This lecture has been presented by DR.Hajer moaweia / Abusetta chest center in Global asthma day 2018.

1. Genetic susceptibility to
bronchial asthma
Presented by
Dr. Hajer Maawe

2. ASTHMA, GENOMICS & FAMILY HEALTH
HISTORIES:
A New Strategy for Disease Prevention,
Education and Treatment

3. Asthma
A serious personal and public health issue with far
reaching medical, economic, and psychosocial
implications. It can be characterized by:
1) Airway inflammation
2) Bronchial hyperreactivity
3) Reversible airway obstruction
4) Chronic eosinophilic bronchitis

4. Asthma Incidence
Most common chronic disease in U.S.
Present in approx. 7.7% population.
8.8% in children <18yrs.
½ stricken before 10 yrs. of age.

5. Asthma Incidence
10.4 million hospital outpatient visits.
2 million emergency dept. visits.
465,000 hospitalizations.
4,500 deaths.

6. Mortality in General Population
1.4/100,000 in 1982
2.0/100,000 in 1991
Mortality by race:
Black
39/1000 pt’s w/asthma in 1982
62/1000 pt’s w/asthma in 1993
White
35/1000 pt’s w/asthma in 1982
51/1000 pt’s w/asthma in 1993
Asthma prevalence is elevated in low-income populations
with substantially higher fatality rates, hospital admissions,
and emergency department visits.

7. Gene Expression & the Environment
It is generally understood that a complex relationship exists
between gene expressions and environmental interactions in
respiratory diseases.
(Kleeberger & Peden, 2005)

8. About half of the patients of asthma have genetic susceptibility.
Presence of a family history of asthma and/or other atopies in
a large population of patients accounts for an important
evidence in favour of genetic basis of asthma.

9. Goals of the follwing studies in this presentation:
1) Identify susceptible individuals.
2) Intervene before the onset of disease.
3) Design drugs that are genospecific.

10. Genetic studies have been helpful to know of the increased risk
of disease from the presence of a susceptible allele or a
‘severity’ allele through candidate gene association studies.
For example, the homozygous individuals for Gly16 are shown to
have more severe corticosteroid dependent asthma. On the
other hand, the genetic polymorphisms can also be used for
disease classification and prospective therapies.

11. Single nucleotide polymorphisms
Single nucleotide polymorphisms (SNPs) constitute the most
common type of genetic variations which occur normally
throughout an individuals’ DNA.

12. polymorphisms of interleukin-4 (IL-4) which is one of the most
important cytokines involved in various allergic disorders and
asthma. Polymorphisms of IL-4 and IL-13 are commonly
described in association with asthma

13. SNP based treatment
Another significant role which is being increasingly assigned to
SNPs is to determine the type of response to a particular
therapy.
In asthma, the polymorphisms may predict the response to oral
and/or inhalational treatments especially the inhaled beta
agonist bronchodilators and corticosteroids. As an example,
the common arginine-16 variants in the beta-adrenergic
receptor gene are shown to have a positive relationship with
response to treatment with beta-adrenergic agonists

14. A recent study from a Korean asthmatic cohort identified SNPs of
the allantoicase (ALLC) gene which showed significant
association with the mean %FEV1 (change in the percentage
of forced expiratory volume in one second) in response to
inhaled corticosteroids.
In view of the wide heterogeneity of asthma, it has been also
suggested to employ genetic-scores to determine “drug
responders and non-responders, patients most susceptible to
adverse effects.

15. REAL TIME PCR SYSTEM

16. TaqMan real-time quantitative PCR

17. Associations of genes with the asthma
(ADRB2 R16G ). This gene encodes beta-2-adrenergic receptor which is a
member of the G protein-coupled receptor superfamily. Different
polymorphic forms, point mutations, and/or downregulation of this gene
are associated with nocturnal asthma, obesity and type 2 diabetes.
MS4A2 (Membrane Spanning 4-Domains A2) is a Protein Coding gene.
Diseases associated with MS4A2 include Ige Responsiveness,
Atopic and Hand Dermatosis.

18. Interleukin-13 (IL-13) is a central regulator of allergic inflammation.
IL-13 +1923C/T polymorphism was significantly associated with increased risk
of asthma under each genetic model.
Subgroup analysis by ethnicity showed that alleles and genotypes of this
variant correlated with asthma among Asians and Caucasians, but only TT
genotype under the homozygote model in Africans. When stratified by age
group, this variant highly correlated with asthma in children and
moderately in adults.
Furthermore, the TT, CT and CC genotypes in asthma group were all
significantly associated with increased IgE levels in sera of asthma
patients.

19. STUDY-1
case-control association study enrolled 382 unrelated Mauritian Indian
children, 193 with asthma and 189 healthy controls, and 384
unrelated Chinese Han children, 192 with asthma and 192 healthy
controls. study objective was to investigate the distributions of six
single nucleotide polymorphisms (SNPs) MS4A2 E237G, MS4A2 C-
109T, ADRB2 R16G, IL4RA I75V,IL4 C-590T, and IL13 C1923T in
Mauritian Indian and Chinese Han children with asthma.
Resut:
The frequency of IL13 C1923T T/T in the Mauritian Indian asthma
group was significantly higher than in the control group The IL13
C1923T locus predisposed to asthma in Mauritian Indian children,
which represents an ethnic difference from the Chinese Han
population. TheMS4A2 C-109T T/T and ADRB2 R16G A/Agenotypes
were associated with asthma in the Chinese Han children.

