Genetic

polymorphisms in
COPD

Ulfianur
Muh. Ilyas

INTRODUCTION
COPD: a disease characterized by breathing
air flow resistance which is usually
progressive and associated with a chronic
inflammatory response in the airways and
lungs to particles or gases are toxic /
hazardous.
WHO : COPD 4th leading cause of death in
the world.
2030 3th leading cause of death in the
world.

INTRODUCTION
The prevalence of COPD:
Latin America : 7.8% - 32.1%.
Asia Pacific : 6.3%
Hong Kong and Singapore : 3.5%
Vietnam : 6.7%
Indonesia: unknown

INTRODUCTION
Risk factors for COPD:

genetic
factors
environmen
tal factors
growth
factors and
developme
nt of the
lung

asthma
nutrition
economic
status
oxidativ
e stress

infection

INTRODUCTION
Several studies have shown
an increased prevalence of
COPD in families than in
controls and suggests that
COPD occurs in genetically
susceptible individuals after
exposure to cigarette smoke
enough.

Genetic polymorphisms in
COPD
1.
DNA sequences in
2. Polymorphism is
the genome
somewhere between
individuals around
the world are not
exactly the same,
but showed
3. A gene is said to
variation.
be polymorphic if
the gene has a
variant with a
frequency of at least
1% in the
population, if it is
smaller than 1%, it
is referred to as rare
variants (rare

defined as the variation

in form of the gene,
protein, or chromosome
that produces two or
more variants and each
variant has a high
enough frequency.
4. There are many types
of polymorphism: due to
deletions, duplications,
and so triplikasi from
several hundred to a
million base pairs.

Genetic polymorphisms in
5. This polymorphism
COPD
was not always
involved in the
emergence of a
genetic disease,
although some of
them can cause
serious genetic
6. disease.
COPD has been
known to be
associated with
genetic disease Until
now there has been all
of the genes that play
a role as a known
genetic component to
COPD.

7. Genes involved in the

pathogenesis of COPD :
- antiproteolisis role in
the mechanism,
- metabolism of toxic
substances in
cigarettes,
- airway
hyperresponsiveness,
and
- inflammatory response
to cigarette smoke.

Genetic polymorphisms in
COPD
Gen
-1 antitripsin

Varian
M1,M2,M3,M3,M4, S dan Z

Matrix metalloproteinase 9

rs 3918242(C-1562 T)

(MMP 9)

rs 1051740(T 113 C)

Microsomalepoxidehydrolase
(EPHX1)

rs 1695(A 105 G)

Heme oxygenase 1 (HMOX1)

Glutathione S-transferase P1
(GST P1)
Vitamin D binding protein

rs 1800629(G-308 A)

1-ANTITRYPSIN
1-antitrypsin: serum protein produced by the
liver and in normal circumstances the lung to
inhibit the action of destructive enzymes elatase
neutrophils to the lung tissue.
1-antitrypsin protesi lung tissue
destruction of the alveoli walls
pulmonary emphysema
1-antitrypsin deficiency is most often caused
by MS and MZ genotypes, the white population
by 10% and 3%.

1-ANTITRYPSIN
Japan, Fukuchi et al found that 1antitrypsin deficiency variant Siiyama more
happening.
Several types of studies have suggested
that genetic factors other than 1antitrypsin deficiency may play a role in the
development of COPD.

Matrix Metalloproitenases (MMPs)

Matrix
metalloproitenases
consists of 20
proteolytic enzymes
that play an important
role in tissue
remodeling and repair
associated with the
development and
inflammation.

MMP-1 (interstitial
collagenase) and
matrix
metalloproitenases12 is machrophage
human elastase.

Matrix Metalloproitenases
(MMPs)
MMP-9 (gelatinase
B) plays an
important role in
airway inflammation
and the
development of
emphysema.

Smokers with
airway obstruction
requiring increased
expression of MMP-1
and MMP-9
compared with
smokers without
COPD and
nonsmokers.

Microsomal Epoxide Hydrolase

(mEPHX)

Microsomal epoxide hydrolase is an enzyme that

converts permetabolisme xenobiotic reactive
epoxide derivatives dihidrodiol become more
soluble in water so that more readily excreted from
the body.
Microsomal epoxide hydrolase is
expressed by a variety of different cells,
including bronchial epithelial cells.
MEPHX gene polymorphisms associated
with oxidative stress due to a direct
effect of the components in tobacco
smoke.

Microsomal Epoxide Hydrolase

(mEPHX)
Smith in the UK showed that gene
polymorphisms mEPHX possibility is
an important risk factor in lung
disease.

But Yim et al, reported that genetic

polymorphisms in genes mEPHX T1
is not associated with the
development of COPD in Koreans.

Glutation S-transferase (GST)

1. Glutathione S-transferase
(GST) are a group of enzymes
that play an important role in
the detoxification of various
aromatic hydrocarbons
contained in cigarette smoke.

