ASTHMA-RELATED TRAITS, SUSCEPTIBILITY TO ASTHMA, PROTECTION AGAINST, INCLUDED
ASTHMA, BRONCHIAL
ASTHMA, DIMINISHED RESPONSE TO ANTILEUKOTRIENE TREATMENT IN, INCLUDED
Bronchial asthma is the most common chronic disease affecting children and young adults. It is a complex genetic disorder with a heterogeneous phenotype, largely attributed to the interactions among many genes and between these genes and the environment. ... Bronchial asthma is the most common chronic disease affecting children and young adults. It is a complex genetic disorder with a heterogeneous phenotype, largely attributed to the interactions among many genes and between these genes and the environment. Asthma-related traits include clinical symptoms of asthma, such as coughing, wheezing, and dyspnea; bronchial hyperresponsiveness (BHR) as assessed by methacholine challenge test; serum IgE levels; atopy; and atopic dermatitis (Laitinen et al., 2001; Illig and Wjst, 2002; Pillai et al., 2006). See 147050 for information on the asthma-associated phenotype atopy.
A critical phenotypic characteristic of human asthma and an important feature of animal models of asthma is airway hyperresponsiveness (Hirshman et al., 1984; Levitt and Mitzner, 1988; Levitt and Mitzner, 1989).
In an Australian population-based sample of 232 Caucasian nuclear families, Palmer et al. (2000) investigated the genetic and environmental components of variance of total and specific serum IgE levels, blood eosinophil counts, forced expiratory volume in 1 second ... In an Australian population-based sample of 232 Caucasian nuclear families, Palmer et al. (2000) investigated the genetic and environmental components of variance of total and specific serum IgE levels, blood eosinophil counts, forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and airway responsiveness. With the exception of FVC levels, all traits were closely associated with the presence of physician-diagnosed asthma. The study also suggested the presence of important genetic determinants of the pathophysiologic traits associated with asthma. The authors proposed that total and specific serum IgE levels, blood eosinophil counts, and airway responsiveness to inhaled agonist are appropriate phenotypes for molecular investigations of the genetic susceptibility to asthma. There was little evidence of shared genetic determinants influencing these traits, i.e., they seemed to be genetically distinct traits. The dramatic increase in asthma and allergic diseases over the second half of the 20th century had been attributed in part to the eradication of many childhood infections, the liberal use of antibiotics, and a 'cleaner' lifestyle in general during this period. This so-called hygiene hypothesis is further supported by epidemiologic studies demonstrating that children who attend day care in infancy and those with older sibs are less likely to develop asthma, presumably because of the increased exposure to infections among these children. These studies and others suggested that exposure to 'germs' in early life may facilitate the development of an immune system that is appropriately balanced with respect to T helper (Th1) and Th2 cytokine-producing cells. Hoffjan et al. (2005) investigated the interactions between day care exposure in the first 6 months of life and genotypes for 72 polymorphisms at 45 candidate loci and their effects on cytokine response profiles and on the development of atopic phenotypes in the first year of life. They found 6 interactions (at 4 polymorphisms in 3 loci) with 'day care' that had an effect on early-life immune phenotypes, with a significance at P less than 0.001. The study identified significant gene-environment interactions influencing the early patterning of the immune system and the subsequent development of asthma and highlighted the importance of considering environmental risk factors in genetic analyses. Millstein et al. (2006) developed an efficient testing strategy called the 'focused interaction testing framework' (FITF) to identify susceptibility genes involved in epistatic interactions useful in case-control studies of candidate genes. In an application to asthma case-control data from the Children's Health Study, FITF identified a significant multilocus effect between the NQO1 gene (125860), the myeloperoxidase gene (MPO; 606989), and the catalase gene (CAT; 115500), 3 genes that are involved in the oxidative stress pathway. In an independent dataset consisting primarily of African American and Asian American children, these 3 genes also showed a significant association with asthma status (P = 0.0008). - Association with KCNS3 on Chromosome 2p24 Using a positional candidate gene approach