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

医学 优势比 病例对照研究 全基因组关联研究 特应性皮炎 遗传关联 免疫学 人口 风险因素 内科学 基因型 遗传学 基因 单核苷酸多态性 生物 环境卫生
作者
Jorge Esparza-Gordillo,Heidi Schaarschmidt,Liming Liang,William Cookson,Anja Bauerfeind,Min-Ae Lee-Kirsch,Katja Nemat,John Henderson,Lavinia Paternoster,John Harper,Elisabeth Mangold,Markus M. Nöthen,Franz Rüschendorf,Tamara Kerscher,Ingo Marenholz,Anja Matanovic,Susanne Lau,Thomas Keil,Carl-Peter Bauer,Michael Kurek,Andrzej Ciechanowicz,Milan Maçek,André Franke,Michael Kabesch,Norbert Hübner,Gonçalo R. Abecasis,Stephan Weidinger,Miriam F. Moffatt,Young-Ae Lee
出处
期刊:The Journal of Allergy and Clinical Immunology [Elsevier BV]
卷期号:132 (2): 371-377 被引量:91
标识
DOI:10.1016/j.jaci.2013.01.057
摘要

BackgroundAtopic 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.ObjectiveWe sought to identify novel genetic risk factors for AD.MethodsWe 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.ResultsA 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 × 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 × 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.ConclusionOur 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. 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. We sought to identify novel genetic risk factors for AD. 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. 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 × 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 × 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. 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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