ABSTRACT
Atopy and asthma are complex genetic diseases resulting from the interactions of a number of genetic and environmental factors. We had previously reported allelic association between the IL9 marker on chromosome 5q31-33 and atopy. In order to further investigate the role of susceptibility genes on 5q31-33 in the development of atopy and asthma we have studied 240 UK families comprising 131 families selected at random, 60 multiplex families with affected sib pairs, and 49 single proband nuclear families. Polymorphic markers on 5q31-33 were genotyped and both single and multipoint linkage analysis was undertaken using the BETA program. We have used both affection status and quantitative scores for atopy and asthma for phenotypic variables, combining data into scores for asthma and atopy. The strongest suggestion of linkage using multipoint analysis was centred around D5S410 with a maximum Lod of 1.946 at location 171.3 cM and a standard error of 3.3 for the asthma quantitative score. There was no evidence of linkage with atopy, the atopy quantitative score or total serum IgE.
Subject(s)
Asthma/genetics , Chromosomes, Human, Pair 5 , Genetic Linkage , Genetic Predisposition to Disease , Humans , Phenotype , United KingdomABSTRACT
OBJECTIVE: To determine the association between the beta2-adrenoceptor polymorphisms at amino acids 16 and 27 and markers of allergic disease and asthma per se in a random adult population, and to determine the degree of linkage disequilibrium existing between polymorphisms at amino acid positions 16, 27, 164 and nucleic acid residue 523. METHODS: We measured serum IgE, skin-prick test positivity, atopy, bronchial hyperreactivity, wheeze and asthma (self-reported and doctor-diagnosed), and determined beta2-adrenoceptor genotype by allele specific oligonucleotide hybridization, in 630 adults aged between 18 and 70, selected from the electoral role in a local health authority in Nottingham. RESULTS: Homozygotes for the Glycine 16 polymorphism had a significantly higher incidence of atopy (chi2=6.44 (Pearson's), P=0.04). We also observed a significant association between the Glycine 16 allele and atopy (chi2=4.13 (Pearson's), P=0.04), when we assumed the Glycine 16 allele to operate in a dominant mode. No other significant associations between beta2-adrenoceptor polymorphisms and markers of allergic disease and asthma per se were observed. Marked linkage disequilibrium exists between the beta2-adrenoceptor polymorphisms at amino acid 16 and 27 (D=0.38, chi2 P<0.0001), and between the beta2-adrenoceptor polymorphisms at amino acid 27 and nucleic acid residue 523 (C-A) (D=0.36, chi2 P<0.0001). CONCLUSION: There is no consistent association between beta2-adrenoceptor polymorphisms and the risk of developing allergic disease or asthma per se in this adult sample. Marked linkage disequilibrium exists between the amino acid 16 and 27 polymorphisms, and also between the amino acid 27 polymorphism and the nucleic acid residue 523 (C-A) polymorphism. This polymorphism accounts for the Ban 1 RFLP previously described at the beta2-adrenoceptor locus on chromosome 5q 31.
Subject(s)
Asthma/genetics , Receptors, Adrenergic, beta-2/genetics , Adolescent , Adult , Aged , Alleles , Analysis of Variance , Asthma/blood , Bronchial Hyperreactivity/genetics , Deoxyribonucleases, Type II Site-Specific/metabolism , Female , Gene Frequency , Genotype , Humans , Hypersensitivity, Immediate/genetics , Immunoglobulin E/blood , Linkage Disequilibrium , Male , Middle Aged , Mutation/genetics , Nucleic Acid Hybridization , Oligonucleotide Probes , Polymorphism, Genetic , Polymorphism, Restriction Fragment Length , Respiratory Sounds/genetics , Skin TestsABSTRACT
BACKGROUND: The beta2-adrenoceptor polymorphisms occurring at amino acid positions 16 (arginine to glycine) and 27 (glutamine to glutamate) are known to be functionally relevant and also disease-modifying in subjects with asthma. However, the contribution of these polymorphisms to the development of the asthmatic phenotype or other markers for allergic disease remains to be established. OBJECTIVE: This large family study examines the contributions of these polymorphisms in determining the heritable component of markers for allergic disease in asthmatic families. METHODS: Three hundred twenty-four individuals from 60 families multiplex for asthma selected by means of an asthmatic proband were characterized for the following markers of allergic disease: asthma, atopy, and serum IgE. The polymerase chain reaction was used to generate a 234 base pair fragment spanning the region of interest, and the beta2-adrenoceptor polymorphism was then defined by allele-specific oligonucleotide hybridization. Segregation analysis was then performed. RESULTS: We found a significant association (p = 0.009) between the glutamine 27 beta2-adrenoceptor polymorphism and elevated levels of IgE, which was supported by the observation of linkage between IgE and beta2-adrenoceptor polymorphisms at locus 27 (p = 0.037). However, there was no association between either the arginine-glycine 16 or the glutamine-glutamate 27 beta2-adrenoceptor polymorphism and an increased risk of asthma or atopy per se. CONCLUSION: The glutamine 27 beta2-adrenoceptor polymorphism appears to contribute to IgE variability in families with asthma. However, it seems that although both amino acid 16 and 27 beta2-adrenoceptor polymorphisms are disease-modifying in subjects with asthma, they do not contribute markedly to the development of the asthmatic phenotype.
