Centre for Musculoskeletal Research, School of Biological Sciences, Faculty of Biological Medicine and Health, The University of Manchester, Manchester, United Kingdom.
Dermatology Centre, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom.
J Allergy Clin Immunol. 2024 Sep;154(3):666-669. doi: 10.1016/j.jaci.2024.05.016. Epub 2024 May 25.
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.
Our aim was to examine the association between IL-6Ri and risk of AD.
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.
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]). The results were replicated using Finnish outcome data (OR = 2.07 [95% CI = 1.58-2.72] [P = 1.57 × 10]) 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]) showed no evidence of heterogeneity (P = .65). We found no statistical evidence for pleiotropy or genetic confounding.
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.
白细胞介素 6 受体（IL-6R）抑制剂（IL-6Ri）启动后会引发皮炎，而特应性皮炎（AD）的遗传关联研究表明 IL-6R 通路信号传导与之相关。然而，因果关系尚不清楚。随着 IL-6Ri 适应证的扩大，确定其与 AD 之间是否存在机制证据的临床重要性也随之增加。
我们旨在研究 IL-6Ri 与 AD 风险之间的关联。
为了在基因水平模拟 IL-6Ri，我们选择了与 343524 名个体全基因组显著相关的 C 反应蛋白内或附近的 IL6R 基因中的单核苷酸多态性。遗传数据来自 10788 名 AD 患者和 30047 名欧洲血统对照者。我们使用逆方差加权和易位稳健方法，并通过共定位检查遗传混杂。通过使用 13473 名芬兰人和 2385 名东亚人进行 AD 分析进行了复制。通过荟萃分析对 3 项独立分析的结果进行了合并。
基因上接近的 IL-6Ri 与 AD 风险增加相关（每降低 4.4mg/L C 反应蛋白水平，比值比[OR]为 1.78[95%置信区间[CI]为 1.28-2.48] [P=6.5×10]）。使用芬兰结局数据（OR=2.07[95%CI为 1.58-2.72] [P=1.57×10]）和东亚数据（OR=1.68[95%CI为 1.12-2.54] [P=0.013]）进行了复制。3 个独立人群的荟萃分析（OR=1.89[95%CI为 1.57-2.28] [P=2.68×10]）显示无异质性（P=0.65）。我们没有发现易位或遗传混杂的统计学证据。
这项遗传研究提供了一致的证据（来自独立的多祖人群），表明 IL-6R 信号传导与 AD 易感性存在因果关系。当使用 IL-6R 抑制剂治疗免疫介导的炎症性疾病时，临床医生应警惕类似 AD 的不良反应。
