Entry - #600807 - ASTHMA, SUSCEPTIBILITY TO

Location	Phenotype	Phenotype MIM number	Inheritance	Phenotype mapping key	Gene/Locus	Gene/Locus MIM number
2q22.1	{Asthma, susceptibility to}	600807	AD	3	HNMT	605238
4q13.3	{Asthma, protection against}	600807	AD	3	MUC7	158375
5q31.1	{Asthma, susceptibility to}	600807	AD	3	IL13	147683
5q32	{Asthma, susceptibility to}	600807	AD	3	SCGB3A2	606531
6p22.1	{Asthma, susceptibility to}	600807	AD	2	HLA-G	142871
6p21.33	{Asthma, susceptibility to}	600807	AD	3	TNF	191160
10q11.21	{Asthma, diminished response to antileukotriene treatment in}	600807	AD	3	ALOX5	152390
17q12	{Asthma, susceptibility to}	600807	AD	3	CCL11	601156

Clinical Synopsis

Resp

- Asthma
- Airway hyperresponsiveness

Inheritance

- Autosomal dominant vs. multifactorial

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▼ TEXT

A number sign (#) is used with this entry because multiple loci and candidate genes have been implicated in the causation of asthma and asthma-related traits (ASRT). See, e.g., ASRT1 (607277), associated with a mutation in the PTGDR gene (604687) on chromosome 14q24; ASRT2 (608584), associated with mutation in the GPRA gene (608595) on 7p15-p14; ASRT3 (609958), which has been mapped to chromosome 2p; ASRT4 (610906), which has been mapped to chromosome 1p31; and ASRT5 (611064), associated with variation in the IRAK3 gene (604459) on 12q14.3. ASRT6 (611403) is associated with markers on chromosome 17q21 and transcript levels of ORMDL3 (610075). ASRT7 (611960) is associated with polymorphism in the CHI3L1 gene (601525) on chromosome 1q32.1, and ASRT8 (613207) has been mapped to chromosome 9q33.

Polymorphisms in the HNMT gene (605238) and the ADRB2 gene (109690) have also been associated with susceptibility to asthma.

Balaci et al. (2007) stated that in the previous decade several loci and more than 100 genes had been found to be associated with asthma in at least 1 population.

▼ Description

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.

▼ Clinical Features

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).

▼ Inheritance

Longo et al. (1987) postulated that asthma can be inherited as a mendelian dominant disorder (with incomplete penetrance); Townley et al. (1986) supported polygenic inheritance. Longo et al. (1987) found that among the healthy parents of asthmatic children, tests of airway responsiveness to carbachol showed a bimodal distribution of responsiveness; in 85% of couples who had an asthmatic child, one or both parents had normal airway responsiveness consistent with an autosomal dominant trait.

Townley et al. (1986) demonstrated a unimodal distribution of airway responsiveness in normal subjects from nonasthmatic and nonallergic families and confirmed a bimodal distribution of bronchial reactivity to methacholine (MCh) in families with and without asthma.

Association with BMI

In a study of 1,001 monozygotic and 383 dizygotic same-sex twin pairs, Hallstrand et al. (2005) analyzed self-reports of a physician diagnosis of asthma and BMI (see 606641) calculated using self-reported height and weight, and found a strong association between asthma and BMI (p less than 0.001). Substantial heritability was detected for asthma (53%) and obesity (77%), indicating additive genetic influences on each disorder. The best-fitting model of shared components of variance indicated that 8% of the genetic component of obesity is shared with asthma.

▼ Pathogenesis

Xiang et al. (2007) reported that an excitatory rather than inhibitory GABAergic system exists in airway epithelial cells. Both GABA-A receptors (see 137160) and the GABA synthetic enzyme glutamic acid decarboxylase are expressed in pulmonary epithelial cells. Activation of GABA-A receptors depolarized these cells. The expression of glutamate decarboxylases GAD65 (138275) and GAD67 (605363) in the cytosol and GABA-A receptors in the apical membranes of airway epithelial cells increased markedly when mice were sensitized and then challenged with ovalbumin, an approach for inducing allergic asthmatic reactions. Similarly, GAD65/67 and GABA-A receptors in airway epithelial cells of humans with asthma increased after allergen inhalation challenge. Intranasal application of selective GABA-A receptor inhibitors suppressed the hyperplasia of goblet cells and the overproduction of mucus induced by ovalbumin or interleukin-13 (147683) in mice. Xiang et al. (2007) concluded that the airway epithelial GABAergic system has an essential role in asthma.

Protectins are natural chemical mediators generated from omega-3 fatty acids that counter leukocyte activation to promote resolution of inflammation. Levy et al. (2007) found that protectin D1 (PD1) was formed from docosahexaenoic acid in human asthma in vivo and exhibited counterregulatory actions in allergic airway inflammation in mice. PD1 and 17S-hydroxy-docosahexaenoic acid were detected in exhaled breath condensates from healthy human subjects, but PD1 levels were significantly lower in exhaled breath condensates from subjects with asthma exacerbations. PD1 was also present in lung extracts of both control mice and mice sensitized and challenged with aeroallergen. Administration of PD1 before aeroallergen challenge decreased recruitment of eosinophils and T cells to mouse airways and also decreased airway mucus and proinflammatory mediators, including Il13 (147683), cysteinyl leukotrienes, and Pgd2 (see 176803). Treatment with PD1 after aeroallergen challenge markedly accelerated the resolution of airway inflammation. Levy et al. (2007) concluded that endogenous PD1 is a pivotal counterregulatory signal in allergic airway inflammation, and they suggested that the PD1 pathway may offer novel therapeutic approaches for asthma.

▼ Mapping

Lympany et al. (1992) could not demonstrate significant linkage between D11S97 and either atopy or bronchial hyperreactivity to methacholine. Amelung et al. (1992) were unable to find linkage between atopy or bronchial hyperresponsiveness and markers on 11q or 6p.

Postma et al. (1995) studied 303 children and grandchildren of 84 probands with asthma selected from a homogeneous population in the Netherlands. Ventilatory function, bronchial responsiveness to histamine, and serum total IgE (147180) were measured, and the association between the last 2 variables was evaluated. By a sib-pair method, they tested for linkage between bronchial hyperresponsiveness and genetic markers on 5q31-q33, previously shown to be linked to a genetic locus regulating serum total IgE levels (147061). Postma et al. (1995) found that total IgE levels were strongly correlated in pairs of sibs concordant for bronchial hyperresponsiveness, suggesting that these traits are coinherited. However, bronchial hyperresponsiveness was not correlated with serum IgE levels in the group as a whole. Analyses of sib pairs showed linkage of bronchial hyperresponsiveness with several genetic markers on chromosome 5q, including D5S436. The results were interpreted as indicating that a gene governing bronchial hyperresponsiveness is located near a major locus that regulates serum IgE levels on 5q.