20. STUDY - 2
The aim of this study was to investigate the associations between 10 single nucleotide
polymorphism (SNP) loci in the development of asthma in children from the
Mauritian population.
Methods: The study population consisted of 193 children with asthma and 189
healthy controls from the Mauritian population. Asthma was diagnosed in
accordance with the American Thoracic Society criteria. TaqMan real-time
quantitative polymerase chain reaction was used to detect the genotypes of the
SNP loci.
Conclusion: The nine loci have little contribution to the development of childhood
asthma in the Mauritian population. IL13 C1923T TT has been detected to be the
susceptible genotype and may have a significant effect on the pathogenesis of
childhood asthma in the Mauritian population.
Identification of IL13 C1923T as a Single Nucleotide Polymorphism for Asthma in Children
from Mauritius Pediatr Allergy Immunol Pulmonol. 2015 Jun 1; 28(2): 92–95.

21. Other genes
ADAM33polymorphisms influence lung function in early life and epithelial-
mesenchymal dysfunction in the airways. This gene may predispose
individuals toward asthma and being present in early childhood before
asthma becomes clinically expressed.
Interleukin-4 (IL-4): This is located on chromosome 5 at position q31 with
32675 bps. IL-4 is a cytokine secreted by helper T cell type 2 (TH-2 cells)
that stimulates the production of IgE and induces eosinophil-mediated
attacks against allergens.
Chiang et al*, established that polymorphism in the promoter of the IL-4 is
associated with asthma and is a disease modifier in terms of the severity
of airway hyper-responsiveness (AHR)
Chiang CH, Tang YC, Lin MW, Chung MT. Association between the IL-4 promoter polymorphisms and
asthma or severity of hyperresponsiveness in Taiwanese. Respirology. 2007;12:42–8*

22. STUDY - 3
Madeira has the highest prevalence of asthma in Portugal (14.6%), Selected single
nucleotide polymorphisms (SNPs) were analysed as potential markers for asthma
susceptibility and severity in the interleukin 4 (IL4), interleukin 13 (IL13), beta-2-
adrenergic receptor (ADRB2), a disintegrin and metalloprotease 33 (ADAM33),
gasdermin-like (GSDML) and the signal transducer and activator of transcription 6
(STAT6) genes comparatively to a population reference set.
RESULTS: IL4-590*CT/TT and IL4-RP2*253183/183183 were found to predict the
risk (2-fold) and severity (3 to 4-fold) of asthma and were associated with a lower
FEV1 index. ADRB2-c.16*AG is a risk factor (3.5-fold), while genotype GSDML-
236*TT was protective (4-fold) for moderate-severe asthma. ADAM33-V4*C was
associated to asthma and mild asthma by the transmission disequilibrium test
(TDT).
CONCLUSION: In Madeira, IL4-590C/T, IL4-RP2 253/183, GSDML-
236C/T and ADAM33-V4C/G SNPs are important risk factors for asthma
susceptibility and severity, with implications for asthma healthcare management.
Biol. Res. vol.47 Santiago 2014 >Genetic polymorphisms and asthma: findings from a case -
control study in the Madeira island population.

23. Gene Exposure Phenotype Comment Reference
LTC4S Aspirin Asthma 2 444C allele ↑ w/
aspirin induced asthma
Sanak et
al.
ADRB 2 Cigarette smoke Asthma ↑ risk among smokers
w/Arg16 genotype
Wang et
al.
ADRB 2 Physical activity Asthma ↑ risk among sedentary
women w/Gly16
genotype Barr et al.
TIM 1 Hep A Atopy HAV protects against
atopy
McIntire
et al.
TLR 4 Endotoxins Asthma ↑ levels of endotoxins
(carriers of Gly299
and Ille399) reduce
risk of asthma
Werner et
al.
CD 14 Dog ownership Atopic
dermatitis
(AD)
2 159TT genotype is
protective against AD
Gern et al.
GSTM 1 Diesel exhaust IgE /
histamine
response
↑ response among
GSTM 1 – null
individuals
Gilliland
et al.
GSTP 1 Diesel exhaust IgE /
histamine
response
↑ response among
individuals w/ lle105
allele Gilliland
NOS 3 Day-care changes in
TH2
cytokine
response in
first yr. of
life
↑ TH2 response in
children not attending
day care
Hofjan et
al.
FCERB 1 Day-care IL5 response
at 1 year
Gly237 associated w/
↑ IL5 responsiveness
for children not
attending day care Hofjan
IL4RA Day-care IFN-g
response at 1
yr. of age
↑ Val50 homozygosity
in children not
attending day care Hofjan
HLAG Maternal Bronchial
hyperresponsiveness
(BHR)
Asthma-
BHR in child
964G allele is
associated w/asthma is
↑ with mothers w/BHR
Nicolae et
al.

24. conclusion
The genotype effects at the loci were modified by the
environment such that the same genotype was
associated with protection from or risk for a phenotype
depending upon an early life exposure.
(Ober, 2005).

25. conclusion
Interaction between gene variants and
environmental exposures hold great promise for
developing new strategies for diagnosing,
managing, and perhaps preventing or curing
asthma.
U of Washington: Center of Genomics and Public Health

26. Q: So, what do we do with this genetic
information?
A: Develop protocols to address and participate in
education, prevention and treatment strategies
that minimize risk!

27. Knowing your family history can save your life!
Dr. Richard Carmona, U.S. Surgeon General

28. Summary
asthma prevalence is on the rise and that the disease contributes to
significant morbidity, mortality, and cost worldwide. Much of this cost is
drug related. The response to inhaled corticosteroids and β2-agonists, the
most common medications for asthma, is highly variable; much of this
variation is genetic.
Pharmacogenetics may eventually lead to ‘individualized’ therapy. Asthma
pharmacogenetics is making progress.
The identification of additional genetic variation predictive of therapeutic
response in both these pathways remains crucial in order to achieve the
goal of the development of prognostic tests to predict treatment
response.