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


  • J. Esparza-Gordillo
  • H. Schaarschmidt
  • L. Liang
  • W. Cookson
  • A. Bauerfeind
  • M.A. Lee-Kirsch
  • K. Nemat
  • J. Henderson
  • L. Paternoster
  • J.L. Harper
  • E. Mangold
  • M.M. Nothen
  • F. Rüschendorf
  • T. Kerscher
  • I. Marenholz
  • A. Matanovic
  • S. Lau
  • T. Keil
  • C.P. Bauer
  • M. Kurek
  • A. Ciechanowicz
  • M. Macek
  • A. Franke
  • M. Kabesch
  • N. Hubner
  • G. Abecasis
  • S. Weidinger
  • M. Moffatt
  • Y.A. Lee


  • Journal of Allergy and Clinical Immunology


  • J Allergy Clin Immunol 132 (2): 371-377


  • 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 x 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 x 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.