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
N1 - Funding Information:
In this study we aimed to identify novel genetic risk factors for AD using a candidate approach based on the selection of genetic markers influencing inflammatory traits. A strong excess of AD-associated markers was observed among the selected candidate SNPs, and 4 loci were significantly associated with AD after correction for multiple testing. Marker rs2040704, which is located within RAD50 and near the IL5 , IL13 , and IL4 genes, was strongly associated with AD (OR, 1.20; P combined = 3 × 10 −11 ). Our finding confirms previous reports of association with different inflammatory traits in the region, such as eosinophil counts, 21 total IgE plasma levels, 22,23 asthma, 24 and psoriasis, 25 supporting a major role for the 5q31 interleukin gene cluster in the susceptibility to immune-related diseases. Importantly, IL4 , IL13 , and IL5 are key factors promoting IgE antibody production and initiating the inflammatory milieu in eczematous skin. 3 In addition, the celiac disease risk SNP rs10903122 located near RUNX3 ( P combined = 1 × 10 −5 ; OR, 1.11) and the type I diabetes risk SNP rs2292239 within ERBB3 ( P combined = 3 × 10 −5 ; OR, 1.11) represent novel candidate risk loci for AD, reinforcing the importance of shared pathways in the development of AD and other immune-related diseases. Additionally, we have identified the functional Asp358Ala IL-6R variant (rs2228145[C]) as a new genetic risk factor for AD (OR, 1.15; P combined = 5 × 10 −9 ). IL-6 signals through the receptor complex formed by membrane-bound IL-6R and glycoprotein 130. This classical signaling mechanism is restricted to cells expressing IL-6R, mainly hepatocytes and leukocyte subsets, and has been linked to the induction of the acute-phase response. Unlike other cytokines, IL-6 also binds to the soluble form of IL-6R and signals through membrane-bound glycoprotein 130. This phenomenon is called IL-6 trans-signaling and allows IL-6 to induce responses in a much wider range of cell types and organs lacking IL-6R expression. 20 The Asp358Ala IL-6R variant is located in the cleavage site that is targeted by proteases during shedding of soluble IL-6R from the membrane-bound form. We found that the risk allele (358Ala) significantly increased soluble IL-6R serum levels ( P = 4 × 10 −14 , Fig 3 ), confirming previous results. 16,17,26 Moreover, we observed significantly higher soluble IL-6R plasma levels in patients with AD compared with those in unaffected control subjects ( P = .001). A logistic regression analysis confirmed the effect of the risk allele on soluble IL-6R plasma levels and showed that AD was associated with an independent increase, underlining the role of increased IL-6R shedding in patients with AD. AD is typically an early-onset disease (<3 years) that can take a very variable clinical course. 3 In approximately 60% of children with early-onset AD, clinical symptoms disappear by school age, whereas 18% have intermittent symptoms and up to 20% have chronic disease. 1,2 AD persistence is associated with an increased risk for allergic airways disease, 27 mental health problems, 28,29 and occupational skin disease. 30 Interestingly, the parental history of AD is one of the strongest risk factors for persistent AD, emphasizing the importance of genetic factors as determinants of prognosis. 2,31 However, to date, mutations in the profilaggrin gene are the only genetic factor known to influence the persistence of AD. 32-34 Importantly, we analyzed the effect of the IL-6R 358Ala allele on AD prognosis on 2 independent population-based cohorts and found that this variant specifically predisposes to AD persistence. This finding fits well with the known role of IL-6R trans-signaling in the transition from acute to chronic inflammation. 20 Recent studies identified IL6R as a risk factor for asthma, 19 decreased pulmonary function, and severe asthma. 35 The study by Ferreira et al 19 reported on the rs4129267 IL6R variant, which is in high linkage disequilibrium with rs2228145 reported in our study ( R 2 = 0.99, see the supplementary material in this article's Online Repository). Because rs2228145 affects IL6R function, 16 it is likely that this variant is responsible for the observed association. We observed a weak effect of rs2228145(C) on asthma in the ALSPAC cohort (OR, 1.04; P = .51; Table II ), which is in agreement with the moderate asthma risk previously reported (OR, 1.09). 19 Importantly, this variant had a stronger effect on AD in the ALSPAC cohort (OR, 1.16) and in the final meta-analysis (OR, 1.15). Furthermore, accounting for asthma status in the ALSPAC cohort revealed that the effect of IL-6R 358Ala on AD is independent of asthma ( Table II ). Tocilizumab is a humanized IL-6R antibody that blocks both soluble and membrane-bound IL-6R and is approved for the treatment of rheumatoid arthritis in adults and children. 36 A recent open-label study showed that tocilizumab significantly reduced AD activity in 3 patients refractory to standard therapies. 37 However, in this small study the treatment was interrupted in 2 of 3 patients because of bacterial infection, which is a well-known side effect reported in clinical efficacy and safety studies of tocilizumab in patients with rheumatoid arthritis. 36 It is likely that the blockade of the classical membrane-bound IL-6R by tocilizumab is responsible for the increased susceptibility to infections because this signaling mechanism is critical for the acute-phase response and the defense against infections. Interestingly, a new molecule specifically targeting trans-signaling through soluble IL-6R (Conaris FE 999301 38 ) is being developed and might be expected to have clinical efficacy in AD treatment with reduced side effects because IL-6 signaling through membrane-bound IL-6R remains unaffected. The IL-6R Asp358Ala is a new risk factor for persistent AD which increases soluble IL-6R plasma levels, suggesting that targeted blocking of IL-6 trans-signaling might be a novel therapeutic approach for persistent AD refractory to conventional treatments, especially in carriers of this very common variant. Clinical implications Targeted blockage of soluble IL-6R trans-signaling might be a novel therapeutic approach for persistent AD, especially in subjects carrying this common variant. We thank all the subjects and families for their participation in this study. We thank C. Flachmeier, S. Kolberg, and I. Szangolies for technical assistance. We also thank all the physicians and nurses involved in patient recruitment for their valuable contribution to the study. We are extremely grateful to all the families who took part in the ALSPAC study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. The UK Medical Research Council, the Wellcome Trust, and the University of Bristol provide core support for ALSPAC.
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 - Atopic dermatitis
KW - candidate association study
KW - genetic risk factor
KW - inflammation
KW - longitudinal study
KW - persistent atopic dermatitis
KW - population-based cohort
KW - prognosis
KW - single nucleotide polymorphism
KW - soluble IL-6 receptor
UR - http://www.scopus.com/inward/record.url?scp=84881153838&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2013.01.057
DO - 10.1016/j.jaci.2013.01.057
M3 - Article
C2 - 23582566
AN - SCOPUS:84881153838
SN - 0091-6749
VL - 132
SP - 371
EP - 377
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 2
ER -