Genetically Proxied Interleukin-13 Inhibition Is Associated With Risk of Psoriatic Disease: A Mendelian Randomization Study

IF 11.4 1区医学 Q1 RHEUMATOLOGY

Arthritis & Rheumatology Pub Date : 2024-07-08 DOI:10.1002/art.42942

Sizheng Steven Zhao, Kimme Hyrich, Zenas Yiu, Anne Barton, John Bowes

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Abstract

Objective

Inhibitors of the interleukin 13 (IL-13) pathway, such as dupilumab, are licensed for atopic dermatitis and asthma. Adverse events resembling psoriatic disease after dupilumab initiation have been reported, but evidence is limited to case reports with uncertain causality. We aimed to investigate whether genetically mimicked IL-13 inhibition (IL-13i) is associated with risk of psoriatic arthritis (PsA) and psoriasis.

Methods

We instrumented IL-13i using a protein-coding variant in the IL13 gene, rs20541, that is associated with circulating eosinophil count (biomarker of IL-13i) at genome-wide significance in a study of 563,946 individuals. Outcome genetic data were taken from studies of PsA, psoriasis, and related spondyloarthritis traits in up to 10,588 cases and 209,287 controls. Colocalization analysis was performed to examine genetic confounding. We additionally used circulating IgE as a biomarker to test whether associations were replicated, both in the test and in an independent genetic dataset. We also replicated analyses using individual-level data from the UK Biobank.

Results

Genetically proxied IL-13i was associated with increased risk of PsA (odds ratio [OR] 37.39; 95% confidence interval [95% CI] 11.52–121.34; P = 1.64 × 10⁻⁹) and psoriasis (OR 20.08; 95% CI 4.38–92.01; P = 1.12 × 10⁻⁴). No consistent associations were found for Crohn disease, ulcerative colitis, ankylosing spondylitis, or iritis. Colocalization showed no strong evidence of genetic confounding for psoriatic disease. Results were replicated using circulating IgE for the exposure, using independent outcome data and using individual-level data.

Conclusion

We provide supportive genetic evidence that IL-13i is linked to increased risk of PsA and psoriasis. Physicians prescribing IL-13 inhibitors should be vigilant for these adverse events.

Abstract Image

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基因代IL-13抑制与银屑病风险有关：孟德尔随机研究

目的：IL-13通路抑制剂，如dupilumab，已被授权用于治疗特应性皮炎和哮喘。有报道称，开始使用杜比鲁单抗后出现了类似银屑病的不良反应，但证据仅限于病例报告，且因果关系不确定。我们旨在研究基因模拟的IL-13抑制（IL-13i）是否与银屑病关节炎（PsA）和银屑病的风险有关：我们利用 IL13 基因中的一个蛋白编码变异 rs20541 对 IL-13i 进行了检测，该变异与循环嗜酸性粒细胞计数（IL-13i 的生物标志物）相关，在一项 563946 人的研究中具有全基因组意义。研究结果的基因数据来自对多达 10,588 例病例和 209,287 例对照的 PsA、银屑病和相关脊柱关节炎特征的研究。我们进行了共定位分析，以检查遗传混杂因素。此外，我们还使用循环免疫球蛋白 E (IgE) 作为生物标记物，以检验相关性是否在测试和独立遗传数据集中得到复制。我们还利用英国生物库的个人水平数据进行了重复分析：结果：IL-13i 的基因代偿与 PsA（OR 37.39；95%CI 11.52，121.34；p=1.64x10-9）和银屑病（OR 20.08；4.38，92.01；p=1.12x10-4）风险增加有关。克罗恩病、溃疡性结肠炎、强直性脊柱炎或虹膜炎均未发现一致的相关性。共定位结果表明，银屑病没有明显的遗传混杂证据。使用循环 IgE 作为暴露因子、使用独立的结果数据以及使用个体水平的数据，结果均得到了重复：我们提供了支持性遗传证据，证明 IL-13i 与 PsA 和银屑病风险增加有关。开具 IL-13 抑制剂处方的医生应警惕这些不良事件。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Arthritis & Rheumatology RHEUMATOLOGY-

CiteScore

20.90

自引率

3.00%

发文量

371

期刊介绍： Arthritis & Rheumatology is the official journal of the American College of Rheumatology and focuses on the natural history, pathophysiology, treatment, and outcome of rheumatic diseases. It is a peer-reviewed publication that aims to provide the highest quality basic and clinical research in this field. The journal covers a wide range of investigative areas and also includes review articles, editorials, and educational material for researchers and clinicians. Being recognized as a leading research journal in rheumatology, Arthritis & Rheumatology serves the global community of rheumatology investigators and clinicians.