Holgate (1997), reporting on a conference on asthma genetics, reviewed comprehensively the state of genetic studies of asthma and atopy, including a catalog of candidate genes and chromosomal regions and the results of random genome searches.

The Collaborative Study on the Genetics of Asthma (1997), conducted by 51 investigators in 3 centers, consisted of a genomewide search in 140 families with 2 or more asthmatic sibs, from 3 racial groups. Evidence was reported for linkage to 6 novel regions: 5p15 (P = 0.0008) and 17p11.1-q11.2 (P = 0.0015) in African Americans; 11p15 (P = 0.0089), and 19q13 (P = 0.0013) in Caucasians; 2q33 (P = 0.0005) and 21q21 (P = 0.0040) in Hispanics. Evidence for linkage was also detected in 5 regions previously reported to be linked to asthma-associated phenotypes: 5q23-q31, 6p23-p21.3, 12q14-q24.2, 13q21.3-qter, and 14q11.2-q13 in Caucasians and 12q14-q24.2 in Hispanics. See Nicolaides et al. (1997) and interleukin-9 (IL9; 146931) for a discussion of IL9 as a candidate gene for asthma.

A second-stage collaborative study on the genetics of asthma (Xu et al., 2001) involving 266 families in 3 U.S. populations found evidence for linkage with the asthma phenotype for multiple chromosomal regions. They found the strongest evidence for linkage at 6p21 in the European American population, at 11q21 in the African American population, and at 1p32 in the Hispanic population. Both the conditional analysis and the affected sib pair 2-locus analysis provided further evidence for linkage at 5q31, 8p23, 12q22, and 15q13. Several of these regions have been observed in other genomewide screens and linkage or association studies.

Following up on the finding of Xu et al. (2001) of linkage of asthma to 11q in African American families but not in Caucasian families, Huang et al. (2003) conducted fine mapping analyses to narrow the critical linkage region. Multipoint analyses of the 51 multiplex families yielded significant evidence of linkage with a peak nonparametric linkage score of 4.38 at marker D11S1337 (map position 68.6 cM). Furthermore, family-based association and transmission disequilibrium tests conducted on all 91 families showed significant evidence of linkage together with disequilibrium for several individual markers in this region. A putative susceptibility locus was estimated to be at map position 70.8 cM.

Founder populations offer many advantages for mapping genetic traits, particularly complex traits that are likely to be genetically heterogeneous. To identify genes that influence asthma and asthma-associated phenotypes, Ober et al. (1998) conducted a genomewide screen in the Hutterites, a religious isolate of European ancestry. A primary sample of 361 individuals and a replication sample of 292 individuals were evaluated for asthma phenotypes according to a standardized protocol. A genomewide screen was performed using 292 autosomal and 3 X-Y pseudoautosomal markers. Using the semiparametric likelihood ratio chi-square test and the transmission/disequilibrium test, they identified 12 markers in 10 regions that showed possible linkage to asthma or an associated phenotype (likelihood ratio P less than 0.01). Markers in 4 regions (5q23-q31, 12q15-q24.1, 19q13, and 21q21) showed possible linkage in both the primary and replication samples and had shown linkage to asthma phenotypes in other samples. In addition, 2 adjacent markers in the region 3p24.2-p22 showed possible linkage for the first time in the Hutterites. The results suggested that even in founder populations with a relatively small number of independent genomes, susceptibility alleles at many loci may influence asthma phenotypes and that these susceptibility alleles are likely to be common polymorphisms in the population. Ober et al. (2000) conducted a further genomewide screen for asthma and atopy susceptibility loci in 693 Hutterites who were members of a single 15-generation pedigree, nearly doubling the sample size from their earlier studies. The resulting increase in power led to the identification of 23 loci in 18 chromosomal regions showing evidence for linkage that is, in general, 10-fold more significant than the linkages reported previously in this population. Moreover, linkages to loci in 11 chromosomal regions were identified for the first time in the Hutterites in this report.

Using quantitative scores as their phenotypic variables, Wilkinson et al. (1998) presented evidence of linkage of asthma to a region on chromosome 12.

Yet another region of linkage mapping was identified by Holroyd et al. (1998). The researchers examined the long arm XY pseudoautosomal region for linkage to asthma, serum IgE, and bronchial hyperresponsiveness. In 57 Caucasian families, multipoint nonparametric analyses provided evidence for linkage between DXYS154 and bronchial hyperresponsiveness (P = 0.000057) or asthma (P = 0.00065). This genomic region is approximately 320 kb long and contains the interleukin-9 receptor gene (IL9R; 300007). These results suggested that a gene controlling asthma and bronchial hyperresponsiveness may be located in this region and that IL9R is a candidate.

Many quantitative trait loci (QTLs) contributing to genetically complex conditions have been discovered, but few causative genes identified. This is mainly because of the large size of QTLs and the subtle connection between specific genotype and quantitative phenotype of the condition studied. Transgenic mice have been successfully used to analyze well-characterized genes suspected of contributing to quantitative traits. Although this approach is powerful for examining one gene at a time, it can be impractical for surveying the large genomic intervals containing many genes that are typically associated with QTLs. To screen for genes contributing to an asthma QTL mapped to human chromosome 5q31 (Marsh et al., 1994; Noguchi et al., 1997) Symula et al. (1999) characterized a panel of large-insert 5q31 transgenics based on studies demonstrating that altering gene dosage frequently affects quantitative phenotypes normally influenced by that gene. This panel of human YAC transgenics, propagating a 1-Mb interval of 5q31 containing 6 cytokine genes and 17 partially characterized genes, was screened for quantitative changes in several asthma-related phenotypes. Multiple independent transgenic lines with altered IgE response to antigen treatment shared a 180-kb region containing 5 genes, including those encoding interleukin-4 (IL4; 147780) and interleukin-13 (IL13; 147683), which induced IgE class switching in B cells. Further analysis of these mice and mice transgenic for mouse Il4 and Il13 demonstrated that moderate changes in Il4 and Il13 expression affect asthma-associated phenotypes in vivo. This functional screen of large-insert transgenics enabled Symula et al. (1999) to identify genes that influence the QTL phenotype in vivo.

