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Other entities represented in this entry:
SNOMEDCT: 200775004, 24079001; ICD10CM: L20, L20.81, L20.9; DO: 3310;
Cytogenetic location: 3q21 Genomic coordinates (GRCh38): 3:122,200,001-129,500,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q21 | {Dermatitis, atopic, susceptibility to, 1} | 603165 | Autosomal dominant | 2 |
Atopic dermatitis (ATOD), also known as eczema, is a common chronic pruritic inflammatory skin disease with a strong genetic component. Onset typically occurs during the first 2 years of life (review by Soderhall et al., 2007).
Genetic Heterogeneity of Atopic Dermatitis
Many inflammatory diseases, such as atopic eczema, are genetically complex, with multiple alleles at several loci thought to be involved in their pathogenesis. Several susceptibility loci for atopic dermatitis have been identified: ATOD1 on chromosome 3q21, ATOD2 (605803) on chromosome 1q21, ATOD3 (605804) on chromosome 20p, ATOD4 (605805) on chromosome 17q25.3, ATOD5 (603165) on chromosome 13q12-q14, ATOD6 (605845) on chromosome 5q31-q33, ATOD7 (613064) on chromosome 11q13.5, ATOD8 (613518) on chromosome 4q22.1, and ATOD9 (613519) on chromosome 3p24.
Atopic dermatitis commonly begins in infancy or early childhood (Kay et al., 1994; Taylor et al., 1984). Eighty percent of cases of ATOD have elevations of the total serum IgE (147050) concentration. The hallmarks of atopic dermatitis are a chronic relapsing form of skin inflammation, a disturbance of epidermal barrier function that culminates in dry skin, and IgE-mediated sensitization to food and environmental allergens. Bieber (2008) reviewed the natural history of ATOD.
The new occurrence of inflammatory diseases after organ transplantation suggests that genetic predisposition may be confined to the particular organs or physiologic systems. A new occurrence of asthma after bone marrow transplantation from a donor who had asthma (Agosti et al., 1988) or new asthma in a recipient who had lungs transplanted from an asthmatic donor (Corris and Dark, 1993) suggests that expression of some inflammatory disorders is a result of both systemic (often immune) influence and end-organ specificity, each under distinct genetic control.
Turner et al. (1998) described an 18-year-old woman who had had an intensely itchy rash on her right leg since childhood. There were no exacerbating factors. Her itch improved with sunlight. Topical corticosteroids gave only a small benefit. The patient also had hayfever, but was otherwise well. Her eczema was in an uninterrupted distribution down the inner aspect of her right leg in a pattern of Blaschko described by Jackson (1976) and thought to be the path of migration of a clone of embryonic keratinocytes. Histology of a biopsy specimen showed features typical of eczema and supported a diagnosis of linear eczema (dermatitic nevus). The rest of her skin was normal. She was found to be atopic with multiple positive prick tests (on normal skin), including house dust mite, feathers, and grass, and a raised IgE of 308 IU. In this patient, Turner et al. (1998) suspected that an aberrant clone of cells with either genetic (or epigenetic) change allowed expression of the atopic eczema phenotype in the mutated area only. As conventional treatments were largely unsuccessful and the area of involvement was small, Turner et al. (1998) excised the most itchy area of skin on her thigh as split skin. This produced only transient relief. Full skin thickness was excised from another area, and grafted with split skin from a donor area on her thigh. She had lasting relief for 6 years, although the itch persisted in her untreated skin.
Atopic dermatitis is one of the most common diseases in childhood, affecting 10 to 20% of children in industrialized societies (Beasley and The International Study of Asthma and Allergies in Childhood Steering Committee, 1998).
ATOD1
To identify susceptibility loci for atopic dermatitis, Lee et al. (2000) ascertained 199 families with at least 2 affected sibs based on established diagnostic criteria. A genomewide linkage study revealed highly significant evidence for linkage on 3q21 (ATOD1) at marker D3S3606. Moreover, this locus provides significant evidence for linkage of allergic sensitization under the assumption of paternal imprinting, further supporting the presence of an atopy gene in this region.
In an analysis of 148 nuclear families recruited through children with active ATOD, Cookson et al. (2001) did not identify linkage to chromosome 3q21 at marker D3S3606. The authors stated that although their study was similar to that of Lee et al., 2000, the 2 studies used different panels of markers and had limited power to exclude linkage to other loci; they concluded that together, the results indicated that several genes influence ATOD.
Soderhall et al. (2007) genotyped additional microsatellite markers and SNPs on chromosome 3q21 in the 199 ATOD families previously studied by Lee et al. (2000) and found the strongest association for a SNP (rs4688761) in the COL29A1 gene (611916) (overall p = 0.0016; maternal p = 0.0006). In a large independent replication set of 292 complete nuclear families including 481 children with ATOD, they confirmed the association with ATOD across all markers with the strongest association at marker A36637742 in the COL29A1 gene (p = 0.00038), which also showed significant overtransmission of the maternal allele (p = 0.0013) that was not predominantly attributable to affected mothers. Haplotype construction over the 96-kb region confirmed the association with ATOD.
In a study involving a total of 346 children with atopic dermatitis and 306 parents from 153 Danish nuclear families, Christensen et al. (2009) obtained a maximum MLS score of 3.3 at 3q21 for IgE-associated ATOD.
