Genes for asthma: much ado about nothing?

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Abstract

The identification of genes that make individuals susceptible to developing asthma is an area of increasing focus by both academic and industrial groups. The complexity of asthma genetics has made the identification of susceptibility genes difficult; however, genome-wide screens followed by positional cloning have started to identify such genes for both asthma and asthma-related traits. In addition, evidence from candidate gene studies indicates that gene–gene interactions also play an important role in conferring genetic risk for asthma development. Although progress in terms of identifying new therapeutic targets has not been dramatic, our understanding of the complexity of the genetic basis of asthma has greatly increased. There can be little doubt that, in the future, this knowledge will lead to fundamental insights into the molecular pathophysiology of asthma and the development of new therapies.

Introduction

‘Since the cure of the Asthma is observed by all Physicians, who have attempted the eradicating that chronical distemper, to be very difficult, and frequently unsuccessful; I may thence infer, that either the true Nature of that Disease is not thoroughly understood by them, or they have not yet found out the Medicines by which the Cure may be effected’. So wrote JA Floyer in ‘A Treatise of the Asthma’ in 1717. In 2003, the situation has changed little; the root causes of asthma are still unknown and current therapies, although effective, are mostly symptomatic with limited capacity to modify the course of the disease, let alone provide a cure [1]. Unfortunately, the prevalence of asthma has increased dramatically in the past 20 years, with around 150 million people currently afflicted worldwide. As a gateway to better understanding the molecular pathogenesis of asthma, both academic and pharmaceutical groups have increasingly focused on trying to delineate the genetic aetiology of this disease. The ultimate goal of this work is to use the knowledge gained to develop new and more effective disease-modifying/curative therapies for the disease [2]. As a result, considerable effort and expense have been expended in attempts to detect ‘susceptibility’ variants of genes in the human population that predispose individuals to developing asthma. Although the identification of asthma susceptibility genes offers great potential for understanding asthma pathophysiology, actually identifying these genes has turned out to be anything but straightforward. The slow progress has led pundits to question the rationale for gene-hunting and raise doubts over the benefits of doing it at all. Therefore, this review summarises the progress made in this field, particularly in the past couple of years, and assesses the prospects for future success in this area.

Section snippets

Asthma genetics

The evidence for a genetic component to asthma derives from two sources. Firstly, it has long been known that asthma clusters in families, and that a positive family history for asthma is a strong risk factor for developing the disease [3]. Secondly, the concordance rates for asthma are higher in identical twins than in non-identical twins, irrespective of whether they are reared apart or together [4]. However, the fact that concordance in identical twins is not 100%, together with the fact

Reducing phenotypic complexity: asthma-associated traits

Asthma is a heterogeneous disorder characterised by airway inflammation, reversible airflow obstruction and bronchial hyperresponsiveness (BHR) to a variety of environmental stimuli [6]. Phenotype definition is, therefore, an important issue in genetic studies of asthma. In these studies, asthma is usually diagnosed by standard symptom questionnaires, physician diagnosis or diagnostic algorithms [7]. Because asthma is closely associated with several ‘intermediate’ phenotypes such as BHR,

Identification of asthma ‘susceptibility’ genes

Two approaches are used to identify asthma genes: genome-wide genetic screens followed by positional cloning, and candidate gene association studies. Both approaches correlate variations (e.g. single nucleotide polymorphisms [SNPs]) in the DNA sequences of genes with the presence of the disease in asthmatic individuals carrying the SNPs (i.e. matching genotype to phenotype) 11., 12.•, 13.•.

Conclusions

A key challenge in the so-called ‘post-genomic era’ is to unravel the genetic architecture of complex diseases, such as asthma, by identifying susceptibility genes and examining the mechanisms by which they exert their effects on the development of the disease. Although this has become almost ‘routine’ for monogenic diseases, it is clear that there is still a long way to go before this is the case for a complex disease like asthma. This is because of the modest effects of genetic variation in

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • of special interest

  • ••

    of outstanding interest

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