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Atopy is an allergic disorder characterized by immunoglobulin E (IgE) responses to environmental proteins that are otherwise innocuous and predominantly found in plant pollen and house dust. It is the major cause of asthma (see 600807), rhinitis (see 607154), and eczema (see 603165) in children and young adults (summary by Young et al., 1992).
Allergists are frequently faced with patients simultaneously suffering from asthma, atopic dermatitis, and allergic rhinitis, a constellation recognized as the 'atopic triad.' Oettgen and Geha (1999) reviewed the role of IgE in asthma and atopy.
The genetics of atopic hypersensitivity is complex.
From determinations of IgE levels in 29 families, Bias et al. (1973) suggested the existence of 'an autosomal dominant gene coding for a substance which represses the biosynthesis or controls the metabolism of IgE.' Complex segregation analysis, as developed by Morton and MacLean (1974), can detect major genes in the presence of polygenic heritability and sib environmental correlation. Gerrard et al. (1978) applied the method to data on IgE levels in 173 nuclear families. They concluded that these data were consistent with a regulatory locus for IgE occupied by 2 alleles, RE and re, with the dominant allele suppressing persistently high levels of IgE. The displacement of mean IgE level in re-re homozygotes was estimated to be 1.67 standard deviations. The frequency of the re gene was estimated to be 0.489 in their population of Saskatchewan white families.
Blumenthal et al. (1981) suggested that the genetics may be more complex than previously reported. Hasstedt et al. (1983) supported this view; their analysis did not show evidence of a major gene effect.
Borecki et al. (1985) presented data that appeared to corroborate a hypothesis relating IgE production and liability to allergy. Homozygous individuals (rr) have persistently elevated levels of IgE. Heterozygotes (Rr), although showing normal IgE levels, have an increased frequency of hypersensitivity, at least to some allergens.
Cookson and Hopkin (1988) studied the familial occurrence of atopy, defined by skin prick test responses and serum IgE titers to common inhaled allergens, in 239 members of 40 nuclear and 3 extended families. Ninety percent of the atopic children in the nuclear families had at least 1 demonstrably atopic parent. In each of the extended families, atopy was vertically transmitted, and 31 of 47 (66%) offspring of marriages between atopic and unaffected parents were atopic. Of the designated atopic subjects, 83% admitted to symptoms suggesting atopic disease, but only 30% regarded themselves as having any such disorder. Cookson and Hopkin (1988) suggested that the propensity to produce IgE in response to common, usually inhaled, allergens is inherited as an autosomal dominant, but that its clinical expression depends on interaction with other factors.
Hanson et al. (1991) showed that monozygotic twins reared apart or together showed greater concordance than dizygotic twins reared apart or together, in prevalence of asthma and seasonal rhinitis, skin-test response, total serum IgE levels, and specific IgE, as measured by the radioallergosorbent test (RAST). Maximum-likelihood tests of genetic and environmental components of the variation of total IgE levels showed a substantial genetic component and a negligible contribution from common familial environmental effects.
Cookson et al. (1989) reexamined the genetics of atopy, using a definition based on specific IgE responses to common antigens or on an abnormally raised total serum IgE. They followed the premise that atopic persons have a propensity to produce prolonged exuberant IgE responses to minute amounts of antigen and that the general state of enhanced IgE responsiveness may cause an increase in antigen-specific IgE antibody levels with or without a high total serum IgE.
Using maximum likelihood analysis of variance components estimates in an Australian population-based sample of 232 Caucasian nuclear families, Palmer et al. (2000) found a narrow-sense heritability of total serum IgE levels of 47.3%, i.e., additive genetic effects contributed just under half of the total variance. Specific serum IgE levels against house dust mite and Timothy grass, measured as a combined RAST index, showed a narrow-sense heritability of 33.8% and with environmental effects common to sibs contributing approximately 15% of the total phenotypic variance, explained by childhood exposure to domestic allergens. The study suggested the presence of important genetic determinants of the pathophysiologic traits associated with asthma. The authors proposed that total and specific serum IgE levels are appropriate phenotypes for molecular investigations of the genetic susceptibility to asthma.