Yokouchi et al. (2000) conducted a genomewide linkage search in 47 Japanese families (197 members) with more than 2 mite-sensitive atopic asthmatics (65 affected sib pairs) using 398 markers. Significant evidence for linkage with maximal lod scores of 4.8 was observed near the IL12B gene (161561) on chromosome 5q31-q33. In addition, suggestive evidence on 4p35 with a lod score of 2.7 and on 13q11 with a lod score of 2.4 was obtained. Other possible linkage regions included 6p22-p21.3, lod 2.1; 12q21-q23, lod 1.9; and 13q14.1-q14.3, lod 2.0. Many of the linkage loci suggested in this study were at or close to those suggested by genomewide studies for asthma in Caucasian populations.

Lonjou et al. (2000) presented preliminary analysis of a retrospective collaboration for positional cloning of asthma susceptibility by the Consortium on Asthma Genetics. Combination of evidence over multiple samples with 1,037 families supported loci contributing to asthma susceptibility in the cytokine region on 5q, with a maximum lod score of 2.61 near the IL4 gene, but no evidence for atopy.

Palmer et al. (2001) combined 11 datasets from 6,277 subjects to investigate evidence for linkage of 35 markers spanning the cytokine cluster on chromosome 5q31-q33 to 'asthma' dichotomy and total serum IgE levels. The results did not provide any evidence significant at the 5% level that loci conferring susceptibility to asthma or atopy are present in the 5q31-q33 region; however, there was some weak evidence (P = 0.077) of linkage to asthma affection. The authors suggested that loci in 5q31-q33 have at most a modest effect on susceptibility to asthma or total serum IgE levels, may not be detectable or present in all human populations, and are difficult to detect even using combined linkage evidence from 2,400-2,600 full sib pairs.

Xu et al. (2001) performed a genomewide screen for quantitative trait loci (QTLs) that underlie asthma in 533 Chinese families with asthma. They studied 9 asthma-related phenotypes. The study showed significant linkage between one of these phenotypes, airway responsiveness to methacholine, and D2S1780 on chromosome 2p25-p24 (P less than 0.00002), and provided suggestive evidence (P less than 0.002) for 6 additional possible QTLs.

Dizier et al. (2001) investigated 107 French families with at least 2 asthmatic sibs from the EGEA study (Epidemiological study on the Genetics and Environment of Asthma) using 157 autosomal microsatellite markers. The triangle test statistic (TTS) applied to 38 asthmatic sib pairs discordant for age at onset indicated linkage and genetic heterogeneity for a region located on chromosome 7q (at 109 cM from pter), which was confirmed by the predivided sample test (PST). This finding suggested a linked genetic factor involved in asthma but with different relative genotype risks according to age at onset, with the age of 4 years as the cutoff point. Dizier et al. (2001) proposed that the gene on 7q could be a modifier gene, specifically involved in age at asthma onset, or a susceptibility gene linked to asthma with an early age at onset in subjects homozygous for the disease allele and a less early age at onset in heterozygotes.

Using 175 extended Icelandic families that included 596 patients with asthma, Hakonarson et al. (2002) performed a genomewide scan with 976 microsatellite markers. The families were identified by cross-matching a list of patients with asthma from the National University Hospital of Iceland with a genealogy database of the entire Icelandic nation. They detected linkage of asthma to chromosome 14q24 with an allele-sharing lod score of 2.66. After they increased the marker density within the locus to an average of 1 microsatellite every 0.2 cM, the lod score rose to 4.00. Hakonarson et al. (2002) designated this locus AS1 (ASRT1; 607277) and concluded that it represents a major susceptibility gene for asthma.

Leaves et al. (2002) investigated 80 families (172 sib pairs) from West Australia selected to include sibships of 3 or greater, with both atopic and nonatopic members represented. Forty-seven microsatellite markers spanning chromosome 7 and spaced on average 2.6 cM apart were typed. Multipoint linkage to bronchial responsiveness to metacholine (dose-response slope) was bimodal and dipped at the centromere. The short arm cluster of significance encompassed 34 cM and the long arm cluster 13.6 cM. Linkage to the peripheral blood eosinophil count closely mirrored linkage to the dose-response slope, suggesting that the locus influences both phenotypes. Separate testing for linkage to paternally and maternally derived alleles showed that the bulk of the linkage on the short arm originated from male meiotic events, whereas maternally derived alleles only showed significant evidence of linkage on the long arm of the chromosome. The proposed mechanisms of a parent of origin effect included parental allele-specific transcription (imprinting) and some unknown in utero mechanism.

Anderson et al. (2002) constructed a BAC/PAC contig physical map of the 1.5 Mb region surrounding the D13S273 microsatellite marker at chromosome 13q14, a region previously linked in a genome screen for asthma and atopy. Association testing between total serum IgE concentration in 172 sib pairs (12% of which children were asthmatic) and microsatellite markers across the contig detected a highly significant association with a novel microsatellite marker within 200 kb of D13S273. The association remained significant when corrected for multiple testing (P less than 0.005). Adjoining microsatellites in the D13S273 vicinity showed weaker association, suggesting that an atopy gene is located within the D13S1307-D13S272 region.

Raby et al. (2003) genotyped 55 nuclear families with at least 2 asthmatic sibs (212 individuals) using 32 microsatellite markers on chromosome 12. Three separate and distinct loci demonstrated evidence suggestive of linkage: asthma at 68 cM (exact P value = 0.05), airways responsiveness (PC20) at 147 cM (P = 0.01), and indices of pulmonary function (FEV1 and BDPR) at 134 cM (P = 0.05 and P less than 0.01, respectively). No linkage was observed for the atopy-related phenotypes.

Murphy et al. (2009) found significant association between BMI (BMIQ15; 612967) and SNPs in the PRKCA gene (176960) on chromosome 17q23.2-q25.1 in 8 extended Costa Rican families involving 415 parent-child trios originally ascertained on asthma affection status (see 611064 and Celedon et al., 2007) and in 457 Caucasian families with 493 offspring diagnosed with asthma. Testing for association between PRKCA SNPs and asthma affection status identified a significantly associated SNP, rs11079657 (combined corrected p = 2.6 x 10(-5)).

