Genetics of Asthma: A Review: Asthma: Studies on the Genetics of Atopy and Asthma
Linkage of Atopy to Chromosome 11
The first evidence for linkage of atopy with a specific chromosomal region was provided by Cookson et al46 in British families. They typed only 17 markers in seven families with atopy and found strong evidence of linkage of atopy to marker D11S97 on chromosome 11 ql3. They confirmed this linkage in 60 nuclear families. The map position was subsequently refined to the region centromeric of D11S97 and in the vicinity of two homologous genes CD20 (a B-cell marker) and the (3-subunit of the high-affinity IgE receptor (FceRI-b).
FceRI-(3 is an attractive candidate gene for atopy. FceRI is comprised of a, (3, and 7 chains. The a and 7 chains are encoded on chromosome-1. FceRI is expressed on mast cells, basophils, and monocytes. Cross-linking of IgE bound to FceRI by the specific antigen results in mast cell degranulation, which plays a central role in allergic reactions. Mast cell degranulation also liberates cytokines such as IL-4 which act on T and B lymphocytes and further amplify the atopic response, at least in part by stimulating IgE production. An isoleucine to leucine polymorphism at 181 position (Ilel81Leu) was identified in the FceRI-(3 gene. This polymorphism was found in 15% of random British individuals and was found to be associated with the phenotype of high total serum IgE. Sixty British families were examined and 10 families were found to have the Leu 181 allele segregating with atopy In an Australian population, Ilel81-^Leu was not detected, but a new polymorphism Glu237-Gly was found in 5.3% of the population and was associated with a higher prevalence of BHR and atopy. In a Japanese population, Gly237 was associated with atopic asthma, but not with “nonatopic” asthma. Despite speculation, there is no evidence to show that Leul81 or Gly237 polymorphism alters receptor function. It is possible that these polymorphisms may cause an as yet unidentified alteration of receptor function and may thus be responsible for a subset of atopy. It is also likely that these polymorphisms are of no functional significance but are in linkage disequilibrium with a different mutation in the same gene or a closely located gene. tadanafil
The linkage of atopy to chromosome llq by the Oxford group has been controversial. Some studies have confirmed this linkage54-56 while many other studies have not. The discrepant findings have been explained in terms of variable definitions of atopy, ascertainment bias, genetic heterogeneity, and environmental differences. This illustrates the difficulties in analyzing genetics of a complex disorder like atopy.