based on the linkage findings from Xu et al. (2001), Hao et al. (2005) analyzed 3 SNPs in the KCNS3 gene (603888) in 228 individuals with extreme airway hyperresponsiveness and 444 controls, all drawn from the same population used by Xu et al. (2001). In single-SNP analysis, the dbSNP rs1031771 G allele (OR, 1.42; p = 0.006) and the dbSNP rs1031772 T allele (OR, 1.40; p = 0.018) were associated with a significantly higher risk of airway hyperresponsiveness; haplotype analysis also detected a significant association (p = 0.006). Hao et al. (2005) suggested that SNPs located in the 3-prime downstream region of KCNS3 have a significant role in the etiology of airway hyperresponsiveness. - Association with HNMT on Chromosome 2q22 See 605238 for a discussion of a possible association of susceptibility with a polymorphism of the HNMT gene. - Association with MUC7 on Chromosome 4q13-q21 Kirkbride et al. (2001) studied a variable number tandem repeat (VNTR) of the MUC7 gene (158375.0001) in a series of Northern European atopic individuals with and without associated asthma. The MUC7*5 allele was rarer in the atopic asthmatics than in the atopic nonasthmatics. Comparison of all atopic individuals with all nonatopic showed no difference, while comparison of all asthmatic individuals with all nonasthmatic showed that the asthmatic group had reduced MUC7*5 frequency. The significantly lower frequency of the MUC7*5 allele in individuals with atopic asthma was explained by the possible association between alleles and different interactions with bacteria, since the glycosylated domain is thought to be responsible, at least in part, for the bacterial binding that allows bacteria to be cleared from the epithelial surfaces. Rousseau et al. (2006) followed up on their earlier report that the MUC7*5 allele is less prevalent in patients with asthma, suggesting a protective role in respiratory function. They identified additional SNPs of the MUC7 gene, and using these newly identified SNPs, conducted haplotype analysis on the cohort and controls previously studied by Kirkbride et al. (2001). There was low haplotype diversity and strong association between each of the loci, and the MUC7*5-carrying haplotype was less frequent in asthmatics than controls. By genotype and haplotype analysis of the MRC National Survey of Health and Development 1946 longitudinal birth cohort, for whom developmental, environmental, and respiratory health data were available, Rousseau et al. (2006) showed that the MUC7*5-carrying haplotype was associated with higher forced expiratory volume in 1 second (FEV1) at age 53 years, reduced age-related decline of FEV1, and reduced incidence of wheeze. - Association with IL13 on Chromosome 5q31 Howard et al. (2001) reported that the -1112C-T promoter variant (147683.0001), which they referred to as -1111C-T, of the IL13 gene contributes significantly to bronchial hyperresponsiveness and asthma susceptibility but not to total serum IgE levels. Heinzmann et al. (2000) determined that a R130Q variant of IL13 (147683.0002), which they referred to R110Q, associated with asthma in case-control populations from Britain and Japan (peak odds ratio (OR) = 2.31, 95% confidence interval, 1.33 - 4.00); the variant also predicted asthma and higher serum IL13 levels in a general, Japanese pediatric population. - Association with IL12B on Chromosome 5q31-q33 In a cohort study involving 844 children in Australia, Morahan et al. (2002) found that heterozygosity for IL12B (161561) promoter polymorphisms contributes to asthma severity. The predisposing genotype is associated with reduced IL12B expression and IL12p70 secretion. In a family-based association study, Randolph et al. (2004) found that the A allele of an intronic SNP (4237G-A; 161561.0003) was undertransmitted to asthmatic children. Randolph et al. (2004) also found a strong association between the IL12B 4237G-A polymorphism and an asthma severity phenotype in white children and in an independent population of white adult asthmatics. - Association with SCGB3A2 on Chromosome 5q31-q34 Niimi et al. (2002) identified a -112G-A polymorphism in the promoter region of the UGRP1 gene (606531.0001). In Japanese subjects those with the -112A allele in either heterozygous or homozygous form were 4.1 times more likely to have asthma than were those with the wildtype allele (G/G). Among the control individuals the frequency of the A allele was 10%; it was 22% among 84 patients with asthma. - Association with ADRB2 on Chromosome 5q32-q34 See (109690) for a discussion of a possible association of susceptibility with polymorphisms of the ADBR2 gene. - Association with HLA-G on Chromosome 6p21 Nicolae et