The Molecular Genetics of Atopy

The word “atopy”, meaning “strange disease” [19] was coined to describe the familial syndrome of asthma and hay fever. Eczema (atopic dermatitis, AD) subsequently came to be considered to be part of the same syndrome. The atopic state is recognized by skin prick tests to common allergens, by the presence of allergenspecific IgE in their serum, and by elevations of the total serum IgE. The word “atopic” is used synonymously with “IgE-mediated” by many scientists, but some paediatricians and dermatologists may also consider atopy a constitutional trait [50], in line with Coca and Cooke’s original intention [19]. Approximately 80% of cases of childhood eczema and 90% of cases of asthma in children and adolescents are atopic by IgE or skin test criteria [50, 51]. Atopic mechanisms consequently dominate current understanding of the pathogenesis of both diseases. However, eczema and asthma in children without atopic manifestations are clinically indistinguishable from disease in children who are atopic [50, 99]. It is therefore not clear whether disease in nonatopics is the result of different processes. Twin studies of eczema show concordance rates of 0.72–0.86 in monozygotic and 0.21–0.23 in dizygotic twin pairs [60, 100]. Physician-diagnosed asthma exhibits a similar pattern, with concordance of 0.65 in monozygotic twins and 0.25 in dizygotic twins (Duffy et al. 1990). Total serum IgE levels show a heritability of approximately 50% [35, 89]. These studies indicate the presence of strong genetic factors underlying the development of atopy and atopic disease. The presence of strong genetic factorsmeans identification of the genes and genetic variants underlying eczema may lead to new treatments and better classification of children with the disease. The study of genetics aims to identify polymorphisms in DNA that cause phenotypic differences between individuals. DNA polymorphism may modify the control or coding regions of genes and can influence protein expression as well as structure. Disease genes can be identified by case–control studies of polymorphisms in candidate genes, or by positional cloning, which begins by the identification of chromosomal regions that are co-inherited with disease in families and ends with the refinement of the segment down to the causal gene. Both of these approaches have led to advancements in understanding the genetic basis of atopic diseases.