title: A functional IL-6 receptor (IL6R) variant is a risk factor for persistent atopic dermatitis.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Pediatric Allergology, Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Jorge
authors.initials: J
authors.lastname: Esparza-Gordillo
authors.forename: Heidi
authors.initials: H
authors.lastname: Schaarschmidt
authors.forename: Liming
authors.initials: L
authors.lastname: Liang
authors.forename: William
authors.initials: W
authors.lastname: Cookson
authors.forename: Anja
authors.initials: A
authors.lastname: Bauerfeind
authors.forename: Min-Ae
authors.initials: MA
authors.lastname: Lee-Kirsch
authors.forename: Katja
authors.initials: K
authors.lastname: Nemat
authors.forename: John
authors.initials: J
authors.lastname: Henderson
authors.forename: Lavinia
authors.initials: L
authors.lastname: Paternoster
authors.forename: John I
authors.initials: JI
authors.lastname: Harper
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mangold
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nothen
authors.forename: Franz
authors.initials: F
authors.lastname: Rüschendorf
authors.forename: Tamara
authors.initials: T
authors.lastname: Kerscher
authors.forename: Ingo
authors.initials: I
authors.lastname: Marenholz
authors.forename: Anja
authors.initials: A
authors.lastname: Matanovic
authors.forename: Susanne
authors.initials: S
authors.lastname: Lau
authors.forename: Thomas
authors.initials: T
authors.lastname: Keil
authors.forename: Carl-Peter
authors.initials: CP
authors.lastname: Bauer
authors.forename: Michael
authors.initials: M
authors.lastname: Kurek
authors.forename: Andrzej
authors.initials: A
authors.lastname: Ciechanowicz
authors.forename: Milan
authors.initials: M
authors.lastname: Macek
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.forename: Michael
authors.initials: M
authors.lastname: Kabesch
authors.forename: Norbert
authors.initials: N
authors.lastname: Hubner
authors.forename: Gonçalo
authors.initials: G
authors.lastname: Abecasis
authors.forename: Stephan
authors.initials: S
authors.lastname: Weidinger
authors.forename: Miriam
authors.initials: M
authors.lastname: Moffatt
authors.forename: Young-Ae
authors.initials: YA
authors.lastname: Lee
mesh_terms: D000293:Adolescent; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003876:Dermatitis, Atopic / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008297:Male; D020641:Polymorphism, Single Nucleotide; D019947:Receptors, Interleukin-6 / Q000097:blood / Q000235:genetics*; D012307:Risk Factors
chemical_list: D015850:Interleukin-6; D019947:Receptors, Interleukin-6
keywords: AD; ALSPAC; Atopic dermatitis; Avon Longitudinal Study of Parents and Children; GWAS; Genome-wide association study; IL-6 receptor; IL-6R; MAS; Multicenter Allergy Study; OR; Odds ratio; SNP; Single nucleotide polymorphism; candidate association study; genetic risk factor; inflammation; longitudinal study; persistent atopic dermatitis; population-based cohort; prognosis; single nucleotide polymorphism; soluble IL-6 receptor