Recent development in genomic and proteomic research for asthma.
ABSTRACT Asthma is a complex genetic disorder with a heterogeneous phenotype attributed to the interactions among many genes and the environment. This review highlights recent developments in asthma genomic and proteomic research.
Numerous loci and candidate genes have been reported to show linkage and association of asthma and the asthma-associated phenotypes, atopy, elevated immunoglobulin E (IgE) levels, and bronchial hyperresponsiveness to alleles of microsatellite markers and single nucleotide polymorphisms within specific cytokine/chemokine, and IgE regulating genes. Although many studies reporting these observations are compelling, only a few genes conferring significant risk have been mapped. Although significant progress has been made in the field of asthma genetics in the past decade, the clinical implications of the genetic variations within the numerous candidate asthma genes, which have been found to associate with the expression of the asthmatic phenotype, remain largely undetermined. However, in the past year the scientific community has benefited from postgenomic discoveries, with the recent cloning of two asthma genes, ADAM 33 and PHF11, and this has generated new information that is benefiting others.
The asthma genetics field has advanced considerably in recent years, with new information being generated that has led to improved understanding of the pathobiology underlying this complex disorder. This has also generated interest in the study of gene-gene interaction and how linkage disequilibrium blocks and haplotypes can be used as functional units to pinpoint mutations and capture relative risk of mutated genes in complex disorders.
- SourceAvailable from: Chandrika B-Rao[show abstract] [hide abstract]
ABSTRACT: Epidemiologic studies in India show that the prevalence of asthma is increasing, but no genetic studies have been reported on the Indian population thus far. We selected the IFNG locus on 12q21 as a candidate gene for asthma on the basis of its role in pathophysiology and positive linkage demonstrated in other populations. The aim of this study was to investigate association of a CA-repeat marker in this gene with asthma and total serum IgE levels in the North Indian population. The repeat region was PCR-amplified from patients and control subjects and analyzed through use of GeneScan. The distributions of allele sizes were found to be significantly different between patients and control subjects (Kolmogorov-Smirnov test, P < 10(-6)). Alleles 10 and 11 were found to be overrepresented in individuals with asthma, whereas alleles 13 and 15 were less likely in asthmatic individuals. We found that the CA-repeat polymorphism in the IFNG gene was significantly associated with total serum IgE levels (ANOVA, P < 10(-4) for control subjects and P =.0036 for patients). Furthermore, a previously reported promoter polymorphism at the -333 base pair position was not detected in our population. This is the first report on the association of a candidate gene with asthma from the Indian subcontinent.Journal of Allergy and Clinical Immunology 10/2002; 110(3):410-2. · 12.05 Impact Factor
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ABSTRACT: The skin prick test is used to examine specific IgE-mediated allergic responses. Generally, results accord well with anamnestic information on atopy. Several genetic factors probably affect the strength of allergen-mediated skin test reactions. We sought to investigate skin test findings in a population-based sample of adult asthmatic patients and control subjects and to establish whether the IL1A genotype affects allergy testing. We analyzed the single G-to-T base exchange polymorphism in exon 5 at +4845 of the gene encoding IL-1alpha (IL1A) in adult asthmatic patients (n = 245) and nonasthmatic control subjects (n = 405). The data were assessed for correlation with data on the skin test responses of these subjects to 22 common allergens. The IL1A genotype distribution and allele frequencies proved similar in patients and control subjects. Surprisingly, the IL1A genotype distribution was markedly different in control subjects with positive (ie, >/=1 positive reaction) and negative skin test responses (P =.006). This difference was caused by an increase in the frequency of the rarer allele 2 in control subjects with negative skin test responses (P =.004). Our study demonstrates that the IL1 gene complex is involved in the regulation of IgE-mediated atopic reactions. The results suggest that skin test responses to specific allergens are differently regulated in nonasthmatic and asthmatic subjects. Because of the potential role of the IL1A genotype as a confounding factor in skin prick testing, these results require special attention and should be further evaluated in other clinical settings.Journal of Allergy and Clinical Immunology 10/2002; 110(3):429-34. · 12.05 Impact Factor
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ABSTRACT: The Class II genes of the MHC represent a major locus with quantified effects on atopic (allergic) phenotypes in many studies of westernized Caucasians. Although asthma is considered a disease of western societies, typical components of the asthma phenotype, such as elevations of the IgE, are seen with parasitic infestation. We have therefore investigated the effects of the HLA-DRB1 locus on asthma and its intermediate phenotypes in Aboriginal people from the Kimberly region of Australia who were suffering from endemic hookworm infection. Recognizable correlates of allergic asthma were present in the subjects, including skin test positivity to house dust mite (HDM), specific IgE responses to HDM, and the total serum IgE. HLA-DRB1 alleles did not predict the presence of asthma, but multi-allelic tests of association showed the locus accounted for approximately 33% of the variance of the total serum IgE concentration and 17% of the variance of the specific IgE titres to HDM. Genetic admixture was excluded as a cause of the results. These effects of the MHC on IgE levels were an order of magnitude greater than that seen in Caucasians, consistent with the hypothesis that the genetic predisposition to allergic disease may be driven by adaptation to helminth infection. The results further suggest that parasitism per se is not protective against asthma.Human Molecular Genetics 04/2003; 12(6):625-30. · 7.69 Impact Factor