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

被引：82

作者：

Esparza-Gordillo, Jorge ^{[1
,2
]}

Schaarschmidt, Heidi ^{[3
]}

Liang, Liming ^{[4
,5
]}

Cookson, William ^{[6
]}

Bauerfeind, Anja ^{[2
]}

Lee-Kirsch, Min-Ae ^{[7
]}

Nemat, Katja ^{[7
]}

Henderson, John ^{[8
]}

Paternoster, Lavinia ^{[8
]}

Harper, John I. ^{[9
]}

Mangold, Elisabeth ^{[10
]}

Nothen, Markus M. ^{[10
,11
]}

Rueschendorf, Franz ^{[2
]}

Kerscher, Tamara ^{[1
,2
]}

Marenholz, Ingo ^{[1
,2
]}

Matanovic, Anja ^{[1
,2
]}

Lau, Susanne ^{[12
]}

Keil, Thomas ^{[13
]}

Bauer, Carl-Peter ^{[14
]}

Kurek, Michael ^{[15
]}

Ciechanowicz, Andrzej ^{[16
]}

Macek, Milan ^{[17
]}

Franke, Andre ^{[3
]}

Kabesch, Michael ^{[18
]}

Hubner, Norbert ^{[2
]}

Abecasis, Goncalo ^{[19
]}

Weidinger, Stephan ^{[20
]}

Moffatt, Miriam ^{[6
]}

Lee, Young-Ae ^{[1
,2
]}

机构：

[1] Charite Univ Med Berlin, Pediat Allergol Expt & Clin Res Ctr, Berlin, Germany

[2] Max Delbruck Ctr Mol Med, Berlin, Germany

[3] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany

[4] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA

[5] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA

[6] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England

[7] Tech Univ Dresden, Klin Kinder & Jugendmed, Dresden, Germany

[8] Univ Bristol, Dept Community Based Med, Bristol BS8 1TH, Avon, England

[9] Great Ormond St Hosp Sick Children, Dept Paediat Dermatol, London WC1N 3JH, England

[10] Univ Bonn, Inst Human Genet, Bonn, Germany

[11] Univ Bonn, Life & Brain Ctr, Dept Genom, Bonn, Germany

[12] Charite, Berlin, Germany

[13] Charite, Inst Social Med Epidemiol & Hlth Econ, Berlin, Germany

[14] Tech Univ Munich, Dept Pediat, D-80290 Munich, Germany

[15] Pomeranian Med Univ, Dept Clin Allergol, Szczecin, Poland

[16] Pomeranian Med Univ, Dept Lab Diagnost & Mol Med, Szczecin, Poland

[17] Charles Univ Prague, Med Sch & Fac 2, Hosp Motol, Dept Biol & Med Genet, Prague, Czech Republic

[18] Univ Childrens Hosp Regensburg KUNO, Dept Pediat Pneumol & Allergy, Regensburg, Germany

[19] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA

[20] Univ Hosp Schleswig Holstein, Dept Dermatol Venereol & Allergy, Kiel, Germany

来源：

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY | 2013年 / 132卷 / 02期

基金：

英国医学研究理事会; 英国惠康基金;

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; ASTHMA; ASSOCIATION; DISEASE; BIRTH; CHILDREN; MECHANISMS; CHILDHOOD; MUTATIONS; BURDEN; ECZEMA;

D O I：

10.1016/j.jaci.2013.01.057

中图分类号：

R392 [医学免疫学];

学科分类号：

100102 ;

摘要：

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.

引用

页码：371 / 377

页数：7

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