Subject(s)
DNA-Binding Proteins/genetics , Dermatitis, Atopic/genetics , Genetic Loci , Genetic Predisposition to Disease , LIM Domain Proteins/genetics , Nuclear Proteins/genetics , Transcription Factors/genetics , Case-Control Studies , Chromosome Mapping , Dermatitis, Atopic/pathology , Genetic Markers , Genome-Wide Association Study , Humans , Polymorphism, Single NucleotideABSTRACT
Atopic dermatitis is a common inflammatory skin disease with a strong heritable component. Pathogenetic models consider keratinocyte differentiation defects and immune alterations as scaffolds, and recent data indicate a role for autoreactivity in at least a subgroup of patients. FLG (encoding filaggrin) has been identified as a major locus causing skin barrier deficiency. To better define risk variants and identify additional susceptibility loci, we densely genotyped 2,425 German individuals with atopic dermatitis (cases) and 5,449 controls using the Immunochip array followed by replication in 7,196 cases and 15,480 controls from Germany, Ireland, Japan and China. We identified four new susceptibility loci for atopic dermatitis and replicated previous associations. This brings the number of atopic dermatitis risk loci reported in individuals of European ancestry to 11. We estimate that these susceptibility loci together account for 14.4% of the heritability for atopic dermatitis.
Subject(s)
Dermatitis, Atopic/genetics , Genetic Loci , Genetic Predisposition to Disease , Asian People/genetics , Case-Control Studies , Dermatitis, Atopic/ethnology , Female , Filaggrin Proteins , Genetic Loci/genetics , Genetic Predisposition to Disease/ethnology , Genetic Predisposition to Disease/genetics , Genome-Wide Association Study , Genotyping Techniques , Germany , High-Throughput Nucleotide Sequencing , Humans , Intermediate Filament Proteins/genetics , Japan , Male , Meta-Analysis as Topic , Polymorphism, Single Nucleotide , White People/geneticsABSTRACT
BACKGROUND: Atopic dermatitis (AD) is a common inflammatory skin disease. Previous studies have revealed shared genetic determinants among different inflammatory disorders, suggesting that markers associated with immune-related traits might also play a role in AD. OBJECTIVE: We sought to identify novel genetic risk factors for AD. METHODS: We examined the results of all genome-wide association studies from a public repository and selected 318 genetic markers that were significantly associated with any inflammatory trait. These markers were considered candidates and tested for association with AD in a 3-step approach including 7 study populations with 7130 patients with AD and 9253 control subjects. RESULTS: A functional amino acid change in the IL-6 receptor (IL-6R Asp358Ala; rs2228145) was significantly associated with AD (odds ratio [OR], 1.15; P = 5 × 10(-9)). Interestingly, investigation of 2 independent population-based birth cohorts showed that IL-6R 358Ala specifically predisposes to the persistent form of AD (ORpersistent AD = 1.22, P = .0008; ORtransient AD = 1.04, P = .54). This variant determines the balance between the classical membrane-bound versus soluble IL-6R signaling pathways. Carriers of 358Ala had increased serum levels of soluble IL-6R (P = 4 × 10(-14)), with homozygote carriers showing a 2-fold increase. Moreover, we demonstrate that soluble IL-6R levels were higher in patients with AD than in control subjects (46.0 vs 37.8 ng/mL, P = .001). Additional AD risk variants were identified in RAD50, RUNX3, and ERBB3. CONCLUSION: Our study supports the importance of genetic variants influencing inflammation in the etiology of AD. Moreover, we identified a functional genetic variant in IL6R influencing disease prognosis and specifically predisposing to persistent AD.
Subject(s)
Dermatitis, Atopic/genetics , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Receptors, Interleukin-6/genetics , Adolescent , Alleles , Child , Child, Preschool , Cohort Studies , Female , Genome-Wide Association Study , Genotype , Humans , Infant , Infant, Newborn , Interleukin-6/genetics , Interleukin-6/metabolism , Male , Receptors, Interleukin-6/blood , Risk FactorsABSTRACT
Atopic dermatitis is a chronic, relapsing form of inflammatory skin disorder that is affected by genetic and environmental factors. We performed a genome-wide association study of atopic dermatitis in a Chinese Han population using 1,012 affected individuals (cases) and 1,362 controls followed by a replication study in an additional 3,624 cases and 12,197 controls of Chinese Han ethnicity, as well as 1,806 cases and 3,256 controls from Germany. We identified previously undescribed susceptibility loci at 5q22.1 (TMEM232 and SLC25A46, rs7701890, P(combined) = 3.15 × 10(-9), odds ratio (OR) = 1.24) and 20q13.33 (TNFRSF6B and ZGPAT, rs6010620, P(combined) = 3.0 × 10(-8), OR = 1.17) and replicated another previously reported locus at 1q21.3 (FLG, rs3126085, P(combined) = 5.90 × 10(-12), OR = 0.82) in the Chinese sample. The 20q13.33 locus also showed evidence for association in the German sample (rs6010620, P = 2.87 × 10(-5), OR = 1.25). Our study identifies new genetic susceptibility factors and suggests previously unidentified biological pathways in atopic dermatitis.