Sleiman et al. (2010) conducted a genomewide association study in 793 North American children of European ancestry with asthma and an independent cohort of 917 persons of European ancestry with childhood-onset asthma, and observed an association between asthma and SNPs at the previously reported locus on chromosome 17q21 (ASRT6; 611403) and an additional 8 SNPs in a 540-kb interval on 1q31.3. The SNP most strongly associated with asthma was rs2786098, which was replicated in the independent series (combined p = 9.3 x 10(-11)). The alternative allele of each of the 8 SNPs on chromosome 1q31 was strongly associated with asthma in 1,667 North American children of African ancestry (comparison across all samples, p = 1.6 x 10(-13)). Sleiman et al. (2010) noted that all of the associated SNPs map to a single linkage disequilibrium block spanning the DENND1B gene (613292) and the 3-prime end of the CRB1 gene (604210).

▼ Molecular Genetics

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 rs1031771 G allele (OR, 1.42; p = 0.006) and the 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

For discussion of a possible association between susceptibility to asthma and variation in the IL12B gene, see 161561.

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

For discussion of a possible association between susceptibility to asthma and variation in the ADBR2 gene, see 109690.

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 (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

See 192020.0001 for discussion of a possible association between susceptibility to asthma variation in the SCGB1A1 gene.

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.

▼ Animal Model

De Sanctis et al. (1995) found that F1 mice derived from A/J and C57BL/6J display a phenotype that resembles the asthma-like phenotype of the A/J mice. Since airway responsiveness to MCh did not segregate as a single locus, they used the approach of Wright (1978) to estimate the segregation index or number of loci responsible for regulating airway responsiveness. This approach made the assumption that all loci make equal contributions to the expression of the phenotype in question.

Gleich and Kita (1997) reviewed the insight on human bronchial asthma coming from the study of murine models.

De Sanctis et al. (1995) showed significant linkage to 2 loci, Bhr1 and Bhr2, on mouse chromosomes 2 and 15. A third locus, Bhr3, mapped to mouse chromosome 17. Collectively, the 3 loci accounted for roughly 26% of the genetic variants in airway responsiveness between A/J and C57BL/6J mice. Each of these loci mapped near candidate loci implicated in the pathobiology of asthma. The candidate genes include the mouse counterparts of interleukin-1-beta (147720) on mouse chromosome 2; receptor for interleukin 2B (146710), and the B chain of platelet-derived growth factor (190040) located on chromosome 15 of the mouse; and tumor necrosis factor-alpha (TNFA; 191160) and other genes located on mouse chromosome 17.

Humbles et al. (2000) showed that in a murine model of allergic airway disease, genetic deletion of the C3a receptor (C3AR1; 605246) protects against the changes in lung physiology seen after allergen challenge. Furthermore, human asthmatics developed significant levels of ligand C3a following intrapulmonary deposition of allergen but not saline. Humbles et al. (2000) proposed that, in addition to acquired immune responses, the innate immune system and complement (C3a in particular) are involved in the pathogenesis of asthma.

Matsuoka et al. (2000) generated mice deficient in the prostaglandin D2 receptor (DP; 604687). Sensitization and aerosol challenge of the homozygous mutant DP -/- mice with ovalbumin induced increases in the serum concentration of IgE similar to those in wildtype mice subjected to this model of asthma. However, the concentrations of TH2 cytokines and the extent of lymphocyte accumulation in the lung of ovalbumin-challenged DP -/- mice were greatly reduced compared with those in wildtype animals. Moreover, DP -/- mice showed only marginal infiltration of eosinophils and failed to develop airway hyperreactivity. Thus, prostaglandin D2 functions as a mast cell-derived mediator to trigger asthmatic responses.

Using microarray analysis of pulmonary gene expression and SNP-based genotyping, Karp et al. (2000) identified C5 (120900) on mouse chromosome 2 as a susceptibility locus for allergen-induced airway hyperresponsiveness in a mouse model of asthma. Backcross and SNP analysis showed that a 2-bp deletion in the C5 gene of A/J and AKR/J mice led to C5 deficiency, correlating with airway hyperresponsiveness, whereas C5-sufficient strains did not develop asthma. Previous studies had shown that administration of IL12 (161560) to susceptible mice rendered them resistant to asthma induction (Gavett et al., 1995). Blockade of C5R1 (113995) in human monocytes caused marked, dose-dependent inhibition of IL12 production, as well as inhibition of TNFA secretion and IFNG (147570)-mediated suppression of IL10 (124092) production, although there was no overall effect on IL10 production. These results suggested that C5 deficiency leads to an antiinflammatory phenotype. Karp et al. (2000) noted that previous genomewide screens had found evidence of linkage of asthma susceptibility to the C5 (Ober et al., 1998; Wjst et al., 1999) and C5R1 (Collaborative Study on the Genetics of Asthma, 1997; Ober et al., 1998) chromosomal regions.

TH2-type cytokines are encoded by genes found on 5q23-q35, which is homologous to a region on mouse chromosome 11. McIntire et al. (2001) generated congenic mice, designated HBA mice, containing a segment of chromosome 11 inherited from DBA/2 mice, which have low TH2 responses on the high-responder BALB/c background. HBA mice produced significantly less IL4, IL13, and IL10 and had lower antigen-induced airway hyperreactivity (AHR) than did BALB/c mice. McIntire et al. (2001) proposed the existence of a T-cell and airway phenotype regulator (Tapr) locus on mouse chromosome 11. By simple sequence length polymorphism and backcross analyses, they narrowed the localization of Tapr to a region more than 5 cM centromeric to the IL4 cytokine cluster. The Tapr locus was nonrecombinant with a marker within the homolog of the rat kidney injury molecule-1 gene (Kim1). By homology of synteny and database analysis, the authors linked the Tapr locus to human chromosome 5q33.2. By EST database analysis, McIntire et al. (2001) identified hepatitis A virus (HAV) cellular receptor-1 (HAVCR1; 606518) as a human homolog of rat Kim1. By PCR of activated mouse splenocytes with primers based on the rat Kim1 sequence, McIntire et al. (2001) obtained cDNAs encoding mouse Tim1 (T-cell, immunoglobulin domain, mucin domain protein-1) and Tim2. The deduced 305-amino acid Tim1 and Tim2 proteins are 42% and 32% identical to HAVCR1, respectively. A third Tim protein, Tim3 (606652), encodes a 281-amino acid protein. Comparison of BALB/c and HBA Tim sequences revealed polymorphisms in Tim1 and Tim3, but none were identified in Tim2. The Tim1 polymorphisms correlated with the development of higher TH2 responses in BALB/c mice compared with HBA mice. McIntire et al. (2001) suggested that the interaction of HAV with a human Tim1 may reduce TH2 differentiation and reduce the likelihood of developing asthma. Variable TIM1 alleles may protect against severe HAV disease while preserving susceptibility to asthma.

