RESUMEN
BACKGROUND: Atopic dermatitis (AD) is a common chronic inflammatory skin disorder where epidermal barrier dysfunction is a major factor in the pathogenesis. The identification of AD susceptibility genes related to barrier dysfunction is therefore of importance. The epidermal transglutaminases (TGM1, TGM3 and TGM5) encodes essential cross-linking enzymes in the epidermis. OBJECTIVE: To determine whether genetic variability in the epidermal transglutaminases contributes to AD susceptibility. METHODS: Forty-seven single nucleotide polymorphisms (SNPs) in the TGM1, TGM3 and TGM5 gene region were tested for genetic association with AD, independently and in relation to FLG genotype, using a pedigree disequilibrium test (PDT) in a Swedish material consisting of 1753 individuals from 539 families. In addition, a German case-control material, consisting of 533 AD cases and 1996 controls, was used for in silico analysis of the epidermal TGM regions. Gene expression of the TGM1, TGM3 and TGM5 gene was investigated by relative quantification with Real Time PCR (qRT-PCR). Immunohistochemical (IHC) analysis was performed to detect TG1, TG3 and TG5 protein expression in the skin of patients and healthy controls. RESULTS: PDT analysis identified a significant association between the TGM1 SNP rs941505 and AD with allergen-specific IgE in the Swedish AD family material. However, the association was not replicated in the German case-control material. No significant association was detected for analyzed SNPs in relation to FLG genotype. TG1, TG3 and TG5 protein expression was detected in AD skin and a significantly increased TGM3 mRNA expression was observed in lesional skin by qRT-PCR. CONCLUSION: Although TGM1 and TGM3 may be differentially expressed in AD skin, the results from the genetic analysis suggest that genetic variation in the epidermal transglutaminases is not an important factor in AD susceptibility.
Asunto(s)
Dermatitis Atópica/genética , Epidermis/metabolismo , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Transglutaminasas/genética , Estudios de Casos y Controles , Dermatitis Atópica/metabolismo , Dermatitis Atópica/patología , Epidermis/patología , Proteínas Filagrina , Alemania , Humanos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Suecia , Transglutaminasas/metabolismo , Población Blanca/genéticaRESUMEN
Eczema is often associated with development of allergic asthma. The Neuropeptide S Receptor 1 (NPSR1) gene has previously been associated with asthma and elevated serum IgE levels. The aim of this study was to investigate a potential association between the NPSR1 gene and eczema in patients and healthy individuals from five different populations in Western Europe, in total 6275 individuals. Seven single nucleotide polymorphisms previously associated with allergic asthma were genotyped. The protein expression of NPSR1 in the skin was studied using immunohistochemistry in six eczema patients and eight healthy individuals. No association was found be tween eczema and the seven single nucleotide polymor phisms in NPSR1 in any of the populations, either independently or in combinations. In addition, no difference was detected in epidermal NPSR1 expression between eczema patients and healthy individuals. These results strongly suggest that NPSR1 is not involved in the pathogenesis of eczema.
Asunto(s)
Dermatitis Atópica/genética , Receptores Acoplados a Proteínas G/genética , Adolescente , Adulto , Agricultura , Asma/complicaciones , Asma/genética , Niño , Preescolar , Conjuntivitis Alérgica/complicaciones , Conjuntivitis Alérgica/genética , Dermatitis Atópica/complicaciones , Dermatitis Atópica/metabolismo , Europa (Continente) , Femenino , Humanos , Inmunoglobulina E/sangre , Inmunohistoquímica , Masculino , Polimorfismo de Nucleótido Simple , Población Rural , Piel/metabolismoRESUMEN
Recent studies have identified 2 loss-of-function variants, R501X and 2282del4, in the filaggrin gene as predisposing factors in the development of eczema. In this study, representing the first analysis of the variants in a Swedish population, we analysed transmission in 406 multiplex eczema families with mainly adult patients. In accordance with previous studies we found association between the filaggrin gene variants and atopic eczema (p=9.5 x 10(-8)). The highest odds ratio for the combined allele, 4.73 (1.98-11.29), p=3.6 x 10(-8), was found for the subgroup with a severe eczema phenotype, and association was also found with raised allergen-specific IgE, allergic asthma and allergic rhinoconjunctivitis occurring in the context of eczema. Our results support an important role for the filaggrin gene variants R501X and 2282del4 in the development and severity of atopic eczema and indicate a possible role for the subsequent progression into eczema-associated phenotypes.
