RESUMEN
Atopic dermatitis is a common inflammatory skin disease caused by interaction of genetic and environmental factors. On the basis of data from a genome-wide association study (GWAS) and a validation study comprising a total of 3,328 subjects with atopic dermatitis and 14,992 controls in the Japanese population, we report here 8 new susceptibility loci: IL1RL1-IL18R1-IL18RAP (P(combined) = 8.36 × 10(-18)), the major histocompatibility complex (MHC) region (P = 8.38 × 10(-20)), OR10A3-NLRP10 (P = 1.54 × 10(-22)), GLB1 (P = 2.77 × 10(-16)), CCDC80 (P = 1.56 × 10(-19)), CARD11 (P = 7.83 × 10(-9)), ZNF365 (P = 5.85 × 10(-20)) and CYP24A1-PFDN4 (P = 1.65 × 10(-8)). We also replicated the associations of the FLG, C11orf30, TMEM232-SLC25A46, TNFRSF6B-ZGPAT, OVOL1, ACTL9 and KIF3A-IL13 loci that were previously reported in GWAS of European and Chinese individuals and a meta-analysis of GWAS for atopic dermatitis. These findings advance the understanding of the genetic basis of atopic dermatitis.
Asunto(s)
Dermatitis Atópica/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Pueblo Asiatico/genética , Proteínas Filagrina , Sitios Genéticos , Humanos , Polimorfismo de Nucleótido SimpleRESUMEN
Atopic dermatitis is a chronic inflammatory skin disease. Multiple genetic and environmental factors are thought to be responsible for susceptibility to AD. In this study, we collected 2,478 DNA samples including 209 AD patients and 729 control subjects from Taiwanese population and 513 AD patients and 1027 control subject from Japanese population for sequencing and genotyping ORAI1. A total of 14 genetic variants including 3 novel single-nucleotide polymorphisms (SNPs) in the ORAI1 gene were identified. Our results indicated that a non-synonymous SNP (rs3741596, Ser218Gly) associated with the susceptibility of AD in the Japanese population but not in the Taiwanese population. However, there is another SNP of ORAI1 (rs3741595) associated with the risk of AD in the Taiwanese population but not in the Japanese population. Taken together, our results indicated that genetic polymorphisms of ORAI1 are very likely to be involved in the susceptibility of AD.
Asunto(s)
Pueblo Asiatico/genética , Canales de Calcio/genética , Dermatitis Atópica/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple/genética , Canales de Calcio/metabolismo , Línea Celular , Mapeo Cromosómico , Dermatitis Atópica/epidemiología , Regulación de la Expresión Génica , Frecuencia de los Genes/genética , Genética de Población , Haplotipos/genética , Humanos , Japón/epidemiología , Desequilibrio de Ligamiento/genética , Linfocitos/metabolismo , Proteína ORAI1 , ARN Mensajero/genética , ARN Mensajero/metabolismo , Piel/metabolismo , Piel/patología , Taiwán/epidemiologíaRESUMEN
PURPOSE: Previous reports have shown genetic predisposition for atopic dermatitis (AD). Some of the severe complications of AD manifest in the eye, such as cataract, retinal detachment, and keratoconjunctivitis. This study was conducted to examine the genetic association between the atopy-related genes and patients with ocular complications (ocular AD). METHODS: Seventy-eighty patients with ocular AD and 282 healthy control subjects were enrolled in an investigation of the association between the atopy-related genes (FCERB, IL13, and IFNGR1) and ocular AD. Genetic association studies and functional analysis of single nucleotide polymorphisms (SNPs) were performed. RESULTS: The -56TT genotype in the IFNGR1 promoter region was significantly associated with an increased risk of ocular AD under recessive models (chi(2) test, raw P = 0.0004, odds ratio 2.57). The -56TT genotype was more common in atopic cataracts. A reporter gene assay showed that, after stimulation with IFN-gamma, the IFNGR1 gene promoter construct that contained the -56T allele, a common allele in ocular AD patients, manifested higher transcriptional activity in lens epithelial cells (LECs) than did the construct with the -56C allele. Real-time PCR analysis demonstrated higher IFNGR1 mRNA expression in the LECs in atopic than in senile cataracts. iNOS expression by IFNGR1-overexpressing LECs was enhanced on stimulation with IFN-gamma and LPS. CONCLUSIONS: The -56T allele in the IFNGR1 promoter results in higher IFNGR1 transcriptional activity and represents a genetic risk factor for atopic cataracts.
