RESUMO
Genetic heterogeneity has been proposed as a hallmark feature of allergic disease. To test the hypothesis that total IgE levels are jointly influenced by a locus on chromosome 12q21.1-q21.31 and a locus on 17q11.2-q21.2, we conducted multipoint allele-sharing analyses using nonparametric linkage (NPL) methods on Afro-Caribbean families from Barbados to test for evidence of gene-gene interactions. Significant correlations were observed between NPL scores at D12S1052 and both D17S1293 and D17S1299 for a dichotomized phenotype of total IgE. An analysis of family-specific NPL scores revealed that evidence for interaction was being driven largely by one multiplex pedigree (NPL = 12.01, 12.23, and 12.16 at D12S1052, D17S1293, and D17S1299, respectively). Using the programs SIMWALK (v2.0) and GOLD, a different set of haplotypes in this influential family was observed around D12S1052 and the 17q loci compared to the other Barbados pedigrees. Our findings are a classic example of founder effect, provide evidence for sensitivity of this type of linkage analysis to unusual pedigrees, and highlight an element of genetic heterogeneity that has been given little attention in the study of complex traits.
Assuntos
Heterogeneidade Genética , Ligação Genética/genética , Imunoglobulina E/genética , Asma/epidemiologia , Barbados/epidemiologia , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 17/genética , Saúde da Família , Feminino , Regulação da Expressão Gênica/genética , Marcadores Genéticos , Predisposição Genética para Doença , Haplótipos , Humanos , Hipersensibilidade/genética , Imunoglobulina E/metabolismo , Masculino , Linhagem , FenótipoRESUMO
As many as 80 percent of asthmatics have atopy and between 60 and 80 percent of allergic asthmatic have coexisting rhinitis. It has been proposed that asthma and allergic rhinitis are essentially the same inflammatory disease of human airways. Previously, we provided the first evidence for linkage of asthma and "high" total serum IgE concentration to chromosome 12q markers among families from Barbados and the US. To identify loci in this chromosome 12q region contributing to the distinct clinical phenotypes of asthma and allergic rhinitis, we conducted linkage analyses among 33 multiplex Barbadian families using densely-spaced microsatellite markers in the 12q14.3-q24.1 region. Maximal evidence for linkage to asthma and allergic rhinitis occurred at markers separated by 4.5 cM. D12S326 and D12S1052 = (NPL = 3.52, p = 0.001 and 1.72, p = 0.039, respectively), these two markers lie 9.13 cM downstream from IFNG. There was no evidence of linkage to either phenotype at markers flanking STAT6. These results suggest that a common gene on the long arm of chromosome 12 is important for both asthma and allergic rhinitis.(AU)
Assuntos
Humanos , Asma/genética , Rinite Alérgica Perene/genética , Cromossomos Humanos Par 12RESUMO
Findings from numerous studies have demonstrated that there is a strong heritable component to asthma and atrophy, although the genetic pathophysiology of these traits is poorly understood. To identify loci in chromosome 12q1s-q24.1 contributing to asthma and asthma-associated traits, we conducted linkage analyses among 29 multiples Barbadian families. Sib-pair analysis of 10 polymorphic micro satellite markers in 345 full and 219 half-sib pairs from Barbados revealed evidence for linkage of certain markers with a gene(s) controlling asthma (D12S379,p=0.001; D12S311,p=0.010; D12S95,p=0.010; D12S360,p=0.018), allergic rhinitis (D12S1052,p=0.040; D12S311,p=0.005; D12S95,p0.021), total serum IgE concentration (D12S1052,p=0.016; D12S311,p=0.007; D12S360,p=0.013; D12S78,p=0.002), and specific IgE antibodies (Alec) to the storage mite Blomia tropicalis (Blot M; D12S311,p=0.006; D12S360,p=0.007; D12S78,p=0.003). Significant evidence of transmission disequilibrium was observe for certain alleles at these loci in addition to high multi allergen IgE Ab. These findings suggest that a gene(s) in the 12q 15-q24.1 region, which contains several candidate genes, including interferon-y (IFNG), is important for asthma and the associated traits of allergic rhinitis, "high" total IgE, and "high" specific IgE (AU).