al. (2005) pointed out that linkage of asthma and related phenotypes to 6p21 had been reported in 7 genome screens, making it the most replicated region of the genome; however, because many genes with individually small effects are likely to contribute to risk, identification of asthma susceptibility loci had been difficult. Nicolae et al. (2005) presented evidence from 4 independent samples (Chicago families, Chicago trios, and Hutterite and Dutch families) in support of HLA-G (142871) as a novel asthma and bronchial hyperresponsiveness susceptibility gene in the HLA region on 6p21. They speculated that this gene might contribute to risk for other inflammatory diseases that show linkage to this region. - Association with PLA2G7 on Chromosome 6p21.2 Kruse et al. (2000) identified PLA2G7 variants associated with atopy and asthma in a Caucasian population: the variant thr198 allele (I198T; 601690.0002) was highly associated with total IgE (147050) concentrations in an atopic population and with asthma in an asthmatic population; and the variant val379 allele (A379V; 601690.0003) was found to be highly associated with specific sensitization in the atopic population and with asthma in an asthmatic population. - Association with TNFA on Chromosome 6p21.3 Witte et al. (2002) evaluated the relation between the -308G-A promoter polymorphism (191160.0004) of the TNF gene and risk of asthma in 236 cases and 275 nonasthmatic controls. Logistic regression analyses indicated that having 1 or 2 copies of the -308A allele increased the risk of asthma (odds ratio = 1.58), the magnitude of which was increased when restricting the cases to those with acute asthma (odds ratio = 1.86, P = 0.04) or further restricting the subjects to those with a family history of asthma and those of European American ancestry (odds ratio = 3.16, P = 0.04). A weaker association was observed for the G-to-A NcoI polymorphism in the first intron of the LTA gene (153440) (adjusted odds ratio = 1.41), and analysis of both genes suggested that only the TNF -308A allele increases the risk of asthma. Shin et al. (2004) genotyped a 550 Korean asthmatics and 171 controls at 5 SNPs in TNFA and 2 SNPs in LTA. Six common haplotypes could be constructed in the TNF gene cluster. The TNFA -308G-A polymorphism showed a significant association with the risk of asthma (p = 0.0004). The frequency of the -308A allele-containing genotype in asthmatics (9.8%) was much lower than that in normal controls (22.9%). The protective effects of this polymorphism on asthma were also evident in separated subgroups by atopic status (p = 0.05 in nonatopic subjects and p = 0.003 in atopic subjects). The most common haplotype of the TNF gene cluster, TNF-ht1-GGTCCGG, was associated with total serum IgE levels (147050) in asthma patients, especially in nonatopic patients (p = 0.004). Aoki et al. (2006) did not find a significant association between the TNF -308G-A polymorphism and childhood atopic asthma in 2 independent Japanese populations; however, metaanalysis of a total of 2,477 asthma patients and 3,217 control individuals showed that the -308G-A polymorphism was significantly associated with asthma. The combined odds ratio was 1.46 for fixed or random effects (p = 0.0000001 and p = 0.00014, respectively). - Association with HLA-DRB1 on Chromosome 6p21.3 In a population sample consisting of 1,004 individuals from 230 families from the rural Australian town of Busselton, Moffatt et al. (2001) examined the association between quantitative traits underlying asthma and the HLA-DRB1 locus (142857). They found no associations to the categorical phenotype of asthma or to the quantitative traits of blood eosinophil counts and bronchial hyperresponsiveness. The authors detected strong associations between HLA-DRB1 alleles and the total serum IgE concentration and IgE titers against individual antigens. The results indicated that HLA-DRB1 alleles do not account for the observations of linkage of asthma to the major histocompatibility complex region on chromosome 6. Moffatt et al. (2010) carried out a genomewide association study of 10,365 persons with physician-diagnosed asthma and 16,110 unaffected persons, all of whom were matched for ancestry. Only HLA-DRB1 showed a significant genomewide association with the total serum IgE concentration (P = 8.3 x 10(-15)), and loci strongly associated with IgE levels were not associated with asthma. Moffatt et al. (2010) noted that elevation of total serum IgE Ievels has a minor role in the development of asthma. - Association with NOD1 on Chromosome 7p15-p14 Hysi et al. (2005) found an insertion-deletion polymorphism (ND1+32656) near the beginning of intron 9 of the NOD1 gene (605980) that accounted for approximately 7% of the variation in total serum IgE in 2 panels of families. The insertion allele was associated with high IgE levels as well as with asthma in an independent study of 600 asthmatic children and 1,194 super-normal controls. Hysi et al. (2005) hypothesized that intracellular recognition of specific bacterial products may affect the presence of childhood asthma. - Association with CCL24 on Chromosome 7q11.23 The eotaxin gene family (CLL11, 601156; CCL24, 602495; and CCL26, 604697) recruits and activates CCR3 (601268)-bearing cells such as eosinophils, mast cells, and Th2 lymphocytes that play a major role in allergic disorders. Shin et al. (2003) genotyped a 721-member asthma cohort at 17 polymorphisms among the 3 eotaxin loci. Statistical analysis revealed that the CCL24 +1265A-G G* allele showed significantly lower frequency in asthmatics than in normal healthy controls (0.14 versus 0.23, P = 0.002), and that distribution of the CCL24 +1265A-G G* allele-containing genotypes was also much lower in asthmatics (26.3 versus 40.8%, P = 0.003). In addition, a nonsynonymous SNP in CCL11, +123Ala to Thr, showed significant association with total serum IgE levels (P = 0.002 to 0.02). The effect of CCL11 +123Ala to Thr on total serum IgE appeared in a gene dose-dependent manner. The authors suggested that the development of asthma may be associated with CCL24 +1265A-G polymorphisms, and the susceptibility to high IgE production may be attributed to the CCL11 +123Ala to Thr polymorphism. - Association with GPR44 on Chromosome 11q12 The CRTH2 gene (GPR44; 604837) encodes a receptor for prostaglandin D2 (PGD2; see 176803) and is located within the peak linkage region for asthma on chromosome 11q in African American families. Huang et al. (2004) conducted a family-based analysis of asthma and the common 1544G/C and 1651G/A (dbSNP rs545659) SNPs in the 3-prime untranslated region of CRTH2. The authors reported significant evidence of linkage for the 1651G allele (P = 0.003). Haplotype analysis yielded additional evidence of linkage disequilibrium for the GG haplotype (P less than 0.001). Population-based case control analyses in 2 independent populations demonstrated significant association of the GG haplotype with asthma in an African American population (P = 0.004) and in Chinese children (P less than 0.001). In the Chinese children, the frequency of the 1651G allele in near-fatal asthmatics was significantly higher than mild to moderate asthmatics (P = 0.001) and normal controls (P less than 0.001). Transcriptional pulsing experiments showed that the GG haplotype conferred a significantly higher level of reporter mRNA stability, when compared with a nontransmitted CA haplotype, suggesting that the CRTH2 gene on chromosome 11q may be a strong candidate gene for asthma. - Association with SCGB1A1 on Chromosome 11q12.3-q13 Laing et al. (1998) demonstrated a polymorphism of the UGB (SCGB2A1) gene (192020.0001), an adenine-to-guanine substitution at position 38 within the noncoding region of exon 1. Those homozygous for the published sequence had a 6.9-fold increased risk of developing asthma, compared to those homozygous for the polymorphism; heterozygotes had a 4.2-fold increased risk of developing asthma. - Association with STAT6 on Chromosome 12q13 Duetsch et al. (2002) identified 13 single-nucleotide polymorphisms (SNPs) in the STAT6 gene (601512), and tested them for linkage/association with asthma and related traits (total serum IgE level, eosinophil cell count, and SLOPE of the dose-response curve after bronchial challenge) in 108 Caucasian sib-pairs. Neither the SNPs nor a GT repeat in exon 1 showed linkage/association to asthma. A significant association was found between a SNP in intron 18 and an increase in total IgE levels (P = 0.0070), as well as an association between allele A4 of the GT repeat polymorphism and an increase in eosinophil cell count (P = 0.0010). The authors concluded that rather than contributing to the pathogenesis of asthma, the human STAT6 gene is more likely involved in the development of eosinophilia and changes in total IgE levels. Using immunocytochemistry, Christodoulopoulos et al. (2001) measured the expression of STAT6 in bronchial biopsy specimens from patients with atopic and nonatopic asthma and controls and found that there were more STAT6-immunoreactive cells in patients with atopic and with nonatopic asthma than in control subjects (p less than 0.0001 and 0.05, respectively). The authors observed fewer cells expressing STAT6 protein in nonatopic versus atopic asthma (p less than 0.0001) and concluded that reduced IL4R signaling, due to lower STAT6 expression, may