respond to these therapeutic
agents.
Evidence suggests that genetic factors may partly
mediate the heterogeneity in asthma treatment response
The lecture will be focused on the two major classes of
asthma medications: -adrenergic receptor agonists
and inhaled corticosteroids
 Factors That Influence Medicine Response

Genetic differences
among patients

Interactions
Compliance with
Patients response concomitant
to drug drugs

Diagnosis Dose
Pharmacogenetics and the concept
of Personalize Medicine
 No Medicine Is Perfect!

People do not respond to

medicines in the same way
Adverse events may occur
in some people, not in
others
Doses can be different
Efficacy can vary
Variable responses to medicines
are known to occur in some
populations
Spear (2001) Trends Mol Medicine 7:201-206
Variable responses (particularly
rare adverse events) are often
difficult to predict
Asthma treatment response phenotypes

Assessment of response to asthma therapy :

bronchodilator response (change in FEV1 shortly
after administration of a short-acting 2-agonist
(SABA)).
The change in lung function associated with
asthma treatment administration demonstrating
substantial interindividual variability with a
significant proportion of both nonresponders and
high responders to therapy This wide
variability in interindividual response, combined
with high intraindividual repeatability, suggests a
genetic basis to the heterogeneity in asthma
treatment response
 Distribution of the
bronchodilator response
across the three major asthma
networks in SHARP.
Note that despite highly
varying enrollment criteria, the
overall distribution of response
is remarkably similar between
the clinical trial networks.
This supports the ability to
harmonize asthma
pharmacogenetic phenotypes
and the likely presence of
common genetic determinants
of response.

Abbreviations:
ACRN, Asthma Clinical Research Network; CAMP, Children Asthma Management
Program; CARE, Childhood Asthma Research and Education, SNP Health
Association Resource (SHARe) Asthma Resource project (SHARP)
 -agonist

The 2-adrenergic receptor agonists

are the most commonly prescribed
medications in the treatment of
asthma
SABAs are the mainstay of treatment
for acute symptoms of bronchospasm,
whereas long-acting 2-agonists
(LABAs) are used as adjuncts to
inhaled corticosteroid therapy to
provide long-term asthma control
SABA (short acting beta agonist)
 Polymorphism of beta2-adrenergic receptor
Am J Respir Crit Care Med 1997; 156: S156S162.

The coding region of the B2AR is located on chromosome 5q31

More recently, 9 single nucleotide polymorphisms have been identified
Four of these variants were found to cause changes of amino acids at
residues 16, 27, 34, and 164, which most frequent were :
the arginine to glycine (Arg16Gly) enhanced agonist-promoted
down-regulation, whilst the Arg16 form represents the wild type.
The glutamine to glutamic acid (Gln27Glu) resistant to
downregulation
The threonine to isoleucine (Thr164Ile) although this
polymorphism is less frequent than the Arg16Gly and Gln27Glu
polymorphisms, agonist binding and coupling to adenylyl cyclase was
altered significantly by this polymorphism
The valine to methionine (Val34Met) very rare occurrence and
does not alter receptor function
 Single Nucleotide Polymorphism (SNP) in
the Coding Region of a Gene

SNP results in alteration of the amino acid sequence of

the corresponding protein
arginine (Arg) substituted for glycine (Gly)
Distinct protein structures could result in phenotypic
differences between the subjects, such as variation in response
to medication.
Location of reported ADRB2 polymorphisms. The location of the reported (literature
and in National Center of Biotechnology Information database) polymorphisms is
shown for ADRB2 genes and the ADRB2 leader peptide sequence. Amino-acid
positions are numbered and the wild-type and polymorphic variant are indicated.
Red diamonds indicate sites of missense polymorphisms that alter the amino-acid
sequence of the protein. Yellow squares indicate polymorphisms of the DNA
sequence that do not translate into an alteration of the amino-acid residue (silent
polymorphisms).
The Pharmacogenomics Journal (2007) 7, 2937
 Impacts on drug response are still conflicting

There is significant association between favorable therapeutic response to

inhaled beta(2)-adrenergic agonists in asthmatic children and the Arg/Arg
phenotype at position 16 of the beta(2)AR. Failure of bronchodilator
response to inhaled beta-agonists in asthmatic children is associated with
the Gly allele (Arg/Gly and Gly/Gly genotypes)
(J Asthma, 2009 Nov;46(9):900-5)

Relative to B16Gly/Gly patients with asthma, B16Arg/Arg patients with

asthma may have an impaired therapeutic response to salmeterol in either
the absence or presence of concurrent ICS use. Investigation of alternate
treatment strategies may benefit this group.
Am J Respir Crit Care Med. 2006

