Genetics of Asthma
Mohamed El Sawy Genetics Unit of Pediatric Dept Ain Shams University
What is asthma?
Bronchial asthma is a disease which is both polygenic and multifactorial in nature. Various genetic factors, coupled with environmental stimuli interact in susceptible individuals to produce the phenotype. The pathophysiology consists of chronic inflammation of the airways accompanied by a degree of airway wall remodelling. This results in decreased airway calibre.
What is asthma? (cont’d)
♥The accumulation of inflammatory cells to the airway lining, the release of proinflammatory substances, contribute to the development of oedema, mucus hypersecretion, and epithelial cell shedding.
Founder Effect
Tristan da Cunha is an island in the middle of the southern Atlantic Ocean. It is the most remote of inhabited islands. It was the only place on earth not visited by the great influenza epidemic of 1918. 97 of the 222 islanders had asthma ( 44% ). The reason for this is that the islanders are, biologically, one family. Asthma on Tristan da Cunha is one example of a "founder effect."
Genetics and genomics of asthma and allergic diseases
• Asthma and eczema are characterized by a number of unexplained phenomena: 1. The familial aggregation of disease 2. The initiation of disease by apparently trivial exposure to allergens 3. The preferential transmission of disease from affected mothers
Can asthma run in families?
In families where neither parent had asthma...6% of the children had asthma. In families where one parent had asthma...20% of the children had asthma. In families where both parents had asthma...60% of the children had asthma.
When asthma runs in families, is the reason genes or environment?
♣ As in most human disease, the answer is "both." Asthma has strong genetic components as well as environmental components. ♣ So, it's a matter of nature and nurture, not nature versus nurture.
Family history as a predictor of asthma risk.
♦ In ten studies, sensitivity and predictive value of a positive family history of asthma were calculated: sensitivity ranged from 4% to 43%. Positive family history predicts an increased risk of asthma, it identifies a minority of children at risk who are targets for prevention .
Why might a person with no family history of asthma develop it?
►One of the parents may have undiagnosed asthma. Sometimes a person can have such mild or atypical disease that it is never recognized. Sometimes a person will die before developing asthma. ►Although each parent may not have enough genetic susceptibility to develop asthma, it's possible that a certain combination of their genes does.
Why might a person with no family history of asthma develop it?(cont,d)
►Although each parent may not have enough genetic susceptibility to develop asthma, it's possible that a new variant found only in the child's DNA results in more susceptibility to the disease. ►Although each parent may not have enough genetic susceptibility to develop asthma, it's possible that the child received an unusually large exposure to environmental agent(s) that contribute to asthma.
Twin Studies
♠ Studies of twins provide the clearest evidence for genes and environment both having a role.
♠ In 1995 researchers looked at 325 pairs of twins. ♠ They found 94 pairs in which at least one twin had asthma.
Twin Studies
Type of twin Number of Twin pairs in which both pair twin pairs twins had asthma ("concordance rate") Identical Twins Non Identical Twins 39 59% 23 of 39 ( pairs) 24% (13 of 55 pairs)
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• If asthma were governed only by genes, then every time one identical twin has asthma, the other should have it, too. In other words, the "concordance rate" should be 100%. The table shows, however, that instead of a 100% concordance, there is a 59% concordance between identical twins. This shows that asthma has an environmental component.
• If asthma were purely an environmental condition, then genes should make no difference at all. The concordance rate would be the same for identical twins and non-identical twins. The table shows, however, that the concordance rate is more than twice as high in identical twins (59%) as in non-identical twins (24%). This shows that asthma has a genetic component.
Genes or Environment?
♫A study of asthmatic twins in Finland showed that when one parent has asthma, genes explain 87% of the concordance difference between their twin children. ♫But, when neither parent has asthma, the environment could explain 100% of the concordance difference between their twin children.
Linkage and Association Polymorphism
RFLP
What genes are involved in asthma?
Gene B2 Adrenergic receptor Chromosome 5 Comments Variations in this gene influence the severity of asthma, not susceptibility to asthma. This gene also influences the response of asthma to medicines.
Gene
HLA class2
Chromosome Comments
6
HLA class II genes may be involved in allergy to mites & pollen. The DPB1*0401 allele (variant) of the HLADP gene protects against asthma. People with the DRB1*13 allele of the HLADRB gene are more susceptible to have an asthma attack.
What genes are involved in asthma?