Genetic Heterogeneity/Linkage Studies
Cookson et al. (2001) examined 148 nuclear families recruited through children with active ATOD. The families contained 383 children and 213 sib pairs; 254 children had physician-diagnosed ATOD, 153 had asthma, and 139 had both. Children with ATOD were aged 6.9 +/- 4.4 years, and 124 were male. The age of onset of disease was less than 2 years in 90% of children. Cookson et al. (2001) found that 51.5% of children had moderate disease and 28.6% had severe disease. The serum IgE concentration was much higher in children with ATOD and asthma together than in children with asthma alone or with ATOD alone. Using 385 microsatellite markers with an average marker spacing of 8.9 cM and an average information content greater than 65%, Cookson et al. (2001) tested 4 phenotypic models for linkage by nonparametric sib pair methods. They identified linkage to ATOD on chromosome 1q21 (ATOD2) and 17q25 (ATOD4), and linkage to asthma on 20p (see ATOD3, 605804). Linkage of chromosome 20p to children with both ATOD and asthma was not greatly different than that to children with asthma alone, indicating that the combination of ATOD and asthma may correspond to a genetic subtype of disease. The total serum IgE concentration was linked to chromosome 16q-tel. Cookson et al. (2001) noted that their 3 chromosome loci, 1q21, 17q25, and 20p, are closely coincident with 3 regions linked to psoriasis. Although ATOD is distinct from psoriasis, both diseases are characterized by dry scaly skin, disturbed epidermal differentiation, and inflammation that is responsive to T cell-specific agents. Cookson et al. (2001) concluded that the colocalization of ATOD to psoriasis loci seen in both their study and that of Lee et al. (2000) indicates that ATOD is influenced by genes that modulate dermal responses independent from atopic mechanisms. The chromosome 1q21 locus is known to contain a cluster of genes influencing epidermal differentiation.
Beyer et al. (2000) found linkage of atopic dermatitis to 13q12-q14 (ATOD5) and 5q31-q33 (ATOD6). In 406 Swedish families, each with at least 2 sibs affected with atopic dermatitis, Soderhall et al. (2001) performed linkage and association studies of 5 chromosomal regions (2q35, 5q31-q33, 6p21, 11q13, and 14q11) previously implicated in atopic diseases. The region on 14q11, which contains the T-cell antigen receptor alpha (TCRA; see 186880) and T-cell antigen receptor delta (TCRD; see 186810) loci, as well as the CMA1 locus (118938), gave evidence for linkage to atopic dermatitis (nonparametric linkage score: 2.36, P less than 0.009). In the 11q13 region, there was association to an intragenic marker in the beta-subunit of the high-affinity IgE receptor (FCER1B; 147138). When a quantitative variable for the severity of atopic dermatitis was studied, evidence was found in favor of linkage to the 5q31-q33 region, with the highest Z-score (2.06) close to the marker D5S458 (P less than 0.005).
Using a nonparametric affected relative-pair method in 109 atopic dermatitis pedigrees, Bradley et al. (2002) conducted a genomewide linkage analysis with 367 microsatellite markers and found suggestive linkage to chromosome 18q21 (D18S851, lod = 2.16, p less than 0.001) for atopic dermatitis combined with raised allergen-specific IgE levels. For the semiquantitative phenotype severity score of atopic dermatitis, suggestive linkage was found to chromosome regions 3q14 (D3S2459, Z = 2.55, p less than 0.001), 13q14 (D13S325, Z = 3.21, p less than 0.001), 15q14-q15 (D15S118, Z = 3.07, p less than 0.001), and 17q21 (D17S1290, Z = 3.08, p less than 0.001). Polymorphic markers at 3p22-p24, 13q14, and 18q21 have also been linked to asthma in various populations, suggesting that more than 1 phenotype of atopic hypersensitivity may be influenced by genes in this region.
For a clinical description of asthma and an overview of linkage studies, see 600807.
Soderhall et al. (2007) analyzed the ATOD1 candidate gene COL29A1 in 46 unrelated children with atopic dermatitis and 2 controls and identified 13 common and 6 rare sequence variations causing nonsynonymous amino acid substitutions. All coding SNPs were genotyped in 199 ATOD families originally studied by Lee et al. (2000); 4 SNPs showed a positive association with ATOD, but that association did not account for the previously observed haplotype association. In situ hybridization and immunohistochemical analysis of normal human skin detected COL29A1 expression in the epidermis with strongest staining in suprabasal viable layers. However, in situ hybridization of the skin of patients with ATOD demonstrated an absence of COL29A1 expression in the most differentiated upper spinous and granular layers, although overall COL29A1 expression levels remained the same between patients and controls. Soderhall et al. (2007) concluded that ATOD patients displayed an abnormal distribution of COL29A1 mRNA and protein in skin and suggested that COL29A1 is involved in the pathogenesis of ATOD.
Among 100 patients with atopic dermatitis and 264 controls, Vasilopoulos et al. (2007) observed an association between risk for ATOD and a 344C-T SNP in the CSTA gene (184600) on 3q21 (OR = 2.13, p = 0.006). The C allele was more common among patients, indicating that the T allele may offer a protective effect. In vitro functional expression studies showed that the 344C allele produced mRNA that was 2.2-fold less stable than the 344T mRNA. Vasilopoulos et al. (2007) noted that since CSTA is a cysteine protease inhibitor of dust mite proteases that breaks down epidermal barriers, a decrease in CSTA mRNA may contribute to a defective epidermal barrier among patients with atopic dermatitis.
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