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: AD; ALSPAC; Atopic dermatitis; Avon Longitudinal Study of Parents and Children; GWAS; Genome-wide association study; IL-6 receptor; IL-6R; MAS; Multicenter Allergy Study; OR; Odds ratio; SNP; Single nucleotide polymorphism; candidate association study; genetic risk factor; inflammation; longitudinal study; persistent atopic dermatitis; population-based cohort; prognosis; single nucleotide polymorphism; soluble IL-6 receptor.