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

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 Rüschendorf; Tamara Kerscher; Ingo Marenholz; Anja Matanovic; Susanne Lau; Thomas Keil; Carl-Peter Bauer; Michael Kurek; Andrzej Ciechanowicz; Milan Macek; Andre Franke; Michael Kabesch; Norbert Hubner; Gonçalo Abecasis; Stephan Weidinger; Miriam Moffatt; Young-Ae Lee

doi:10.1016/j.jaci.2013.01.057

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

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 Rüschendorf, Tamara Kerscher, Ingo Marenholz, Anja Matanovic, Susanne Lau, Thomas Keil, Carl-Peter Bauer, Michael KurekAndrzej Ciechanowicz, Milan Macek, Andre Franke, Michael Kabesch, Norbert Hubner, Gonçalo Abecasis, Stephan Weidinger, Miriam Moffatt, Young-Ae Lee

Research output: Contribution to journal › Article (Academic Journal) › peer-review

90 Citations (Scopus)

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 × 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.

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.

Original language	English
Pages (from-to)	371-7
Number of pages	7
Journal	Journal of Allergy and Clinical Immunology
Volume	132
Issue number	2
DOIs	https://doi.org/10.1016/j.jaci.2013.01.057
Publication status	Published - Aug 2013

Bibliographical note

Keywords

Adolescent
Alleles
Child
Child, Preschool
Cohort Studies
Dermatitis, Atopic
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Humans
Infant
Infant, Newborn
Interleukin-6
Male
Polymorphism, Single Nucleotide
Receptors, Interleukin-6
Risk Factors

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MRC Population Health Scientist Fellowship
Paternoster, L. (Principal Investigator)
1/10/12 → 1/10/16
Project: Research
EXTENSION OF RD1321 VIA IOP.
Golding, J. (Principal Investigator)
1/02/01 → 1/02/06
Project: Research

Cite this

Esparza-Gordillo, J., Schaarschmidt, H., Liang, L., Cookson, W., Bauerfeind, A., Lee-Kirsch, M.-A., Nemat, K., Henderson, J., Paternoster, L., Harper, J. I., Mangold, E., Nothen, M. M., Rüschendorf, F., Kerscher, T., Marenholz, I., Matanovic, A., Lau, S., Keil, T., Bauer, C.-P., ... Lee, Y.-A. (2013). A functional IL-6 receptor (IL6R) variant is a risk factor for persistent atopic dermatitis. Journal of Allergy and Clinical Immunology, 132(2), 371-7. https://doi.org/10.1016/j.jaci.2013.01.057

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

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 × 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.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 = "Adolescent, Alleles, Child, Child, Preschool, Cohort Studies, Dermatitis, Atopic, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Infant, Infant, Newborn, Interleukin-6, Male, Polymorphism, Single Nucleotide, Receptors, Interleukin-6, Risk Factors",

author = "Jorge Esparza-Gordillo and Heidi Schaarschmidt and Liming Liang and William Cookson and Anja Bauerfeind and Min-Ae Lee-Kirsch and Katja Nemat and John Henderson and Lavinia Paternoster and Harper, \{John I\} and Elisabeth Mangold and Nothen, \{Markus M\} and Franz R{\"u}schendorf and Tamara Kerscher and Ingo Marenholz and Anja Matanovic and Susanne Lau and Thomas Keil and Carl-Peter Bauer and Michael Kurek and Andrzej Ciechanowicz and Milan Macek and Andre Franke and Michael Kabesch and Norbert Hubner and Gon{\c c}alo Abecasis and Stephan Weidinger and Miriam Moffatt and Young-Ae Lee",

year = "2013",

month = aug,

doi = "10.1016/j.jaci.2013.01.057",

language = "English",

volume = "132",

pages = "371--7",

journal = "Journal of Allergy and Clinical Immunology",

issn = "1097-6825",

publisher = "Elsevier Inc.",

number = "2",

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Esparza-Gordillo, J, Schaarschmidt, H, Liang, L, Cookson, W, Bauerfeind, A, Lee-Kirsch, M-A, Nemat, K, Henderson, J, Paternoster, L, Harper, JI, Mangold, E, Nothen, MM, 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 & Lee, Y-A 2013, 'A functional IL-6 receptor (IL6R) variant is a risk factor for persistent atopic dermatitis', Journal of Allergy and Clinical Immunology, vol. 132, no. 2, pp. 371-7. https://doi.org/10.1016/j.jaci.2013.01.057

TY - JOUR

T1 - A functional IL-6 receptor (IL6R) variant is a risk factor for persistent atopic dermatitis

AU - Esparza-Gordillo, Jorge

AU - Schaarschmidt, Heidi

AU - Liang, Liming

AU - Cookson, William

AU - Bauerfeind, Anja

AU - Lee-Kirsch, Min-Ae

AU - Nemat, Katja

AU - Henderson, John

AU - Paternoster, Lavinia

AU - Harper, John I

AU - Mangold, Elisabeth

AU - Nothen, Markus M

AU - Rüschendorf, Franz

AU - Kerscher, Tamara

AU - Marenholz, Ingo

AU - Matanovic, Anja

AU - Lau, Susanne

AU - Keil, Thomas

AU - Bauer, Carl-Peter

AU - Kurek, Michael

AU - Ciechanowicz, Andrzej

AU - Macek, Milan

AU - Franke, Andre

AU - Kabesch, Michael

AU - Hubner, Norbert

AU - Abecasis, Gonçalo

AU - Weidinger, Stephan

AU - Moffatt, Miriam

AU - Lee, Young-Ae

PY - 2013/8

Y1 - 2013/8

N2 - 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 × 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.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.

AB - 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 × 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.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.

KW - Adolescent

KW - Alleles

KW - Child

KW - Child, Preschool

KW - Cohort Studies

KW - Dermatitis, Atopic

KW - Female

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Genotype

KW - Humans

KW - Infant

KW - Infant, Newborn

KW - Interleukin-6

KW - Male

KW - Polymorphism, Single Nucleotide

KW - Receptors, Interleukin-6

KW - Risk Factors

U2 - 10.1016/j.jaci.2013.01.057

DO - 10.1016/j.jaci.2013.01.057

M3 - Article (Academic Journal)

C2 - 23582566

SN - 1097-6825

VL - 132

SP - 371

EP - 377

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

IS - 2

ER -

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

Abstract

Bibliographical note

Keywords

Access to Document

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Fingerprint

Projects

MRC Population Health Scientist Fellowship

EXTENSION OF RD1321 VIA IOP.

Cite this