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Wednesday, 21 November 2007

Genetics and asthma

While the inheritable nature of allergic conditions has been known for more than a century, it is clearly a hot topic with a rapidly proliferating literature.

Allergic conditions each involve complex cellular and molecular interactions that converge to produce common mechanisms of disease. As a result, new studies in a range of allergic conditions continue to highlight novel genes and pathways that may be critical in particular clinical situations.

Of the various allergic conditions, asthma has attracted most attention in terms of defining its precise genetic basis and serves as a model for considering progress. Asthma is a common heterogeneous respiratory condition characterised by several pathological features, including chronic inflammation of the airways, reversible bronchorestriction, excessive mucous production and airway hyperreactivity.

Affected individuals generally present with chest tightness, wheezing and breathlessness. Asthma is a complex disease and poses a number of research challenges in terms of identifying susceptibility determinants, including the changing nature of the disease throughout life.
The long-held clinical tenet in asthma is that the disease arises in a subset of individuals with genetic susceptibility, after exposure to an environmental trigger. This is based on early epidemiological and twin studies which confirmed a role for both genetic and environmental influences.

Early findings included a four- to five-fold increase in asthma prevalence in first-order relatives of affected individuals and greater concordance of the disease in monozygotic twins relative to dizygotic twins.

As is the case with many other complex diseases, this clear evidence of genetic influence coupled with new technological advances raised the hope of relatively rapid advances in gene-based diagnostic and therapeutic approaches for asthma. For example, gene arrays predicting asthma risk with reasonable precision early in life seemed realistic within a limited timeframe. The reality is, however, a little more measured.

Given the high prevalence of the condition, interest in identifying genes involved in asthma susceptibility has been necessarily intense, with many candidate genes identified from both guided association studies and exploratory whole genome linkage analyses. Genes so far identified encode a diverse array of molecules including ion channels, cytokines, receptors, enzymes and transporters.

Despite the high level of genetic scrutiny in asthma and plethora of candidate genes, evidence relating to the majority of genes remains patchy and in many cases, controversial. Many factors have been identified as contributing to this lack of clarity including a range of methodological issues and the heterogeneous nature of the disease itself.
Two major issues loom in most studies of asthma genetics. Firstly, many genetic variants associated with asthma appear to be only important in a relatively small number of individuals. Secondly, considerable difficulty has been experienced in replicating studies across ethnically or geographically diverse populations. As a result, there is no genetic test available that would reliably predict asthma risk in a clinically meaningful way. There is a major upside, however, to all of this genetic trawling, with exciting new insights into the biological pathways of asthma that are likely to lead to novel therapeutic approaches.

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