SCHOOL OF PHARMACEUTICAL SCIENCES, USM

Pharmacogenomics
Asthma
Learning
objectives
To describe gene functions in
Asthma therapy

To explain the effect of gene

alteration towards asthma therapy

To recommend intervention based

on pharmacogenomics data
What is
asthma?
"a chronic inflammatory disorder of the airways in which
many cells play a role, including mast cells and
eosinophils. In susceptible individuals this inflammation
causes symptoms which are usually associated with
widespread, but variable, airflow obstruction that is often
reversible either spontaneously or with treatment, and
causes an associated increase in airway responsiveness
to a variety of stimuli.”
 • Chronic inflammatory disorder of
airways —> airflow obstruction.
• Asthma exacerbations:
o Inflammatory and
immunological cell infiltration.
o Smooth muscle hypertrophy
o Combination of both

Mucus plugs
Serum protein
deposition
Inflammatory cell
Cellular debris
 Pharmacogenomic Overview of
Beta 2 -Agonists, Leukotriene
Modifiers and Corticosteroids

drug responders from non-responders and those most

susceptible to adverse effects: personalised medicine.
Antiasthma
medications
Bronchodilators
beta 2 -adrenergic agonists

anti-inflammatory agents
glucocorticoids and leukotriene modifiers
β2-adrenergic receptor activate

adenyl cyclase through stimulatory Gs protein

activate

protein kinase A phosphorylates

several target proteins

smooth-muscle relaxation in the airways

β2-adrenergic receptor activate

adenyl cyclase through stimulatory Gs protein

activate

protein kinase A phosphorylates

several target proteins

smooth-muscle relaxation in the airways

Beta 2 -Agonists
bronchodilator and rapid relief from asthma symptoms

Adrenergic Receptor B2 subtype (ADRB2)

• chromosome 5q31-33
• Encodes B2-adrenergic receptor
• This region has linkage to asthma and related phenotypes (e.g
allergy/atopy etc.)
• B2AR is a G-protein coupled receptor (GPCR)
⚬ Gs activation coupled to increased cAMP and bronchodilation
⚬ Stimulation of B2AR results in rapid and potent relaxation of airway
smooth muscle
• SABA and LABA target G-Protein coupled B2AR.
The B2AR receptor encoded by the ADRB2 gene is
HIGHLY polymorphic. The most common are
• Allelic frequencies for Arg/Gly16 and Gln/Glu27 are significantly different
among groups.
• Ile/Ile164 has not been found in an individual to date.
• No dosing/selection or toxicity suggestions to date in literature.
 The Arg16 variant has been shown to have pharmacogenetic
potential through association with:

A decline of asthma A subsensitivity of

An enhanced acute
control following response for
response to β2-
prolonged use of β2- bronchoprotection
adrenergic receptor
adrenergic receptor by β2-adrenergic
agonists
agonists receptor agonists
 CASE
A 51 year old African-American female presents to the emergency department with
acute SOB. Patient history reveals she had multiple hospitalizations for asthma. She
reports very frequent use of her SABA.

Physical examination: BP 133/92 mmHg, HR 137, respiratory rate 24 breaths/min, 81%

O2 saturation
Past medical history: asthma, hypertension, CAP, OSA, bilateral pulmonary emboli,
DVT
Labs: blood glucose 13 mmol/L, calcium 8.2mg/dL, phosphate 2.2 mg/dL
Asthma meds: salbutamol, fluticasone/salmeterol, montelukast, levalbuterol and
ipratropium
Allergies: NKDA
Inhaled Corticosteroid and
Corticotropin-releasing
hormone receptor 1 (CRHR1)

• ICS decreases airway inflammation and

hyperresponsiveness
• Some patients resistant to ICS
• ICS – bind to GC receptor
• GC can inhibit pro-inflammatory gene
expression OR stimulate anti-
inflammatory gene expression
• CRHR1 - chromosome 17q21-22 and
encodes CRHR (a G-protein coupled
receptor (GPCR))
• CRHR1 is a major regulator of GC
synthesis (e.g cortisol)
• SNPs of intrest:rs242941, rs1876828, rs242939
rs242941
rs1876828
Leukotriene modifiers & arachidonate 5-lipoxygenase
(ALOX5)
• Multiple genes are involved in the leukotriene signaling pathways
• Patients on leukotriene modifiers have variable response due to multiple genetic
variations

• alter the efficiency of gene transcription : variation from the wild type decreased gene
transcription.

• treatment with ALOX5 inhibitor in patient who carried at least one wild-type allele of the
ALOX5 promoter locus: shown to have greater improvement in FEV 1 than those
without any wild-type alleles.
Thank you