Genetic Basis of Asthma

Asthma is the most common chronic childhood disease in developed nations and its prevalence has increased in the world over the last 25 years. It is a complex disease with both genetic and environmental risk factors. Asthma is caused by multiple interacting genes, some having a protective effect and others contributing to the disease pathogenesis, with each gene having its own tendency to be influenced by the environment. This article reviews the current state of the genetics of asthma in six categories, viz. epidemiology, management, aetiology, family and twin studies, segregation and linkage studies, and candidate genes and single nucleotide polymorphisms (SNPs).

Asthma is one of the most serious allergic diseases and the most common chronic childhood disease in developed nations1. It has been characterized by increased responsiveness of the tracheobronchial tree to a multiplicity of stimuli2–4, increased infiltration of various inflammatory cells especially eosinophils into the airway, epithelial damage, airway smooth-muscle hypertrophy5, constriction, variable airway obstruction usually associated with inflammation in the conducting airways of the lungs6 and mucous hypersecretion in the bronchiolar walls of the lung7. Asthma is critically dependent on a series of cell adhesion molecule-mediated interactions between vascular endothelium and leukocytes7, leading to symptoms8 and elevation in total serum IgE9. It is manifested physiologically by widespread narrowing of the air passages and clinically by paroxysms of dyspnoea, cough, wheezing and tightness, provoked by one or more triggers such as physical exertion and airway irritants (cold, dry air, smoke, etc.)4,10. It is an episodic disease, with acute exacerbations interspersed with symptom-free periods. Typically, most attacks are short-lived, lasting minutes to hours, and clinically the patient seems to recover completely after an attack. However, there can be a phase in which the patients experience some degree of airway obstruction daily. This phase can be mild, with or without superimposed severe episodes, or can be much more serious, with severe obstruction persisting for days or weeks; the latter condition is known as “acute severe asthma”. In unusual circumstances, acute episodes can cause death4. Asthma exacerbations are characteristically worse at night and can progress to severe airflow obstruction, shortness of breath, and respiratory distress and insufficiency. Rarely, severe sequel such as hypoxic seizures, respiratory failure, and death can occur.

Here we review the latest information on the genetic basis of asthma which is one of the most intriguing diseases affecting people of all ages, gender, race and ethnicities. Familial and segregation studies have an important role in asthma aetiology and several candidate genes on all the human chromosomes play their roles in initiation and/or inhibition of different pathways of asthma disease.

Note from the WAF editorial board: We wish to acknowledge and thank Mahdi Bijanzadeh, Padukudru A. Mahesh,* and Nallur B. Ramachandra
at the Indian Journal of Medical Research for their dedication to Asthma education and research.

Conclusion and future prospects

Asthma is one of the most serious and intriguing allergic diseases. Asthma aggregates within families and is a complex multifactorial disease with the involvement of environment and genetic components. Our preliminary pedigree analysis revealed that autosomal recessive pattern of inheritance was prominent in asthma; parental consanguinity100 and serum intracellular cell adhesion molecule-1 (ICAM-1)101 was significantly associated with asthma, whereas the ABO blood system102, IL-4 and ADAM33 specific gene variants81, and serum E-selectin101 were not associated with asthma. More than 100 loci have been reported to be associated with asthma and there are also indications that mutation in a major gene can cause asthma. Due to an increasing number of current studies being done in genetics of asthma, there is an increasing list of inducer and inhibitor candidate genes for asthma. There are more than 100 candidate genes in every chromosome which are identified to have an association with asthma and the strength of association of these SNPs with asthma varies in different parts of the world. More studies are needed to determine the exact function of these genes, gene-gene interactions and the gene-environment interactions which are undoubtedly complex and remain elusive for the time being even with whole genome-wide association studies.

Further studies on asthma with the genomics data and tools, to map, identify the specific gene/s, and phenotype specific SNPs will help to unravel the pathways involved in asthma aetiology and employ pharmacogenomics to design better drugs for an individualized treatment plan. Thus with a fruitful interaction among researchers involved in pathophysiology, epidemiology, clinical research and genetics of asthma, this century holds promise for a better understanding of the pathology, diagnosis, prevention, treatment and management of asthma.