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

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Item Type:	Article
Title:	A functional IL-6 receptor (IL6R) variant is a risk factor for persistent atopic dermatitis
Creators Name:	Esparza-Gordillo, J., Schaarschmidt, H., Liang, L., Cookson, W., Bauerfeind, A., Lee-Kirsch, M.A., Nemat, K., Henderson, J., Paternoster, L., Harper, J.L., Mangold, E., Nothen, M.M., Rüschendorf, F., Kerscher, T., Marenholz, I., Matanovic, A., Lau, S., Keil, T., Bauer, C.P., Kurek, M., Ciechanowicz, A., Macek, M., Franke, A., Kabesch, M., Hubner, N., Abecasis, G., Weidinger, S., 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
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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