- 作者：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 R¨¹schendorf ; Tamara Kerscher ; Ingo Marenholz ; Anja Matanovic ; Susanne Lau ; Thomas Keil ; Carl-Peter Bauer ; Michael Kurek ; et al.
- 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
- 刊名：Journal of Allergy and Clinical Immunology
- 出版年：2013
- 出版时间：August, 2013
- 年：2013
- 卷：132
- 期：2
- 页码：371-377
- 全文大小：692 K
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?¡Á?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?¡Á?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.