Finn (1992) suggested a relationship between environmental factors and genetic factors in hay fever. History suggests that in the United Kingdom hay fever was unknown until after the advent of the Industrial Revolution with its accompanying chemical pollution. Indeed, it was first described by John Bostock (1773-1846), who practiced in Liverpool for 20 years before moving to London in 1817. Remarkably, hay fever seems to have been unknown, for all practical purposes, before Bostock's description of his personal case in 1819. Bostock (1828) noted that 'one of the most remarkable circumstances respecting this complaint is its not being noticed as a specific affection, until the last 10 or 12 years.' Finn (1992) suggested that chemical damage to the mucous membrane of the nose is a primary event in hay fever and that without such damage, hay fever would not occur or would occur only very rarely. The nasal mucosa has evolved to prevent the entry of antigens, but the sudden onset of massive chemical pollution overwhelms the natural resistance of the nasal mucous membrane.
Mathias et al. (2005) studied the inheritance of total serum IgE in the isolated Tangier Island population in the Chesapeake Bay where Tangier disease (205400) was first described. All 664 current Tangier Island residents belonged to 1 large extended pedigree spanning 13 generations, with an average inbreeding coefficient of 0.009. Familial correlations and heritability calculations revealed a significant genetic component to total IgE (heritability = 26%).
Milgrom et al. (1999) showed that the role of immune responses mediated by IgE in the pathogenesis of allergic asthmas is reflected in the successful use of recombinant 'humanized' monoclonal antibody against IgE in the treatment of moderate to severe allergic asthma. The antibody forms complexes with free IgE and blocks its interaction with mast cells and basophils.
Chromosome 13
Eiberg et al. (1985) found a strong suggestion of linkage of IgE response to ESD (133280), which would put the locus on chromosome 13. The maximum lod score (male and female) was 2.67 at theta 0.00.
Anderson et al. (2002) constructed a BAC/PAC contig physical map of the 1.5 Mb region surrounding the D13S273 microsatellite marker at the chromosome 13q14 atopy locus. Association testing between total serum IgE concentration in 172 sib pairs 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 this interval.
Other studies had shown consistent linkage of 13q14 to atopy and total serum IgE concentration (Eiberg et al., 1985; Kimura et al., 1999). 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 a single gene, PHF11 (607796). They also found association with these variants to severe clinical asthma.
Chromosome 11
Cookson et al. (1989) found linkage of IgE response to a hypervariable minisatellite probe (Jeffreys et al., 1985) that had been assigned to chromosome 11 in the region 11q12-q13. These studies gave a maximum lod score of 6.39 at a theta of 0.10. In studies of 64 nuclear families recruited through symptomatic children, the linkage to a marker locus at 11q13, or D11S97, was again confirmed.
In 4 Japanese families, Shirakawa et al. (1991) and Shirakawa et al. (1994) reported a lod score of 4.88 at theta = 0.07 for linkage to D11S97. In a linkage study of 64 nuclear families, Young et al. (1992) found a 2-point lod score of 3.8 at theta = 0.07 for linkage to D11S97. A test of genetic heterogeneity showed that atopic IgE responses are linked to this locus in 60 to 100% of families, these values representing the approximate 95% confidence limits.
Since previous studies had suggested that the risk of atopy is higher for children of atopic mothers than for those of atopic fathers, Cookson et al. (1992) sought differences between maternal and paternal patterns of transmission at the 11q13 locus among pairs of sibs in families affected by atopy. When they defined atopy as the presence of a positive skinprick test (equal to or larger than 2 mm) to any of a panel of common allergens, a higher than normal concentration of total serum IgE, or a positive radioallergosorbent test for a specific IgE, Cookson et al. (1992) found that 125 (62%) of the sib-pairs affected by atopy shared the maternal 11q13 allele (and D11S97 marker) and 78 (38%) did not. This distribution differed significantly from the expected 50/50 distribution (p = 0.001). Of paternally derived alleles, 83 (46%) were shared and 96 (54%) were not (not significantly different from 50/50). The result was similar whatever definition of atopy was used and with other genetic markers on 11q. The pattern of inheritance through the maternal line is consistent either with paternal genomic imprinting or with maternal modification of developing immune responses.
Lympany et al. (1992) could not demonstrate significant linkage between D11S97 and either atopy or bronchial hyperreactivity to methacholine. The use of either a positive skin prick test or a positive RAST as the definition of atopy did not significantly alter the lod scores. Hizawa et al. (1992) and Rich et al. (1992) failed to find linkage of atopy and 11q13. Amelung et al. (1992) were unable to find linkage between atopy or bronchial hyperresponsiveness and markers on 11q or 6p.
Moffatt et al. (1992) concluded that affected sib-pair analysis supported linkage to 11q, giving evidence that was not dependent on the definition of atopy or the specification of model.
