Genetic susceptibility to asthma in a changing environment.

Abstract

There is a major interest in investigating the genetic components of allergy and asthma. Four different areas are involved in the study of complex genetic diseases: family studies, assessment of phenotype, segregation analysis and gene mapping. Initial assessment of phenotype must be practical, reproducible and relatively independent of compounding variables. Phenotypes important in allergy and asthma include atopic parameters such as total serum IgE, bronchial hyper-responsiveness and the presence/ absence of clinical asthma. Numerous family and twin studies have suggested the presence of a heritable component for allergy, bronchial hyper-responsiveness and asthma. The number of genes involved in these complex genetic disorders and their mode of inheritance have not been fully determined. Our group has been involved in a collaborative US-Dutch study in which 92 families with over 500 individuals have been phenotyped and DNA has been obtained for genotyping. Initial results of the classification of family members show that approximately 26% of the offspring of families ascertained through a parent with asthma have an asthmatic phenotype. A large number of these offspring with clinical evidence of asthma do not have a prior physician diagnosis of asthma, suggesting that there is a spectrum which ranges from preclinical to symptomatic asthma. The familial aggregation of asthma and other obstructive airway diseases in these families is consistent with a significant genetic component. Initial linkage studies have been performed on two characteristics of the allergic and asthmatic phenotype. Total serum IgE was analysed because this measure correlates with the clinical expression of allergy, bronchial hyper-responsiveness and asthma. Segregation analysis of total serum IgE provided evidence for a recessive mode of inheritance. Sib pair analyses and maximum likelihood scores suggest that a gene regulating IgE production maps to chromosome 5q. Bronchial hyper-responsiveness and total serum IgE are related to asthma in population-based studies. Sib pair analyses for bronchial responsiveness showed significant linkage to markers on chromosome 5q.