期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 132, 期 2, 页码 371-377出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2013.01.057
关键词
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
资金
- German Ministry of Education and Research (BMBF)
- Wellcome Trust
- ThermoFisher Scientific
- Nutricia GmbH
- Novartis Pharma AG
- Bencard Allergie GmbH
- UK Medical Research Council
- European Union FP7 Programme
- DFG
- European Respiratory Society
- EIAACI
- American Thoracic Society
- Novartis
- GlaxoSmithKline
- BMBF
- European Union
- BMBF-NGFN
- MRC [MR/J012165/1] Funding Source: UKRI
- Medical Research Council [MR/J012165/1, G9815508, G0801056B] Funding Source: researchfish
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 5 4 3 10 214), 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.
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