UGT1A1 genetic variants are associated with increases in bilirubin levels in rheumatoid arthritis patients treated with sarilumab

IF 2.9 3区医学 Q2 GENETICS & HEREDITY

Pharmacogenomics Journal Pub Date : 2022-02-11 DOI:10.1038/s41397-022-00269-5

Nan Lin, Amy Damask, Anita Boyapati, Jennifer D. Hamilton, Sara Hamon, Nils Ternes, Michael C. Nivens, John Penn, Alexander Lopez, Jeffrey G. Reid, John Overton, Alan R. Shuldiner, Goncalo Abecasis, Aris Baras, Charles Paulding

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引用次数: 1

Abstract

Sarilumab is a human monoclonal antibody against interleukin (IL)-6Rα that has been approved for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) and an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs). Mild liver function test abnormalities have been observed in patients treated with sarilumab. We describe a genome-wide association study of bilirubin elevations in RA patients treated with sarilumab. Array genotyping and exome sequencing were performed on DNA samples from 1075 patients. Variants in the UGT1A1 gene were strongly associated with maximum bilirubin elevations in sarilumab-treated patients (rs4148325; p = 2.88 × 10−41) but were not associated with aminotransferase elevations. No other independent loci showed evidence of association with bilirubin elevations after sarilumab treatment. These findings suggest that most bilirubin increases during sarilumab treatment are related to genetic variation in UGT1A1 rather than underlying liver injury.

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UGT1A1 基因变异与接受沙利鲁单抗治疗的类风湿性关节炎患者胆红素水平升高有关

沙利单抗是一种抗白细胞介素（IL）-6Rα的人类单克隆抗体，已被批准用于治疗中度至重度活动性类风湿性关节炎（RA）以及对一种或多种疾病修饰抗风湿药（DMARDs）反应不足或不耐受的成年患者。在接受萨利单抗治疗的患者中观察到了轻微的肝功能检测异常。我们描述了一项关于接受萨利单抗治疗的 RA 患者胆红素升高的全基因组关联研究。我们对 1075 例患者的 DNA 样本进行了阵列基因分型和外显子测序。UGT1A1基因中的变异与沙利鲁单抗治疗患者的胆红素最大值升高密切相关（rs4148325；p = 2.88 × 10-41），但与转氨酶升高无关。没有其他独立位点显示与沙利单抗治疗后胆红素升高有关。这些研究结果表明，沙利鲁单抗治疗期间胆红素升高大多与 UGT1A1 的遗传变异有关，而不是潜在的肝损伤。

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

Pharmacogenomics Journal 医学-药学

CiteScore

7.20

自引率

0.00%

发文量

审稿时长

6-12 weeks

期刊介绍： The Pharmacogenomics Journal is a print and electronic journal, which is dedicated to the rapid publication of original research on pharmacogenomics and its clinical applications. Key areas of coverage include: Personalized medicine Effects of genetic variability on drug toxicity and efficacy Identification and functional characterization of polymorphisms relevant to drug action Pharmacodynamic and pharmacokinetic variations and drug efficacy Integration of new developments in the genome project and proteomics into clinical medicine, pharmacology, and therapeutics Clinical applications of genomic science Identification of novel genomic targets for drug development Potential benefits of pharmacogenomics.