Candidate gene and mutational analysis in asthma and atopy

Background: Using quantitative phenotype scores, we have genotyped four mar kers close to the Fc epsilon RI-beta gene on chromosome 11q and 17 markers on chromosome 12, We have also determined the frequency of the 1181L/V183L and E237G polymorphisms in our population. Methods: 131 randomly ascertained families and 109 families with an asthmat ic proband were recruited. Written and video questionnaires, bronchial chal lenge, and skinprick tests were administered and IgE levels measured. Pheno type scores were derived using principal-component analysis. The asthma sco re incorporated the questionnaire data reduced to two variables (wheeze and video), the ratio of predicted to observed FEV1, and bronchial hyperrespon siveness calculated as the slope of the dose-response curve. Total IgE, wit h the highest heritability of the atopy variables, was used as the atopy sc ore. 1181L/V183L polymorphism was determined by sequencing and E237G polymo rphism by the amplification refractory mutation system. The data were analy zed using the BETA programme. Results: No examples of the 1181L/V183L polymorphism were identified. The E 237G polymorphism was identified with a frequency of 3.5% with weak evidenc e for linkage (lod 1.522) to asthma. Linkage was found to markers on chromo some 12 and asthma. The largest single locus rod was achieved for D12S366 a nd wheeze (lod 3.307). Using multipoint analysis, a maximum lod score of 2. 29 centres around D12S97 at location 173.5 cM for the asthma score. Conclusion: The linkage results for chromosome 12 justify further interest in this region. Future endeavours will be directed towards fine mapping in the hope of identifying novel candidate genes.