Candidate gene and mutational analysis in asthma and atopy.
BACKGROUND
Using quantitative phenotype scores, we have genotyped four markers close to the FcepsilonRI-beta gene on chromosome 11q and 17 markers on chromosome 12. We have also determined the frequency of the I181L/V183L and E237G polymorphisms in our population.


METHODS
131 randomly ascertained families and 109 families with an asthmatic proband were recruited. Written and video questionnaires, bronchial challenge, and skinprick tests were administered and IgE levels measured. Phenotype scores were derived using principal-component analysis. The asthma score incorporated the questionnaire data reduced to two variables (wheeze and video), the ratio of predicted to observed FEV1, and bronchial hyperresponsiveness calculated as the slope of the dose-response curve. Total IgE, with the highest heritability of the atopy variables, was used as the atopy score. I181L/V183L polymorphism was determined by sequencing and E237G polymorphism by the amplification refractory mutation system. The data were analyzed using the BETA programme.


RESULTS
No examples of the I181L/V183L polymorphism were identified. The E237G polymorphism was identified with a frequency of 3.5% with weak evidence for linkage (lod 1.522) to asthma. Linkage was found to markers on chromosome 12 and asthma. The largest single locus lod was achieved for D12S366 and 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.


CONCLUSIONS
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.
Wilkinson
J
J
Department of Medicine and Human Genetics, University of Southampton, UK.
Thomas
N S
NS
Morton
N
N
Holgate
S T
ST
D001249:Asthma / Q000235:genetics*; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11; D002881:Chromosomes, Human, Pair 12; D004252:DNA Mutational Analysis; D008040:Genetic Linkage; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000235:genetics*; D017455:Receptors, IgE / Q000235:genetics*
D017455:Receptors, IgE