Using natural killer T (NKT) cell-deficient mice, Akbari et al. (2003) showed that allergen-induced airway hyperreactivity, a cardinal feature of asthma, does not develop in the absence of the V-alpha-14i NKT cells. The failure of NKT cell-deficient mice to develop airway hyperreactivity was not due to an inability of these mice to produce type 2 T-helper (Th2) responses because NKT cell-deficient mice that are immunized subcutaneously at nonmucosal sites produce normal Th2-biased responses. The failure to develop airway hyperreactivity could be reversed by the adoptive transfer of tetramer-purified NKT cells producing IL4 (147780) and IL13 (147683) to Ja281 -/- mice, which lack the invariant T-cell receptor of NKT cells, or by the administration to Cd1d-deficient mice of recombinant IL13, which directly affects airway smooth muscle cells. Thus, pulmonary V-alpha-14i NKT cells crucially regulate the development of asthma and Th2-biased respiratory immunity against nominal exogenous antigens.

Kwak et al. (2003) found that intratracheal administration of PI3K inhibitors or adenoviruses carrying PTEN (601728) cDNA reduced bronchial inflammation and airway hyperresponsiveness in a mouse model of asthma. Pi3k activity increased after allergen (ovalbumin) challenge, while Pten protein expression and activity decreased after allergen challenge. Immunoreactive Pten localized in epithelial layers around the bronchioles in control mice, but Pten staining disappeared in asthmatic lungs. PI3K inhibitors or adenovirus PTEN administration reduced the Il4, Il5 (147850), and eosinophil cationic protein (RNASE3; 131398) levels in bronchoalveolar lavage fluids. Kwak et al. (2003) concluded that PTEN may play a role in the pathogenesis of asthma.

Lee et al. (2004) created a transgenic line of mice, which they called PHIL, that are specifically devoid of eosinophils but otherwise have a full complement of hematopoietically-derived cells. Allergen challenge of PHIL mice demonstrated that eosinophils were required for pulmonary mucus accumulation and the airway hyperresponsiveness associated with asthma. Lee et al. (2004) suggested that the development of an eosinophil-less mouse permits an unambiguous assessment of a number of human diseases that have been linked to this granulocyte, including allergic diseases, parasite infections, and tumorigenesis.

Humbles et al. (2004) studied eosinophil-depleted mice generated by Yu et al. (2002). They showed that in mice with a total ablation of the eosinophil lineage, increases in airway hyperresponsiveness and mucus secretion were similar to those observed in wildtype mice, but eosinophil-deficient mice were significantly protected from peribronchiolar collagen deposition and increases in airway smooth muscle. Humbles et al. (2004) concluded their data suggested that eosinophils contribute substantially to airway remodeling but are not obligatory for allergen-induced lung dysfunction, and support an important role for eosinophil-targeted therapies in chronic asthma.

S-nitrosoglutathione (GSNO), an endogenous bronchodilator, is depleted from asthmatic airways, suggesting a protective role. Que et al. (2005) reported that, following allergen challenge, wildtype mice exhibiting airway hyperresponsivity had increased airway levels of the enzyme GSNO reductase (GSNOR; 103710) and were depleted of lung S-nitrosothiols (SNOs). In contrast, mice with genetic deletion of Gsnor exhibited increases in lung SNOs and were protected from airway hyperresponsivity. Que et al. (2005) concluded that endogenous SNOs, governed by GSNOR, are critical regulators of airway responsivity.

Shum et al. (2006) examined Fabp4 (600434)-deficient mice in a model of allergic airway inflammation and found that infiltration of leukocytes, especially eosinophils, into the airways was highly dependent on Fabp4 function. T-cell priming was unaffected by Fabp4 deficiency, suggesting that Fabp4 was acting locally within the lung, and analysis of bone marrow chimeras implicated nonhematopoietic cells, most likely bronchial epithelial cells, as the site of action of Fabp4 in allergic airway inflammation. Shum et al. (2006) concluded that FABP4 regulates allergic airway inflammation and may provide a link between fatty acid metabolism and asthma.

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Contributors:

Ada Hamosh - updated : 10/26/2010

Marla J. F. O'Neill - updated : 10/22/2010
Marla J. F. O'Neill - updated : 8/6/2010
Marla J. F. O'Neill - updated : 3/4/2010
Marla J. F. O'Neill - updated : 7/30/2009
George E. Tiller - updated : 4/22/2009
Paul J. Converse - updated : 10/22/2008
George E. Tiller - updated : 4/29/2008
Ada Hamosh - updated : 2/25/2008
Paul J. Converse - updated : 1/4/2008
Ada Hamosh - updated : 8/20/2007
Marla J. F. O'Neill - updated : 7/11/2007
George E. Tiller - updated : 6/13/2007
Victor A. McKusick - updated : 5/23/2007
Cassandra L. Kniffin - updated : 4/3/2007
Marla J. F. O'Neill - updated : 3/8/2007
George E. Tiller - updated : 12/4/2006
Marla J. F. O'Neill - updated : 10/24/2006
Victor A. McKusick - updated : 9/19/2006
Cassandra L. Kniffin - updated : 3/15/2006
Victor A. McKusick - updated : 2/9/2006
Ada Hamosh - updated : 2/3/2006
Marla J. F. O'Neill - updated : 6/21/2005
George E. Tiller - updated : 5/25/2005
Victor A. McKusick - updated : 3/11/2005
Victor A. McKusick - updated : 1/21/2005
Ada Hamosh - updated : 12/29/2004
Victor A. McKusick - updated : 9/20/2004
Marla J. F. O'Neill - updated : 8/27/2004
George E. Tiller - updated : 6/18/2004
Ada Hamosh - updated : 4/20/2004
Patricia A. Hartz - updated : 11/17/2003
Victor A. McKusick - updated : 6/10/2003
Victor A. McKusick - updated : 5/19/2003
Ada Hamosh - updated : 3/31/2003
Michael B. Petersen - updated : 12/2/2002
Michael B. Petersen - updated : 10/31/2002
George E. Tiller - updated : 10/9/2002
Victor A. McKusick - updated : 10/7/2002
Matthew B. Gross - reorganized : 10/7/2002
Michael B. Petersen - updated : 9/6/2002
Michael B. Petersen - updated : 8/30/2002
Ada Hamosh - updated : 7/22/2002
Victor A. McKusick - updated : 1/22/2002
Victor A. McKusick - updated : 12/20/2001
Paul J. Converse - updated : 11/29/2001
Michael B. Petersen - updated : 11/1/2001
Michael B. Petersen - updated : 11/1/2001
George E. Tiller - updated : 7/24/2001
Victor A. McKusick - updated : 6/20/2001
Victor A. McKusick - updated : 4/24/2001
Michael B. Petersen - updated : 2/7/2001
Victor A. McKusick - updated : 11/21/2000
Victor A. McKusick - updated : 10/26/2000
Paul J. Converse - updated : 9/20/2000
Ada Hamosh - updated : 8/30/2000
Ada Hamosh - updated : 8/14/2000
Ada Hamosh - updated : 3/16/2000
Victor A. McKusick - updated : 9/29/1999
Victor A. McKusick - updated : 7/20/1999
Victor A. McKusick - updated : 1/25/1999
Victor A. McKusick - updated : 9/17/1998
Michael J. Wright - updated : 6/30/1998
Victor A. McKusick - updated : 12/17/1997
Victor A. McKusick - updated : 4/21/1997
Victor A. McKusick - updated : 3/31/1997
Victor A. McKusick - updated : 3/2/1997