2. Glutathione S-transferase is
divided into several classes
alpha (GSTA) mu (GSTM), pi
(GSTP), theta (GSTT), sigma
(GSTS), and kappa (GSTK).

3. GST-M1 enzyme
expression by type 1
and 2 pneumocytes,
bronchial
epithelium, and
alveolar
macrophages
4. GST-M1
homozygous
deficiency
associated with
emphysema and
lung cancer in
patients with severe
chronic bronchitis in
heavy smokers.

Glutation S-transferase
(GST)
5. Yim et al reported that
genetic polymorphisms of GSTM1 and GST-T1 was not
associated with the
development of COPD in Korea
6. Ischii et al Genetic
polymorphisms of exon 5 of
GST-P1 may be associated with
COPD because GST-P1/I1e105
obtained predominant
genotype in COPD.

Vitamin D Binding Protein (VDBP)

VDBP a potential inflammatory mediators due
to its ability to enhance the chemotactic
activity of C5a and C5a des-Arg on neutrophil
and can serve as macropaghe activating
factor (MAF).
There is no significant difference between the
three isoforms VDBP in their ability to
enhance neutrophil chemotaxis to C5a
VDBP that isoforms may be associated with
COPD because of its effect on the ability of a
protein that functions as a MAF

Tumor Nekrosis
Faktor
the
It is still
a debate about
influence of experts TNF-
gene allele 308 G / A and -238
(TNF-)
Tumor nekcrosis faktor
is a multifunctional
cytokine
proinflammatory
cytokines, may also
increase tracheal
smooth muscle
proliferation and alter
smooth muscle
function.
There is no clear
mechanism of the
involvement of TNF- in
the pathogenesis of
COPD.

G / A with respect to the

incidence of COPD
- Huang, Sakao, Jiang and
Hers:
these genes contribute
to the
occurrence of chronic
bronchitis.
- Ishi, Hegab and
Chierakul: that
a single nucleotide
polymorphism allele
-308 G /
A TNF- was not
significantly
different between
smokers

Summary
COPD is the 4th leading cause of death in the world
and will be the 3rd leading cause of death in 2030.
Besides cigarettes are becoming a risk factor for
chronic obstructive pulmonary disease, is also
influenced by environmental and genetic factors.
Candidate genes associated with susceptibility to
onset of COPD include a deficiency of alpha1antitripsin, matrix metalloproteinase 9 (MMP 9),
microsomal epoxide hydrolase (EPHX1), heme
oxygenase 1 (HMOX1), Glutathione S-transferase P1
(GST P1), Vitamin D binding protein, and TNF

THANK YOU

>2

Risk

(GOLD Classification of Airflow Limitation)

4
(Exacerbation
history)

Risk

Combined Assessment of
COPD

0
mMRC 0-1
CAT < 10

GOLD: Global Initiative for Obstructive Lung Disease

mMRC: modified British Medical Research Council
CAT: COPD Assessment Test

mMRC > 2
CAT > 10

Symptoms
(mMRC or CAT score))

GOLD
2013

KLASIFIKASI PPOK
Derajat

Spirometri

GOLD 1

VEP1 > 80%

GOLD 2
GOLD 3
GOLD 4

80% > VEP 1 > 50%

50% > VEP 1 > 30%
VEP 1 < 30%

Combined Assessment of COPD

Assess Symptoms first

C
A
mMRC 0-1
CAT < 10

D
B

If mMRC 0-1 or CAT < 10:

Less Symptoms (A or C)
If mMRC > 2 or CAT > 10:
More Symptoms (B or D)

mMRC > 2
CAT > 10

Symptoms
(mMRC or CAT score))

mMRC: modified British Medical Research Council

CAT: COPD Assessment Test

GOLD
2013

Patofisiologi PPOK dan Asma

Noxious
agent

COPD
Alveolar
macrophage

CD8+
lymphocyte

Asthma

CD4+
lymphocyte

Mast cell

Eosinophil
Cytokines (IL-8)
Mediators (LTB4)

Sensitizing
agent

Histamine
Cytokines
(IL-4, IL-5, IL-13)

Neutrophil

Mediators (LTD4)

Proteases
Alveolar wall
destruction

Mucus
hypersecretion

Epithelial
shedding

Inflammatory
mediators

Airway
hyperreactivity

Airway
thickening

Barnes PJ (1999; 2000)

Diagnosis Banding PPOK dan Asma

PPOK
Onset

Biasanya >35
4
- 0 th

Asma
Semua umur, biasanya
40 th)

Riwayat merokok Biasanya >20 bks- tahun

Riwayat
Keluarga
Family history
Reversibel
Airway
Saluran napas

Umunya tdk ada, kec

1antitrypsin
disease)

