Genetically proxied IL-6 receptor inhibition is associated with increased risk of atopic dermatitis - 14/06/24
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Abstract |
Background |
Dermatitis has been reported after initiation of IL-6 receptor (IL-6R) inhibitors (IL-6Ri), while genetic association studies of atopic dermatitis (AD) have implicated IL-6R pathway signaling. However, causality remains unclear. As the indications for IL-6Ri expand, so do the clinical importance of determining whether there is mechanistic evidence linking it to AD.
Objective |
Our aim was to examine the association between IL-6Ri and risk of AD.
Methods |
To genetically mimic IL-6Ri, we selected single-nucleotide polymorphisms within or near the IL6R gene associated with C-reactive protein at genome-wide significance among 343,524 individuals. Genetic data were obtained from 10,788 individuals with AD and 30,047 controls of European ancestry. We used inverse variance–weighted and pleiotropy-robust methods and examined genetic confounding using colocalization. Analyses were replicated by using 13,473 Finnish and 2,385 East Asian individuals with AD. The results from 3 independent analyses were pooled by meta-analysis.
Results |
Genetically proxied IL-6Ri was associated with increased risk of AD (odds ratio [OR] = 1.78 per 4.4-mg/L reduction in C-reactive protein level [95% CI = 1.28-2.48] [P = 6.5 × 10–4]). The results were replicated using Finnish outcome data (OR = 2.07 [95% CI = 1.58-2.72] [P = 1.57 × 10–7]) and Eastern Asian data (OR = 1.68 [95% CI = 1.12-2.54] [P = .013]). Meta-analysis of 3 independent populations (OR = 1.89 [95% CI = 1.57-2.28] [P = 2.68 × 10–11]) showed no evidence of heterogeneity (P = .65). We found no statistical evidence for pleiotropy or genetic confounding.
Conclusion |
This genetic investigation provides consistent evidence (across independent multiancestry populations) that IL-6R signaling is causally implicated in AD susceptibility. Clinicians should remain vigilant for adverse effects resembling AD when using IL-6R inhibitors for immune-mediated inflammatory diseases.
Le texte complet de cet article est disponible en PDF.Key words : IL-6 receptor, tocilizumab, atopic dermatitis, eczema, mendelian randomization, transethnic
Abbreviations used : AD, CRP, ICD, IL-6R, IL-6Ri, GWAS, LD, MR, OR
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