Marsh and Meyers (1992) reviewed the evidence for a major gene for atopy on 11q and concluded that the evidence cannot be considered convincing. They quoted Risch (1992) as suggesting that, especially in complex diseases like atopy, one should always be willing to consider that a 'significant' lod score (equal to or more than 3.0) may represent a false positive. They discussed several possible reasons for the failure to replicate the earlier linkage results.
Coleman et al. (1993) studied genetic linkage in 95 multiplex families recruited through probands with active atopic eczema. Linkage analyses between atopy and markers on 11q13 excluded a major susceptibility locus for atopy in that region. There was no significant deviation from the expected proportion of alleles shared by affected sib-pairs. When they analyzed families according to parental atopic phenotype, they observed a positive lod score (0.8) in 19 families with unaffected fathers, in contrast to markedly negative scores for other combinations of affected parental phenotype. The possibility of a maternal influence on the inheritance of atopy could not, therefore, be excluded.
Sandford et al. (1993) demonstrated that a Ca microsatellite repeat in the fifth intron of the FCER1B gene (MS4A2; 147138) is located on 11q13. Sandford et al. (1993) also found that the FCER1B gene was linked to clinical atopy. Maternally derived alleles were used in the analysis. The known roles of the high-affinity IgE receptor in antigen-induced mast-cell degranulation and in the release of cytokines that enhance IgE production, along with the map location, made the FCER1B gene a candidate for the chromosome 11 atopy locus. However, in a study of allele sharing in sibs with asthma and atopy, Collee et al. (1993) could find no significantly increased proportion of shared alleles at the FCER1B locus. They also found no significant difference in the proportion of maternal and paternal alleles shared at 2 other loci in 11q13. Their results supported linkage of atopy to this region.
In Japanese families, Hizawa et al. (1995) could not confirm the existence of a major gene for atopy located at 11q13 under the model of autosomal dominant inheritance. However, they observed a significant association between serum total IgE levels and genetic markers at this locus both in 14 Japanese atopic families and in 120 unrelated Japanese subjects. For these association studies they detected 8 alleles at the D11S97 locus and 8 alleles in the CA/GT repeat region in the fifth intron of the FCER1B gene.
Associations Pending Confirmation
Bottazzo and Lendrum (1976) reported a strong association between HLA W6 and intrinsic asthma.
Hill and Cookson (1996) identified a novel coding polymorphism in exon 7 of the FCER1B (MS4A2) gene (E237G; 147138.0001). The substitution occurs adjacent to the immunoreceptor tyrosine activation motif (ITAM). The E237G mutation was detected in 53 subjects from a general Australian population of 1004 (5.3%). E237G subjects had a significantly elevated skin test response to grass (p = 0.0004) and house dust mite (p = 0.04), RAST to grass (p = 0.0020), and bronchial reactivity to methacholine (p = 0.0009). Hill and Cookson (1996) reported that the relative risk of individuals with E237G having asthma compared to subjects without the variant was 2.3.
Kruse et al. (2000) identified polymorphisms in the PLA2G7 gene that were highly associated with specific sensitization in an atopic population and with asthma (601690.0002-601690.0003).
Using sib-pair analysis in 51 English families with asthma and atopy, Wheatley et al. (2002) described significant association (p = 0.008) for a polymorphism in the SART1 gene (605941) with atopy, but not with asthma. The authors hypothesized that polymorphic variation within the SART1 gene may account for some individuals developing atopy.
Moffatt et al. (2001) examined the association between the HLA-DRB1 locus (142857) and quantitative traits underlying asthma in a population sample consisting of 1,004 individuals from 230 families from the rural Australian town of Busselton. They detected strong associations between HLA-DRB1 alleles and the total serum IgE concentration and IgE titers against individual antigens, with the HLA-DRB1 locus accounting for 4% of the variation in total serum IgE level and 2 to 3% of the variation in specific IgE titers. Alleles associated with elevations of the total serum IgE were different from those associated with specific allergens, suggesting that specific and total serum IgE concentrations may have separate genetic controls.
Hecker et al. (2003) identified a SNP in the promoter region of the IL21R gene, -83T-C (605383.0001), that was significantly associated with elevated IgE levels in females, but not in males.
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 found replicated association to IgE levels that was attributed to several alleles in a single gene, PHF11 (607796). They also found association with these variants to severe clinical asthma. The gene product contains 2 plant homeodomain (PHD) zinc fingers and probably regulates transcription. Distinctive splice variants were expressed in immune tissues and cells.