Creation Date:

Victor A. McKusick : 10/17/1995

Edit History:

carol : 01/26/2021

alopez : 05/16/2019
carol : 04/11/2017
carol : 05/22/2015
carol : 6/6/2014
terry : 12/20/2012
terry : 10/2/2012
terry : 6/20/2011
carol : 6/1/2011
carol : 2/9/2011
wwang : 2/7/2011
alopez : 11/10/2010
alopez : 10/26/2010
wwang : 10/26/2010
terry : 10/22/2010
wwang : 8/6/2010
wwang : 8/6/2010
carol : 8/2/2010
wwang : 3/17/2010
carol : 3/4/2010
wwang : 3/4/2010
ckniffin : 1/6/2010
carol : 10/15/2009
wwang : 8/18/2009
terry : 7/30/2009
terry : 6/4/2009
wwang : 5/7/2009
terry : 4/22/2009
mgross : 10/22/2008
wwang : 5/1/2008
terry : 4/29/2008
carol : 4/17/2008
mgross : 3/24/2008
terry : 3/21/2008
alopez : 3/3/2008
terry : 2/25/2008
carol : 1/4/2008
alopez : 8/31/2007
terry : 8/20/2007
wwang : 7/12/2007
terry : 7/11/2007
wwang : 6/18/2007
terry : 6/13/2007
alopez : 5/30/2007
terry : 5/23/2007
wwang : 4/3/2007
wwang : 4/3/2007
wwang : 3/12/2007
terry : 3/8/2007
wwang : 12/4/2006
terry : 12/4/2006
wwang : 10/24/2006
terry : 10/24/2006
wwang : 10/5/2006
terry : 9/19/2006
carol : 9/5/2006
terry : 8/30/2006
wwang : 4/10/2006
wwang : 4/7/2006
ckniffin : 3/15/2006
alopez : 2/14/2006
terry : 2/9/2006
alopez : 2/6/2006
alopez : 2/6/2006
terry : 2/3/2006
carol : 12/22/2005
carol : 12/22/2005
carol : 12/7/2005
alopez : 9/30/2005
terry : 9/9/2005
wwang : 6/29/2005
terry : 6/21/2005
alopez : 5/25/2005
alopez : 3/16/2005
terry : 3/11/2005
terry : 2/7/2005
tkritzer : 1/21/2005
alopez : 12/30/2004
terry : 12/29/2004
carol : 12/8/2004
tkritzer : 9/21/2004
tkritzer : 9/20/2004
carol : 9/1/2004
terry : 8/27/2004
alopez : 6/18/2004
alopez : 6/18/2004
alopez : 6/3/2004
carol : 6/2/2004
alopez : 6/1/2004
alopez : 4/21/2004
terry : 4/20/2004
carol : 11/24/2003
mgross : 11/17/2003
carol : 7/10/2003
cwells : 6/12/2003
terry : 6/10/2003
alopez : 6/3/2003
alopez : 5/19/2003
alopez : 5/16/2003
alopez : 4/1/2003
terry : 3/31/2003
cwells : 12/2/2002
cwells : 10/31/2002
cwells : 10/9/2002
mgross : 10/7/2002
mgross : 10/7/2002
mgross : 10/7/2002
alopez : 9/6/2002
cwells : 8/30/2002
alopez : 7/25/2002
terry : 7/22/2002
alopez : 2/11/2002
carol : 2/5/2002
mcapotos : 1/31/2002
terry : 1/22/2002
alopez : 1/11/2002
cwells : 1/9/2002
terry : 12/20/2001
mgross : 11/29/2001
joanna : 11/26/2001
carol : 11/13/2001
cwells : 11/9/2001
cwells : 11/9/2001
cwells : 11/6/2001
cwells : 11/6/2001
cwells : 11/1/2001
cwells : 7/27/2001
cwells : 7/24/2001
mcapotos : 6/26/2001
mcapotos : 6/22/2001
terry : 6/20/2001
carol : 5/9/2001
cwells : 5/4/2001
alopez : 4/27/2001
terry : 4/24/2001
terry : 2/7/2001
terry : 1/18/2001
terry : 11/21/2000
mcapotos : 11/8/2000
mcapotos : 10/31/2000
terry : 10/26/2000
mgross : 9/20/2000
mgross : 9/20/2000
mgross : 8/30/2000
terry : 8/30/2000
alopez : 8/18/2000
terry : 8/14/2000
terry : 8/14/2000
mgross : 4/17/2000
carol : 3/16/2000
alopez : 3/16/2000
alopez : 3/16/2000
terry : 3/16/2000
terry : 11/30/1999
alopez : 9/30/1999
terry : 9/29/1999
jlewis : 8/5/1999
terry : 7/20/1999
carol : 1/28/1999
terry : 1/25/1999
dkim : 12/10/1998
carol : 9/21/1998
terry : 9/17/1998
alopez : 7/6/1998
alopez : 7/6/1998
alopez : 7/6/1998
alopez : 7/6/1998
terry : 6/30/1998
mark : 12/17/1997
terry : 11/11/1997
terry : 11/11/1997
mark : 4/21/1997
terry : 4/14/1997
mark : 3/31/1997
terry : 3/28/1997
mark : 3/2/1997
terry : 2/28/1997
mark : 2/19/1996
terry : 2/15/1996
mimadm : 11/3/1995
terry : 10/30/1995
mark : 10/17/1995

# 600807

ASTHMA, SUSCEPTIBILITY TO

Alternative titles; symbols

ASTHMA, BRONCHIAL
ASTHMA-RELATED TRAITS, SUSCEPTIBILITY TO

Other entities represented in this entry:

