A functional IL-6 receptor (IL6R) variant is a risk factor for persistent atopic dermatitis

Jorge Esparza-Gordillo, Heidi Schaarschmidt, Liming Liang, William Cookson, Anja Bauerfeind, Min-Ae Lee-Kirsch, Katja Nemat, John Henderson, Lavinia Paternoster, John I Harper, Elisabeth Mangold, Markus M Nothen, Franz Rüschendorf, Tamara Kerscher, Ingo Marenholz, Anja Matanovic, Susanne Lau, Thomas Keil, Carl-Peter Bauer, Michael KurekAndrzej Ciechanowicz, Milan Macek, Andre Franke, Michael Kabesch, Norbert Hubner, Gonçalo Abecasis, Stephan Weidinger, Miriam Moffatt, Young-Ae Lee

Research output: Contribution to journalArticle (Academic Journal)peer-review

56 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)371-7
Number of pages7
JournalJournal of Allergy and Clinical Immunology
Issue number2
Publication statusPublished - Aug 2013

Bibliographical note

Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.


  • Adolescent
  • Alleles
  • Child
  • Child, Preschool
  • Cohort Studies
  • Dermatitis, Atopic
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Infant
  • Infant, Newborn
  • Interleukin-6
  • Male
  • Polymorphism, Single Nucleotide
  • Receptors, Interleukin-6
  • Risk Factors

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