What are we learning from genetic cohort studies?

What are we learning from genetic cohort studies?

PAEDIATRIC RESPIRATORY REVIEWS (2006) 7S, S90–S92 What are we learning from genetic cohort studies? Adnan Custovic* and Angela Simpson Academic Divis...

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PAEDIATRIC RESPIRATORY REVIEWS (2006) 7S, S90–S92

What are we learning from genetic cohort studies? Adnan Custovic* and Angela Simpson Academic Division of Medicine and Surgery South, University of Manchester, North West Lung Centre, Wythenshawe Hospital, Southmoor Road, Manchester M23 9LT, UK KEYWORDS gene-environment interactions; asthma; birth cohorts

Summary Although genetic component of asthma has been well recognised, genetics alone cannot explain the rise in asthma prevalence. This increase is likely a consequence of environmental factors increasing the risk in genetically susceptible individuals. As wheezing illness usually begins within months of birth, prospective birth cohorts with detailed measures of environmental exposures and objective measures of disease are essential to study gene-environment interactions in the development of different wheeze phenotypes. Such studies will enable identification of children at increased risk of disease because of a genetic predisposition when exposed to a particular environmental factor. Tailor-made evidence-based strategies for prevention of asthma and atopic sensitization applicable to individuals at risk (rather than the whole population) will then be developed to reduce the risk of asthma and allergy development. ß 2006 Elsevier Ltd. All rights reserved.

The inherited basis of disease due to single gene defects is well recognised, but these conditions are rare. The major burden of ill health is due to common diseases which have a complex aetiology, with multiple genes interacting with each other and with environmental factors. Asthma is the most common chronic disease of childhood, and has increased in prevalence over the last 3 to 4 decades.1 An estimated 5.1 million people in the UK are currently receiving treatment for asthma.2 A genetic component of asthma has been confirmed by twin studies.3 Whilst several genes have a moderate effect in asthma,4 genetics alone cannot explain the rise in prevalence. The time course of this increase has directed attention towards environmental changes which have occurred in parallel, including diet, microbial exposure, antibiotics, immunisations, childcare arrangements and changes to the home. The increase in asthma prevalence is likely a consequence * Corresponding author. Tel.: +44 161 291 2494; Fax: +44 161 291 5057. E-mail address: [email protected] (A. Custovic). 1526-0542/$ – see front matter ß 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.prrv.2006.04.164

of environmental factors increasing the risk in genetically susceptible individuals mediated through gene-environment interactions.

GENETIC COMPONENT OF ASTHMA Several genome-wide screens for asthma and its related traits have identified evidence for linkage on most chromosomes.5–10 Despite the fact that some regions of linkage have been replicated, it has proven difficult to identify susceptibility genes from a region of linkage. The first examples of susceptibility genes for an asthma phenotype identified using a positional cloning approach have recently been published.11,12 Association studies often focus on candidate genes likely to be involved in the immunological pathways of asthma, including IL-4 receptor,13 IL-13,14 FceR115 and glutathione S–transferase genes.16 Candidate genes may also be prioritised for investigation if they map to regions of linkage. A further refinement has been to identify candidate genes with plausible environmental interactions (e.g. CD14 with endotoxin17) to explain the increase in asthma prevalence.

WHAT ARE WE LEARNING FROM GENETIC COHORT STUDIES?

WHY DO WE NEED COHORT STUDIES? A study from Melbourne has clearly identified that patterns of lung function and asthma displayed at age 7 years track into adulthood.18 These deficits in lung function do not appear to be present soon after birth19 and are likely to be acquired in the first few years of life. As wheezing illness can begin within months of birth, to study gene-environment interactions in asthma development it is essential to utilise prospective birth cohorts with detailed measures of environmental exposures and objective measures of lung function in addition to parentally reported symptoms. The National Asthma Campaign Manchester Asthma and Allergy Study (NACMAAS) is a population-based prospective birth cohort study (n  1000) investigating risk factors for the development of asthma and allergies in children.20–31 Objective clinical outcome measures include lung function (specific airways resistance and spirometry), airway reactivity and atopic sensitization (skin tests and IgE). Subjective measures include questionnaire data on parentally-reported symptoms. Comprehensive measurements of environmental exposures include indoor allergens (mite, cat and dog), endotoxin, pet ownership and exposure, childcare arrangements, family size, antibiotic usage, maternal asthma medication usage during pregnancy and a detailed dietary questionnaire (Diet Q). We therefore have a unique opportunity to explore the interactions between genes and environment on the risk of asthma and atopic sensitisation. In a first study utilizing this strategy we have provided the first evidence that the association of ADAM33 with asthma may be mediated via its effects on lung function in childhood.31 Our data support the hypothesis that reduced early-life lung function is in part a genetically determined trait. Polymorphisms were associated with reduced lung function at both three and five years of age. In this study we were unable to show any association between ADAM33 SNPs and allergic sensitization, suggesting that separate genetic factors contribute to disordered airway function and the immunological component of asthma. Future studies will enable identification of children at increased risk of disease because of a genetic predisposition. Evidence-based strategies for prevention of asthma and atopic sensitization will then be developed to reduce the risk of asthma and allergy development.

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