The eotaxin gene family (eotaxin 1, 601156; eotaxin 2, 602495; and eotaxin 3, 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 eotaxin 2 +1272A-G G* allele showed significantly lower frequency in asthmatics than in normal healthy controls (0.14 vs 0.23, P = 0.002), and that distribution of the eotaxin 2 +1272A-G G* allele-containing genotypes was also much lower in asthmatics (26.3 vs 40.8%, P = 0.003). In addition, a nonsynonymous SNP in eotaxin 1, +123Ala to Thr, showed significant association with total serum IgE levels (P = 0.002-0.02). The effect of eotaxin 1 +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 eotaxin 2 +1272A-G polymorphisms, and the susceptibility to high IgE production may be attributed to the eotaxin 1 +123Ala to Thr polymorphism. In an erratum, the authors noted that the first base of the translation start site of the eotaxin 2 genomic reference sequence had been denoted as +1, introducing some errors in the numbering of the eotaxin 2 SNPs.
Tumor necrosis factors TNFA (191160) and TNFB (LTA; 153440) are major proinflammatory cytokines that are thought to be important in the pathogenesis of asthma. Shin et al. (2004) genotyped 550 Korean asthmatics and 171 Korean controls at 5 SNPs in TNFA and 2 SNPs in TNFB. Six common haplotypes could be constructed in the TNF gene cluster due to very strong linkage disequilibrium between TNFA and TNFB, which are located 13 kb apart on chromosome 6p21. The TNFA-308G-A SNP (191160.0004) showed a significant association with the risk of asthma (p = 0.0004). The frequency of TNFA-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 in asthma patients, especially in nonatopic patients (p = 0.004). Shin et al. (2004) concluded that genetic variants of TNF may be involved in the development of asthma and total serum IgE level in bronchial asthma patients.
Polymorphisms in the PLA2G7 (601690) and IL4R (147781) genes have been associated with susceptibility to atopy.
Sharma et al. (2005) studied the association of a polymorphism in the CMA1 gene (118938), -1903G-A, and a (TG)n(GA)n repeat polymorphism located 254 bp downstream of the gene with asthma and IgE levels in Indian asthmatic patients with a family history of asthma and atopy. A significant association was observed between -1903G-A genotype and serum IgE levels (p = 0.003 and p = 0.0004 for a northern and a western cohort, respectively). Comparing major haplotypes with respect to log total serum IgE levels, a significant difference was obtained between patients and controls (p = 0.018 and p = 0.046 for the northern and western cohorts, respectively). Sharma et al. (2005) suggested that the CMA1 gene contributes to asthma susceptibility and may be involved in regulating IgE levels in atopic asthma.
Hysi et al. (2005) found an insertion-deletion polymorphism (ND1+32656) near the beginning of intron 9 in 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.
The early history of the genetics of asthma was reviewed by Bias et al. (1978), beginning with the perceptive observation of Salter in 1864. Bias et al. (1978) reviewed the evidence for genetic control of the several steps in the allergic process.
Tips (1954) thought that each of the 3 forms of atopy is determined by homozygosity at a single and separate locus. The study of Lubs (1972) suggested, however, a more general increased risk of allergic manifestations. Others (Cooke and Vander Veer, 1916; Clarke et al., 1928; Schwartz, 1952) proposed dominant inheritance.
Hargrave et al. (2003) reviewed the records of 84 consecutive patients who underwent penetrating keratoplasty for keratoconus (148300). Because an association between keratoconus and atopic disease had been documented in the literature and had been considered significant since 1937, careful attention was paid to the clinical history of atopy in this study. Atopic patients have been shown to have a 'Th2 immune bias.' Of the 7 patients who rejected their corneal allografts, 4 had repeat penetrating keratoplasty. Of these 4 repeat corneal allografts, 3 showed eosinophilia when compared with rejected grafts in control (nonkeratoconic, nonatopic) patients. Atopic keratoconus patients had a mixed inflammatory cellular infiltrate in the rejected corneal tissue specimen with a significantly greater density of eosinophils compared with patients who did not have a preexisting Th2 bias. The histopathology was comparable to the authors' murine model of rejection in Th2 mice, characterized by a predominantly eosinophilic infiltrate when compared with wildtype (Th1) mice that had a predominantly mononuclear infiltrate in the rejected corneal graft bed.
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