be a feature of nonatopic asthma. In a case-control association study of 214 white British subjects, Gao et al. (2004) demonstrated a significant association with asthma of an allele with a 13-GT repeat sequence in exon 1 of the STAT6 gene (OR, 1.52; 95% CI, 1.02-2.28; p = 0.027), whereas the 16-GT allele showed an inverse association with asthma (p = 0.018). Furthermore, individuals with the 13-GT allele had higher IgE levels compared with individuals with the 16-GT allele (p = 0.004). Transient transfection assays of different alleles revealed significantly higher transcriptional activity with the 13-GT allele compared to the 16-GT allele in Jurkat, HMC-1, and BEAS-2B cell lines. Gao et al. (2004) concluded that their findings suggested that the GT repeat polymorphism of the STAT6 gene contributes to susceptibility to atopic asthma and total serum IgE levels, and that variation in the length of the GT repeat sequence influences the regulation of promoter activity. - Association with PHF11 on Chromosome 13q14 Zhang et al. (2003) used serum IgE concentration as a quantitative trait to map susceptibility gene(s) for atopy and asthma in the 13q14 region. They localized the quantitative trait locus (QTL) in a comprehensive single-nucleotide polymorphism (SNP) map. They found replicated association to IgE levels that was attributed to several alleles in the PHF11 gene (607796). They also found association with these variants to severe clinical asthma. - Association with IL4R on Chromosome 16p12.1-p11 Binding of interleukin-13 or interleukin-4 to the IL4 receptor (IL4R; 147781) induces the initial response for Th2 lymphocyte polarization. Both IL13 and IL4 are produced by Th2 cells and are capable of inducing isotype class-switching of B cells to produce IgE after allergen exposure. These cytokines also share a common receptor component, IL4R-alpha (IL4RA). Howard et al. (2002) investigated 5 IL4RA single-nucleotide polymorphisms in a population of Dutch families ascertained through a proband with asthma. By considering the probands and their spouses as an unrelated sample, they observed significant associations of atopy and asthma-related phenotypes with several IL4RA polymorphisms, including S503P (147781.0003), and total serum IgE levels (P = 0.0007). A significant gene-gene interaction between S503P in IL4RA and the -1112C-T promoter variation (147683.0001) in IL13, previously shown to be associated with bronchial hyperresponsiveness, was detected. Individuals with the risk genotype for both genes were at almost 5 times greater risk for the development of asthma compared to individuals with nonrisk genotypes. These data suggested that variations in IL4RA contribute to elevated total serum IgE levels, and interaction between IL4RA and IL13 markedly increases an individual's susceptibility to asthma. - Association with CCL11 on Chromosome 17q21.1-q21.2 Batra et al. (2007) analyzed 3 polymorphisms in the CCL11 gene and a hexanucleotide (GAAGGA)n repeat (601156.0002) located 10.9 kb upstream of the gene in 235 patients with asthma and 239 age-, sex-, and ethnically matched controls and in 230 families with asthma from northern India. The authors found a highly significant association of the hexanucleotide repeat with asthma (p = 3 x 10(-6)). - Association with ADAM33 on Chromosome 20p13 Van Eerdewegh et al. (2002) performed a genomewide scan on 460 Caucasian families and identified a locus on chromosome 20p13 that was linked to asthma (lod = 2.94) and bronchial hyperresponsiveness (lod = 3.93). A survey of 135 polymorphisms in 23 genes identified the ADAM33 gene (607114) as being significantly associated with asthma using case control, transmission disequilibrium, and haplotype analyses (P = 0.04-0.000003). - Sex-Specific Modifier of Asthma Severity on Chromosome 5q34 In 2 independent groups of African American asthma patients, totaling 199 males and 310 females, Seibold et al. (2008) genotyped variants in the KCNMB1 gene (603951) and found that an 818C-T variant in exon 4, resulting in an arg140-to-trp (R140W) substitution, was associated with a clinically significant decline in FEV1 (-13%) in male but not female asthma patients (combined p = 0.0003). Patch-clamp electrophysiologic studies of R140W-mutant channels demonstrated significantly reduced channel openings. The R140W variant had an allelic frequency of 5.9% in African American asthma patients, but was not found in 96 Puerto Rican, 96 Mexican, 86 Caucasian, and 7 Asian asthma patients. Seibold et al. (2008) estimated that 10% of African American males with asthma carry the 818T allele and have the potential risk for greater airway obstruction and increased asthma morbidity.