Biasanya tidak
merokok
Biasanya ada

Tidak reversibel enuh

Sangat reversibel
Hanya reversibel sebagian Biasanya faal- paru
Dengan bronkodilator
Hampir normal
Berhenti merokok dapat
Mengurangi penurunan faal paru
Barnes PJ (1999)

Dianosis Banding PPOK dan Asma

PPOK
Pola Gejala

Biasanya kronik
Progresif lambat
Tidak spesifik

Asma

Bervariari dari hari ke har

Malam/menjelang
pagi

Batuk (paling
Menonjol)

Dini hari

Sputum purulen

Khasl

PeningkatanIgE

Jarang

Sering

Eosinofil

Jarang

Sering

Malam
Setelah
- latihan
Jarang

Barnes PJ (1999)

PENATALAKSANAAN PPOK
Menilai dan memonitor penyakit
Mengurangi faktor risiko
Penanganan PPOK stabil
Penanganan eksaserbasi

MANFAAT TERAPI OKSIGEN

Mengurangi sesak
Memperbaiki aktivitas
Mengurangi hipertensi pulmoner
Mnegurangi vasokosnrtiksi
Mengurangi hematokrit
Meningkatkan kualitas hidup

TUJUAN PENATALAKSANAAN
PPOK

Mencegah progresivitas penyakit

Menghilangkan gejala
Memperbaiki toleransi exercise
Memperbaiki status kesehatan
Mencegah dan mengobati komplikasi
Mencegah dan mengobati eksaserbasi
Mengurangi mortalitas

MENGURANGI FAKTOR RISIKO

Mengurangi pajanan
~ asap rokok
~ debu
~ zat tempat kerja
~ polusi udara
Berhenti merokok (evidence A)
Berhenti merokok dengan cepat adalah
efektif (evidence A)

Berhenti Merokok
Mempunyai kontribusi yang
besar dalam pelaksanaan
PPOK
Pasien hendaklah selalu
disarankan untuk berhenti
merokok
Berhenti meokok terbukti
sebagai faktor terpenting

Strategi Singkat Untuk

Berhenti Merokok
ASK

Systematically identify all tobacco

users at every visit
ADVISE
Strongly urge all tobacco users to quit
ASSESS
Determine willingness to make a quit
attempt
ASSIST
Aid the patient in quitting
ARRANGE Schedule follow-up contact

Patients should also be empowered to help

them stop smoking
From the Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease,
Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2008. Available from: http://www.goldcopd.org.

Modified MRC (mMRC)Questionnaire

GOLD
2013

CAT
COPD Assessment
Test (CAT):
An 8-item measure
of health status
impairment in COPD
(http://catestonline.o
rg).

Catestonline.or
g

3
2
1

C
A

D
B

>2

1
0

Risk

(GOLD Classification of Airflow Limitation)

4
(Exacerbation
history)

Risk

Combined Assessment of COPD

Assess risk of exacerbations next

If GOLD 1 or 2 and only

0 or 1 exacerbations per
year:
Low Risk (A or B)
If GOLD 3 or 4 or two or
more exacerbations per
year:
High Risk (C or D)

(One or more hospitalizations for COPD exacerbations

should be considered high risk.)
GOLD
2013

Management of COPD
Pharmacological First choice
GOLD 4

Classification of
Airflow Limitation

ICS + LABA or
LAMA
GOLD 3

ICS + LABA or
LAMA

2 or
more

Exacerbations

per year

GOLD 2

SABA or SAMA prn

GOLD 1

LABA or LAMA
0

A
mMRC 0-1
CAT <10

Source: GOLD guideline 2011 Update

mMRC 2+
CAT 10+

Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary
Disease, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2013. Available from

Initial Pharmacologic Management of

COPD*
Patient
Group

Recommended First
Choice

Alternative Choice

Other Possible
Treatments**

SAMA or SABA

LAMA or
LABA or
SABA and SAMA

Theophylline

LAMA or LABA

LAMA and LABA

SABA and/or SAMA

Theophylline

ICS+LABA or LAMA

LAMA and LABA or

LAMA and PDE-4 inhibitor or
LABA and PDE-4 inhibitor

SABA and/or SAMA

Theophylline

ICS+LABA and/or
LAMA

ICS+LABA and LAMA or

Carbocysteine
D
ICS+LABA and PDE-4
SABA and/or SAMA
inhibitor or
Theophylline
LAMA and LABA or
dications in each box are mentioned in alphabetic order, and therefore
necessarily
in order
of preference
LAMAnot
and
PDE-4
inhibitor
dications in this column can be used alone or in combination with other options in the Recommended First Choice and Alternative Choice column

PD: Chronic Obstructive Pulomnary Disease; SAMA: short-acting muscarinic antagonist; SABA: short-acting 2-agonist;
MA: Long-acting muscarinic antagonist; LABA: Long-acting 2-agonist;; ICS: Inhaled corticosteroid; PDE-4: phophodiesterase-4

GOLD 2013