Assuntos
Humanos , Asma/genética , Ligação Genética , Rinite Alérgica Perene/genética , BarbadosRESUMO
To identify genes potentially relevant in atopic asthma, we analyzed markers in chromosome 12q15-q24.1 for linkage to asthma and total serum IgE concentration. Sib-pair analyses of 10 markers in 345 full- and 219 half-sib pairs from 29 multiplex Afro-Caribbean families provided evidence for linkage to this region for both asthma and total serum IgE. Certain alleles at these loci showed significant evidence of transmission disequilibrium with both asthma and high IgE. Using 6 of these markers and 11 additional markers, evidence for linkage of total IgE to 12q was also found in 12 Caucasian Amish kindreds (24 nuclear families) by both sib-pair and transmission disequilibrium analyses. These findings suggest that the 12q15-q24.1 region may contain a gene(s) controlling asthma and the associated "high total IgE" trait.
Assuntos
Asma/genética , População Negra/genética , Cromossomos Humanos Par 12 , Ligação Genética , Imunoglobulina E/sangue , População Branca/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Marcadores Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Núcleo Familiar , Índias OcidentaisRESUMO
To identify genes potentially relevant in atopic asthma, we analyzed markers in chromosome 12q15-q24.1 for linkage to asthma and total serum Ige concentration. Sib-pair analyses of 10 markers in 345 full- and 219 half-sib pairs from 29 multiplex Afro-Caribbean families provided evidence for linkage to his region for both asthma and total serum IgE. Certain alleles at these loci showed significant evidence of transmission disequilibrium with both asthma and high IgE. Using 6 of these markers and 11 additional markers, evidence for linkage of total IgE to 12q was also found in 12 Caucasian Amish kindreds (24 nuclear families) by both sib-pair and transmission disequilibrium analyses. These findings suggest that the 12q15-q24.1 region may contain a gene(s) contolling asthma and the associated high total IgE. trait.(AU)
Assuntos
Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Asma/genética , /genética , Cromossomos Humanos Par 12 , Imunoglobulina E/sangue , Ligação Genética , /genética , Núcleo Familiar , Índias Ocidentais , Marcadores GenéticosRESUMO
Assessment of the epidemiology of asthma requires that the asthma phenotype be characterized. A study was conducted in Barbados among 24 families (n = 175 persons). The geometric mean serum total IgE (tIgE) was 559.8 ng/ml, and was significantly higher in asthmatic subjects (n = 88; means = 1352.1) than in non-asthmatic subjects (n = 87; means = 229.6; t-test, p < 0.001). Asthma subjects reported shortness of breath (80.7 percent), cough (77.3 percent), wheezing (72.7 percent). An index of asthma severity was created based on questionnaire data. Shortness of breath, cough and wheeze were similarly correlated with the index of severity; however, none of the symptoms were significantly correlated with tIgE. Similarly, tIgE was not correlated with the severity score of any of the individual variables that comprised the severity score. The findings in this study of Afro-Caribbean subjects living in a tropical setting concur with those of Caucasian subjects living in developed, temperate locales, whereby tIgE is a good means of classifying the presence or absence of asthma. The poor association between tIgE and severity of asthma and asthma symptoms warrants further investigation into the validation of the severity scale, but raises the question regarding the absence of a relationship between tIgE and asthma severity (AU)
Assuntos
Humanos , Masculino , Feminino , Asma/diagnóstico , Asma/epidemiologia , Imunoglobulina E/diagnóstico , Barbados/epidemiologiaRESUMO
The prevalence of specific IgE (RAST) to tropical house dust mite Blomia tropicalis (Bt) was studied in 126 related individuals with self-reported atopic asthma (AA) and/or self-reported allergic rhinitis (AR) and individuals with no reported atopic disease. RAST results were considered positive when a serum bound > 5 percent of the total counts (percent TCB) added; 17 (65.4 percent) AA were positive to Bt, 7 (29.2 percent) AR without AA were positive to Bt, and 16 (21.9 percent) individuals reporting no AA or AR were positive to Bt. Total serum IgE was significantly higher in individuals with self-reported AA (750 ng/ml) than in individuals reporting no AA (282 ng/ml; Student's t test, p = 0.02). There was no association between total serum IgE and self-reported AR. Additionally, total IgE was weakly correlated with RAST (Bt) for all individuals (r=0.349, p=0.001). Subjects with self-reported AA had a significantly higher mean percentage TCB (19 + 17) than individuals without self-reported AA (10 + 14; Student's test, p<0.05). This study suggests that sensitivity to Bt is common in individuals with atopic asthma living in Barbados (AU)