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 journalArticlepeer-review

77 Scopus citations


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)371-377
Number of pages7
JournalJournal of Allergy and Clinical Immunology
Issue number2
StatePublished - Aug 2013


  • Atopic dermatitis
  • candidate association study
  • genetic risk factor
  • inflammation
  • longitudinal study
  • persistent atopic dermatitis
  • population-based cohort
  • prognosis
  • single nucleotide polymorphism
  • soluble IL-6 receptor


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