ASTHMA, PROTECTION AGAINST, INCLUDED

ASTHMA, DIMINISHED RESPONSE TO ANTILEUKOTRIENE TREATMENT IN, INCLUDED

DO: 2841;

Phenotype-Gene Relationships

Location	Phenotype	Phenotype MIM number	Inheritance	Phenotype mapping key	Gene/Locus	Gene/Locus MIM number
2q22.1	{Asthma, susceptibility to}	600807	Autosomal dominant	3	HNMT	605238
4q13.3	{Asthma, protection against}	600807	Autosomal dominant	3	MUC7	158375
5q31.1	{Asthma, susceptibility to}	600807	Autosomal dominant	3	IL13	147683
5q32	{Asthma, susceptibility to}	600807	Autosomal dominant	3	SCGB3A2	606531
6p22.1	{Asthma, susceptibility to}	600807	Autosomal dominant	2	HLA-G	142871
6p21.33	{Asthma, susceptibility to}	600807	Autosomal dominant	3	TNF	191160
10q11.21	{Asthma, diminished response to antileukotriene treatment in}	600807	Autosomal dominant	3	ALOX5	152390
17q12	{Asthma, susceptibility to}	600807	Autosomal dominant	3	CCL11	601156

TEXT

Polymorphisms in the HNMT gene (605238) and the ADRB2 gene (109690) have also been associated with susceptibility to asthma.

Balaci et al. (2007) stated that in the previous decade several loci and more than 100 genes had been found to be associated with asthma in at least 1 population.

Description

Clinical Features

Inheritance

Association with BMI

Pathogenesis

Mapping

Using quantitative scores as their phenotypic variables, Wilkinson et al. (1998) presented evidence of linkage of asthma to a region on chromosome 12.

Molecular Genetics

Association with KCNS3 on Chromosome 2p24

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

Association with IL13 on Chromosome 5q31

Association with IL12B on Chromosome 5q31-q33

For discussion of a possible association between susceptibility to asthma and variation in the IL12B gene, see 161561.

Association with SCGB3A2 on Chromosome 5q31-q34

Association with ADRB2 on Chromosome 5q32-q34

For discussion of a possible association between susceptibility to asthma and variation in the ADBR2 gene, see 109690.

Association with HLA-G on Chromosome 6p21

Association with PLA2G7 on Chromosome 6p21.2

Association with TNFA on Chromosome 6p21.3

Association with HLA-DRB1 on Chromosome 6p21.3

Association with NOD1 on Chromosome 7p15-p14

Association with CCL24 on Chromosome 7q11.23

Association with GPR44 on Chromosome 11q12

Association with SCGB1A1 on Chromosome 11q12.3-q13

See 192020.0001 for discussion of a possible association between susceptibility to asthma variation in the SCGB1A1 gene.

Association with STAT6 on Chromosome 12q13

Association with PHF11 on Chromosome 13q14

Association with IL4R on Chromosome 16p12.1-p11

Association with CCL11 on Chromosome 17q21.1-q21.2

Association with ADAM33 on Chromosome 20p13

Sex-Specific Modifier of Asthma Severity on Chromosome 5q34

Animal Model

Gleich and Kita (1997) reviewed the insight on human bronchial asthma coming from the study of murine models.

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Contributors:

Ada Hamosh - updated : 10/26/2010
Marla J. F. O'Neill - updated : 10/22/2010
Marla J. F. O'Neill - updated : 8/6/2010
Marla J. F. O'Neill - updated : 3/4/2010
Marla J. F. O'Neill - updated : 7/30/2009
George E. Tiller - updated : 4/22/2009
Paul J. Converse - updated : 10/22/2008
George E. Tiller - updated : 4/29/2008
Ada Hamosh - updated : 2/25/2008
Paul J. Converse - updated : 1/4/2008
Ada Hamosh - updated : 8/20/2007
Marla J. F. O'Neill - updated : 7/11/2007
George E. Tiller - updated : 6/13/2007
Victor A. McKusick - updated : 5/23/2007
Cassandra L. Kniffin - updated : 4/3/2007
Marla J. F. O'Neill - updated : 3/8/2007
George E. Tiller - updated : 12/4/2006
Marla J. F. O'Neill - updated : 10/24/2006
Victor A. McKusick - updated : 9/19/2006
Cassandra L. Kniffin - updated : 3/15/2006
Victor A. McKusick - updated : 2/9/2006
Ada Hamosh - updated : 2/3/2006
Marla J. F. O'Neill - updated : 6/21/2005
George E. Tiller - updated : 5/25/2005
Victor A. McKusick - updated : 3/11/2005
Victor A. McKusick - updated : 1/21/2005
Ada Hamosh - updated : 12/29/2004
Victor A. McKusick - updated : 9/20/2004
Marla J. F. O'Neill - updated : 8/27/2004
George E. Tiller - updated : 6/18/2004
Ada Hamosh - updated : 4/20/2004
Patricia A. Hartz - updated : 11/17/2003
Victor A. McKusick - updated : 6/10/2003
Victor A. McKusick - updated : 5/19/2003
Ada Hamosh - updated : 3/31/2003
Michael B. Petersen - updated : 12/2/2002
Michael B. Petersen - updated : 10/31/2002
George E. Tiller - updated : 10/9/2002
Victor A. McKusick - updated : 10/7/2002
Matthew B. Gross - reorganized : 10/7/2002
Michael B. Petersen - updated : 9/6/2002
Michael B. Petersen - updated : 8/30/2002
Ada Hamosh - updated : 7/22/2002
Victor A. McKusick - updated : 1/22/2002
Victor A. McKusick - updated : 12/20/2001
Paul J. Converse - updated : 11/29/2001
Michael B. Petersen - updated : 11/1/2001
Michael B. Petersen - updated : 11/1/2001
George E. Tiller - updated : 7/24/2001
Victor A. McKusick - updated : 6/20/2001
Victor A. McKusick - updated : 4/24/2001
Michael B. Petersen - updated : 2/7/2001
Victor A. McKusick - updated : 11/21/2000
Victor A. McKusick - updated : 10/26/2000
Paul J. Converse - updated : 9/20/2000
Ada Hamosh - updated : 8/30/2000
Ada Hamosh - updated : 8/14/2000
Ada Hamosh - updated : 3/16/2000
Victor A. McKusick - updated : 9/29/1999
Victor A. McKusick - updated : 7/20/1999
Victor A. McKusick - updated : 1/25/1999
Victor A. McKusick - updated : 9/17/1998
Michael J. Wright - updated : 6/30/1998
Victor A. McKusick - updated : 12/17/1997
Victor A. McKusick - updated : 4/21/1997
Victor A. McKusick - updated : 3/31/1997
Victor A. McKusick - updated : 3/2/1997