There was no evidence of a pharmacogenetic effect of ADRB2 gene

polymorphisms on salmeterol response, in particular at the Arg16Gly
position (Am J Respir Crit Care Med 2010)
Implications :
genetic test
Example of test results
 Inhaled corticosteroids (ICS)

Corticosteroids are the primary or first-line anti-

inflammatory therapy in asthma.
It reduce bronchial hyper-responsiveness, inhibit
inflammatory cell migration and activation, and
reduce late-phase reactions to allergen.
Inhaled corticosteroids (ICS), including the older
ICS (beclomethasone, triamcinolone, and
flunisolide) and newer, less systemically available
ICS (budesonide, ciclesonide, and fluticasone),
are the most consistently effective long-term
control medication for persistent asthma in both
children and adults.
Efek seluler kortikosteroid pada asma
 Variability in Steroid Response
in Asthma

KG Tantisira et al: Human Molecular Genetics, 13(13), 1353-1359, 2004

 Polymorphism in CRHR1 gene

Polymorphisms in the corticotrophin-releasing

hormone receptor type 1 gene (CRHR1) have been
associated with variations in the therapeutic response to
ICS
The corticotropin-release factor (CRF) 1 receptor is a
member of the corticotropin-releasing factor family of G-
protein-coupled receptors
CRF1 receptors regulate ACTH release and the stress
response.
The human gene encoding the CRF1 receptor is localized
on chromosome 17 (17q12-q22)
 Polymorphism in CRHR1

CRHR1 showed positive association with significantly improved lung function

after 8 weeks of inhaled corticosteroid therapy in a study. Specifically,
rs242941 (minor allele frequency 30%) was associated with positive treatment
response
(Human Molecular Genetics, 2004, Vol. 13, No. 13)
 Association of CRHR1 with Response
to Inhaled Corticosteroid

KG Tantisira et al: Human Molecular Genetics, 13(13), 1353-1359, 2004

 Association of CRHR1 Haplotype with
Response to Inhaled Corticosteroid

KG Tantisira et al: Human Molecular Genetics, 13(13), 1353-1359, 2004

selesai
 Frequency Response: Leukotriene Receptor
Antagonists

Zafirlukast Montelukast

80
Number of Patients

60

40

20

Change in FEV1 (% of Predicted)

Data on file, GlaxoSmithKline: FAS40023 and SAS40020-21.

 BAL LTC4 Concentrations After Segmental
Antigen Challenge

1000
LTC4 Concentration (pg / ml)

0 LTC4

p=0.0003
1000

100

1
0

Low LT High LT

Adapted from Hasday, JD et al. AJRCCM 161; 1229-1236, 2000

5-Lipoxygenase Gene Polymorphisms

Location: Chromosome 10

3,4,5,6
G-1761A Tandem SP1
G-1708A Repeats
C21T G270A A1728G

-1,557 -854 -88

-292 -88
to to toto to 1 2 3 4 5 6 7 8 9 10 11 12 13 14
-1,844 -931 -727
-212 -212
ATG

Transcription Factor Binding Region

Negative Regulatory Regions
Positive Regulatory Region
 Pharmacogenetic Association Between ALOX5 Promoter
Genotype and the Response to the ALOX5 Inhibitor ABT-761

Randomized, double-blind,
ABT-761
35 parallel-group trial of ABT-761
FEV1 % CHANGE FROM

30 (n=221)
25
84-day treatment period
BASELINE

20
15 Clinically stable asthma
10 patients, using 2-agonists only
5
0 FEV1 = 40%-75% predicted
-5 5,5 5,X Mutant * ABT-761 150 and 300 mg/day
GENOTYPE
~6% of patients without wild-
type allele
* Significantly different from 5,5 P< 0.0001

Drazen et al. Nat Genet. 1999;22:168-170.

Effect of 5-Lipoxygenase Genotype on Response
to Fluticasone Propionate and Zafirlukast
Change From Baseline

20

15
(% predicted)

10 FP 88
5 Zafirluk ast
44 44 31 19 5
0 5

5,5 5 ,X X,X
-5 (59.5%) (33.8%) (6.8%)

Anderson et al. European Respiratory Society, 2000.

 Combined ALOX5 and LTC4 Polymorphisms

Change from baseline in FEV1 % 20

15
P= 0.003
predicted

10
FP88
ZA
5

-5 P= 0.038

Group1 Group2
Genotype Grouping

Group 1: ALOX5 Sp-1 X,X; ALOX5 (1728G), 1,2 or 2,2 or LTC4 S (-444) 2,2
Group 2: All others
The end