Gene
TNF_ alpha chromosome
Comments
Some variants of this gene lead to increased production of TNF-alpha and asthma. TNF-alpha contributes to inflammation and increases the sensitivity of airways.
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Association of polymorphisms within the TNF genes and asthma
♣ Tumour necrosis factor alpha (TNF ) is a potent modulator of immune and inflammatory responses, and has been implicated in a variety of autoimmune diseases, including asthma. ♣ Increased levels of TNF have been detected in both sputa and bronchoalveolar lavage fluid of asthmatic subjects during acute attacks.
♣ Interindividual variation in TNF levels may be genetically determined and polymorphisms within the TNF genes and nearby HLA Class II region have been associated with differences in TNF production.
What genes are involved in asthma?
Gene Chromosome Comments
Genes related to IgE
11
IgE is an important molecule in allergies & asthma. Variations of IgE molecules exist in all people. Some of these genes are on chromosome 11.
What genes are involved in asthma?
Chromoso Comments me Un 12 There is substantial evidence that genes on the Known long arm of chromosome 12 are related to asthma. However, scientists have not yet determined which gene(s) it is. Gene
What genes are involved in asthma?
Gene alpha TcR Chromosome
Comments The results on this gene have been conflicting.
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What genes are involved in asthma?
Gene C_C Chemokine Receptor-5 (CCR5) Chromoso me Comments
A study of 425 Scottish children showed that children with one variant of this gene were 64% less likely to have asthma than other children. The same variant of the CCR5 gene lowers the risk of becoming infected with HIV-1.
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Association of CCR5 delta32 with reduced risk of asthma.
♥ Individuals carrying the CCR5 delta32 mutation, a naturally occurring variant of the C-C chemokine receptor 5 (CCR5), are at reduced risk of developing asthma. These data suggest a possible explanation for the high prevalence of this mutation in the general population
IL-13 variants.
♥ (IL)-13 is a central regulator of allergic inflammation. ♥ Numerous polymorphisms have been recently identified in the IL-13 gene and have been found to be associated with allergic & asthmatic phenotypes.
♥ Functional genomics studies are highlighting mechanistic pathways that may link genetic variation in IL-13 and disease .
Polymorphism 4G/5G in the PAI-1 gene is associated with IgE-mediated allergic diseases and asthma
Plasminogen activator inhibitor type 1 (PAI1) is a glycoprotein that belongs to the serine protease inhibitor superfamily and has an essential role in tissue remodeling after inflammation. Recently, a single base pair deletion/insertion polymorphism of the PAI-1 gene has been associated with an increased risk of asthma.
Interindividual genetic variation in drug treatment targets and drug metabolizing enzymes
Whilst the genes coding for key treatment targets contain little polymorphic variation (e.g. M2 and M3 receptors) other genes contain extensive genetic variation.
The best examples of the latter are the B 2adrenoceptor and the 5-lipoxygenase genes.
Interindividual genetic variation in drug treatment targets and drug metabolizing enzymes (cont’d)
◊ Genetic variability in both of these genes may account in part for interindividual variability in treatment response. ◊ A number of key targets within the airways remain to be adequately screened for polymorphic variation.
Pharmacogenetics of asthma
At present, the magnitude of effect of known polymorphisms in asthma treatment targets suggests that routine genotyping of all patients before treatment is unlikely to be cost-effective. As new data becomes available, novel therapies are developed, the knowledge of patients' genotypes will be necessary to enable clinicians to optimize management. With the reducing cost of genotyping, it may prove in the future to be cost-effective to screen individuals before treatment.
Pharmacogenetics of asthma (cont,d)
Polymorphic variation within appropriate genes may explain variations in treatment responses in terms of : (i) Efficacy and potency (ii) Half-life (iii) Composition of metabolites (iv) Duration of action (v) The development of adverse drug reactions.
Conclusions
Bronchial asthma is increasing in prevalence, and is now a major source of disability. It is the result of complex interactions between largely unknown genetic and environmental mechanisms.
Conclusions (cont’d)
The identification of the environmental factors offers the real possibility of prevention of disease, and understanding the genetics of allergic illnesses is likely to change their classification and treatment Early life seems particularly important, as the initiation of allergic disease results from genetic and environmental modification.
Conclusions (cont’d)
Further discoveries about asthma genes will lead to more individualized medicine. Prevention, diagnosis, treatment, and prognosis will be personalized, based largely on polymorphism & variation in genes.
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