Creation Date:

Victor A. McKusick : 10/17/1995

Edit History:

carol : 01/26/2021
alopez : 05/16/2019
carol : 04/11/2017
carol : 05/22/2015
carol : 6/6/2014
terry : 12/20/2012
terry : 10/2/2012
terry : 6/20/2011
carol : 6/1/2011
carol : 2/9/2011
wwang : 2/7/2011
alopez : 11/10/2010
alopez : 10/26/2010
wwang : 10/26/2010
terry : 10/22/2010
wwang : 8/6/2010
wwang : 8/6/2010
carol : 8/2/2010
wwang : 3/17/2010
carol : 3/4/2010
wwang : 3/4/2010
ckniffin : 1/6/2010
carol : 10/15/2009
wwang : 8/18/2009
terry : 7/30/2009
terry : 6/4/2009
wwang : 5/7/2009
terry : 4/22/2009
mgross : 10/22/2008
wwang : 5/1/2008
terry : 4/29/2008
carol : 4/17/2008
mgross : 3/24/2008
terry : 3/21/2008
alopez : 3/3/2008
terry : 2/25/2008
carol : 1/4/2008
alopez : 8/31/2007
terry : 8/20/2007
wwang : 7/12/2007
terry : 7/11/2007
wwang : 6/18/2007
terry : 6/13/2007
alopez : 5/30/2007
terry : 5/23/2007
wwang : 4/3/2007
wwang : 4/3/2007
wwang : 3/12/2007
terry : 3/8/2007
wwang : 12/4/2006
terry : 12/4/2006
wwang : 10/24/2006
terry : 10/24/2006
wwang : 10/5/2006
terry : 9/19/2006
carol : 9/5/2006
terry : 8/30/2006
wwang : 4/10/2006
wwang : 4/7/2006
ckniffin : 3/15/2006
alopez : 2/14/2006
terry : 2/9/2006
alopez : 2/6/2006
alopez : 2/6/2006
terry : 2/3/2006
carol : 12/22/2005
carol : 12/22/2005
carol : 12/7/2005
alopez : 9/30/2005
terry : 9/9/2005
wwang : 6/29/2005
terry : 6/21/2005
alopez : 5/25/2005
alopez : 3/16/2005
terry : 3/11/2005
terry : 2/7/2005
tkritzer : 1/21/2005
alopez : 12/30/2004
terry : 12/29/2004
carol : 12/8/2004
tkritzer : 9/21/2004
tkritzer : 9/20/2004
carol : 9/1/2004
terry : 8/27/2004
alopez : 6/18/2004
alopez : 6/18/2004
alopez : 6/3/2004
carol : 6/2/2004
alopez : 6/1/2004
alopez : 4/21/2004
terry : 4/20/2004
carol : 11/24/2003
mgross : 11/17/2003
carol : 7/10/2003
cwells : 6/12/2003
terry : 6/10/2003
alopez : 6/3/2003
alopez : 5/19/2003
alopez : 5/16/2003
alopez : 4/1/2003
terry : 3/31/2003
cwells : 12/2/2002
cwells : 10/31/2002
cwells : 10/9/2002
mgross : 10/7/2002
mgross : 10/7/2002
mgross : 10/7/2002
alopez : 9/6/2002
cwells : 8/30/2002
alopez : 7/25/2002
terry : 7/22/2002
alopez : 2/11/2002
carol : 2/5/2002
mcapotos : 1/31/2002
terry : 1/22/2002
alopez : 1/11/2002
cwells : 1/9/2002
terry : 12/20/2001
mgross : 11/29/2001
joanna : 11/26/2001
carol : 11/13/2001
cwells : 11/9/2001
cwells : 11/9/2001
cwells : 11/6/2001
cwells : 11/6/2001
cwells : 11/1/2001
cwells : 7/27/2001
cwells : 7/24/2001
mcapotos : 6/26/2001
mcapotos : 6/22/2001
terry : 6/20/2001
carol : 5/9/2001
cwells : 5/4/2001
alopez : 4/27/2001
terry : 4/24/2001
terry : 2/7/2001
terry : 1/18/2001
terry : 11/21/2000
mcapotos : 11/8/2000
mcapotos : 10/31/2000
terry : 10/26/2000
mgross : 9/20/2000
mgross : 9/20/2000
mgross : 8/30/2000
terry : 8/30/2000
alopez : 8/18/2000
terry : 8/14/2000
terry : 8/14/2000
mgross : 4/17/2000
carol : 3/16/2000
alopez : 3/16/2000
alopez : 3/16/2000
terry : 3/16/2000
terry : 11/30/1999
alopez : 9/30/1999
terry : 9/29/1999
jlewis : 8/5/1999
terry : 7/20/1999
carol : 1/28/1999
terry : 1/25/1999
dkim : 12/10/1998
carol : 9/21/1998
terry : 9/17/1998
alopez : 7/6/1998
alopez : 7/6/1998
alopez : 7/6/1998
alopez : 7/6/1998
terry : 6/30/1998
mark : 12/17/1997
terry : 11/11/1997
terry : 11/11/1997
mark : 4/21/1997
terry : 4/14/1997
mark : 3/31/1997
terry : 3/28/1997
mark : 3/2/1997
terry : 2/28/1997
mark : 2/19/1996
terry : 2/15/1996
mimadm : 11/3/1995
terry : 10/30/1995
mark : 10/17/1995

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ASTHMA, BRONCHIAL ASTHMA-RELATED TRAITS, SUSCEPTIBILITY TO

Phenotype-Gene Relationships

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▼ Description

▼ Clinical Features

▼ Inheritance

▼ Pathogenesis

▼ Mapping

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# 600807

ASTHMA, SUSCEPTIBILITY TO

ASTHMA, BRONCHIAL ASTHMA-RELATED TRAITS, SUSCEPTIBILITY TO

Phenotype-Gene Relationships

TEXT

Description

Clinical Features

Inheritance

Pathogenesis

Mapping

Molecular Genetics

Animal Model

REFERENCES

▼

External Links

ASTHMA, BRONCHIAL
ASTHMA-RELATED TRAITS, SUSCEPTIBILITY TO

ASTHMA, BRONCHIAL
ASTHMA-RELATED TRAITS, SUSCEPTIBILITY TO