白细胞介素-6 受体多态性 rs12083537、rs2228145 和 rs4329505 作为类风湿关节炎患者对托珠单抗治疗反应的预测因子。

Interleukin-6-receptor polymorphisms rs12083537, rs2228145, and rs4329505 as predictors of response to tocilizumab in rheumatoid arthritis.

机构信息

aDepartment of Infectious Diseases and Rheumatology, Institute for Inflammation Research, Copenhagen University Hospital, Rigshospitalet, Copenhagen bDepartment of Rheumatology, Copenhagen University Hospital, Gentofte cDepartment of Rheumatology, Aarhus University Hospital, Aarhus dDepartment of Rheumatology, Odense University Hospital, Odense, Denmark.

出版信息

Pharmacogenet Genomics. 2014 Aug;24(8):401-5. doi: 10.1097/FPC.0000000000000071.

DOI:10.1097/FPC.0000000000000071

PMID:24978393

Abstract

Tocilizumab (TCZ), a monoclonal antibody targeting the human interleukin-6-receptor (IL-6R), is indicated for the treatment of rheumatoid arthritis (RA). We examined whether three IL6R single-nucleotide polymorphisms rs12083537, rs2228145 (formerly rs8192284), and rs4329505 with previously reported functional effects were associated with clinical response to TCZ in a retrospective study cohort consisting of 79 RA patients. Three months after initiation of TCZ therapy, changes in swollen joint count (SJC) and, subordinately, tender joint count (TJC), serum-CRP, DAS28-CRP, and EULAR-response were tested for association with the IL6R-haplotype or genotype. The major allele (A) of rs12083537 and the minor allele (C) of rs4329505 were associated with a poor SJC response (P=0.02 and 0.02, respectively). Moreover, the AAC-haplotype (for rs12083537, rs2228145, and rs4329505, respectively) was associated with a poor SJC response (P=0.00004) and, with borderline significance, EULAR-response (P=0.05). These data suggest that genetic variation in IL6R may aid in predicting TCZ therapy outcome in RA patients.

摘要

托珠单抗（TCZ）是一种针对人白细胞介素 6 受体（IL-6R）的单克隆抗体，用于治疗类风湿关节炎（RA）。我们在一个由 79 名 RA 患者组成的回顾性研究队列中，检查了三个具有先前报道的功能影响的 IL6R 单核苷酸多态性 rs12083537、rs2228145（以前称为 rs8192284）和 rs4329505 是否与 TCZ 的临床反应相关。在 TCZ 治疗开始后 3 个月，测试肿胀关节计数（SJC）的变化，其次是压痛关节计数（TJC）、血清 CRP、DAS28-CRP 和 EULAR 反应，以与 IL6R 单倍型或基因型相关。rs12083537 的主要等位基因（A）和 rs4329505 的次要等位基因（C）与 SJC 反应不良相关（P=0.02 和 0.02）。此外，AAC 单倍型（分别针对 rs12083537、rs2228145 和 rs4329505）与 SJC 反应不良相关（P=0.00004），且与 EULAR 反应相关具有边缘显著性（P=0.05）。这些数据表明，IL6R 中的遗传变异可能有助于预测 RA 患者 TCZ 治疗的结果。