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

Item Type:Article
Title:A functional IL-6 receptor (IL6R) variant is a risk factor for persistent atopic dermatitis
Creators Name:Esparza-Gordillo, J. and Schaarschmidt, H. and Liang, L. and Cookson, W. and Bauerfeind, A. and Lee-Kirsch, M.A. and Nemat, K. and Henderson, J. and Paternoster, L. and Harper, J.L. and Mangold, E. and Nothen, M.M. and Rueschendorf, F. and Kerscher, T. and Marenholz, I. and Matanovic, A. and Lau, S. and Keil, T. and Bauer, C.P. and Kurek, M. and Ciechanowicz, A. and Macek, M. and Franke, A. and Kabesch, M. and Hubner, N. and Abecasis, G. and Weidinger, S. and Moffatt, M. and Lee, Y.A.
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 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.
Keywords:Atopic Dermatitis, Persistent Atopic Dermatitis, Prognosis, Inflammation, Soluble Il-6 Receptor, Single Nucleotide Polymorphism, Longitudinal Study, Population-Based Cohort, Candidate Association Study, Genetic Risk Factor
Source:Journal of Allergy and Clinical Immunology
ISSN:0091-6749
Publisher:Mosby (U.S.A.)
Volume:132
Number:2
Page Range:371-377
Date:August 2013
Official Publication:https://doi.org/10.1016/j.jaci.2013.01.057
PubMed:View item in PubMed

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