Variations in the C3, C3a receptor, and C5 genes affect susceptibility to bronchial asthma

Abstract

Bronchial asthma (BA) is a common chronic inflammatory disease characterized by hyperresponsive airways, excess mucus production, eosinophil activation, and the production of IgE. The complement system plays an immunoregulatory role at the interface of innate and acquired immunities. Recent studies have provided evidence that C3, C3a receptor, and C5 are linked to airway hyperresponsiveness. To determine whether genetic variations in the genes of the complement system affect susceptibility to BA, we screened single nucleotide polymorphisms (SNPs) in C3, C5, the C3a receptor gene (C3AR1), and the C5a receptor gene (C5R1) and performed association studies in the Japanese population. The results of this SNP case-control study suggested an association between 4896C/T in the C3 gene and atopic childhood BA (P = 0.0078) as well as adult BA (P = 0.010). When patient data were stratified according to elevated total IgE levels, 4896C/T was more closely associated with adult BA (P = 0.0016). A patient-only association study suggested that severity of childhood BA was associated with 1526G/A of the C3AR1 gene (P = 0.0057). We identified a high-risk haplotype of the C3 gene for childhood (P = 0.0021) and adult BA (P = 0.0058) and a low-risk haplotype for adult BA (P = 0.00011). We also identified a haplotype of the C5 gene that was protective against childhood BA (P = 1.4 x 10(-6)) and adult BA (P = 0.00063). These results suggest that the C3 and C5 pathways of the complement system play important roles in the pathogenesis of BA and that polymorphisms of these genes affect susceptibility to BA.

Association of the hCLCA1 gene with childhood and adult asthma

“…In the association study between a single SNP and asthma or an asthma-related phenotype, we performed many statistical tests; therefore, inflation of the false-positive results (type 1 error) is a concern. Because all eight SNPs were significantly in linkage disequilibrium (Table 2) and asthma-related phenotypes (seven variables for children and seven variables for adults) are significantly related, 28 the simple multiplication of P-values by the number of SNPs or phenotypes tested is too conservative and the appropriate value for the correction is not evident. Thus, to deal with the multiple comparisons, we did not apply Bonferroni corrections but rather set the significant P-value at 0.01 rather than 0.05.…”

“…28 Briefly, 80% of the children with asthma were found to be positive for mite-specific IgE (atopic), 54% were found to have high serum IgE concentrations (4400 U/ml), and 46% were found to have atopic dermatitis. Of the adults with asthma, 28% were found to have high serum IgE concentrations and 22% experienced the onset of asthma before the age of 18 years.…”

“…Details of these patients are described elsewhere. 28 All participants with asthma were selected according to the American Thoracic Society criteria. 35 Regarding the children with asthma, we recorded their age, sex, age at asthma onset, serum total IgE level, mitespecific IgE level, eosinophil count, clinical severity, incidence of atopic dermatitis, and the number of parents and siblings affected with asthma.…”

Replication of genetic association studies in asthma and related phenotypes

“…The details of these subjects have been described elsewhere. 10,12,14 For childhood controls and the investigation of total and specific IgE levels, we recruited children attending an elementary school in Chiba City, Japan. The clinical characteristics of this population as well as inclusion and exclusion criteria have been described previously.…”

An association study of asthma and related phenotypes with polymorphisms in negative regulator molecules of the TLR signaling pathway

“…Improvement in their FEV 1 measurement was at least 12% in childhood asthma and 20% in adult asthma after b 2 -agonist inhalation (National Heart, Lung, and Blood Institute 1991;Hasegawa et al 2004;Kamada et al 2004). Diagnosis of atopic asthma was based on one or more positive skinscratch-test responses to a range of seven common aeroallergens in the presence of a positive histamine control and a negative vehicle control.…”