Interleukin 1 receptor antagonist (IL1RN) gene variants predict radiographic severity of knee osteoarthritis and risk of incident disease
Interleukin 1 receptor antagonist (IL1RN) gene variants predict radiographic severity of knee osteoarthritis and risk of incident disease
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DOI：
10.1136/annrheumdis-2019-216055
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发表时间：
2020-03-01
影响因子：
27.4
通讯作者：
Abramson, Steven B.
中科院分区：
文献类型：
--
作者：
Attur, Mukundan;Zhou, Hua;Abramson, Steven B.
目的 在这些研究中，我们检测了白细胞介素1受体拮抗剂（IL1RN）基因的单核苷酸多态性（SNP）与症状性膝关节骨关节炎（SKOA）的影像学严重程度以及发生骨关节炎的风险之间的关联。我们还在新发类风湿关节炎（RA）患者中探究了这些基因多态性。
方法 从三个由美国国立卫生研究院（NIH）资助的独立队列中，选取了1000多名符合美国风湿病学会胫股关节骨关节炎标准的受试者。对由IL1RN基因的三个SNP（rs419598、rs315952、rs9005）形成的CTA和TTG单倍型进行评估，以确定其与影像学严重程度以及在一个巢式病例对照队列中发生影像学骨关节炎（rOA）的风险之间的关联。还评估了这些IL1RN单倍型与类风湿关节炎患者的疾病活动度（DAS28）和血浆炎症标志物之间的关联。
结果 与年龄、性别和体重指数匹配的个体相比，携带IL1RN TTG单倍型与更严重的rOA的患病几率增加有关。对骨关节炎倡议发病亚队列的研究表明，携带TTG单倍型与发生rOA的几率增加4.1倍（p = 0.001）有关。TTG携带者的血浆白细胞介素 - 1受体拮抗剂（IL - 1Ra）水平较低，而来自TTG携带者的软骨细胞表现出白细胞介素 - 1受体拮抗剂（IL - 1Ra）分泌减少。在类风湿关节炎患者中，TTG单倍型与DAS28增加、血浆白细胞介素 - 1受体拮抗剂（IL - 1Ra）降低以及血浆炎症标志物（超敏C反应蛋白、白细胞介素6（IL - 6））升高有关。
结论 携带IL1RN TTG单倍型与更严重的rOA、发生骨关节炎的风险增加以及类风湿关节炎中炎症证据增加有关。这些数据表明，与白细胞介素 - 1受体拮抗剂（IL - 1Ra）血浆水平降低相关的IL1RN TTG风险单倍型损害了内源性“抗炎”机制。
Objective In these studies, we examined the association of single nucleotide polymorphisms (SNPs) of the IL1RN gene with radiographic severity of symptomatic knee osteoarthritis (SKOA) and the risk of incident OA. We also explored these genetic polymorphisms in patients with new onset rheumatoid arthritis (RA).Methods Over 1000 subjects who met American College of Rheumatology criteria for tibiofemoral OA were selected from three independent, National Institute of Health (NIH)-funded cohorts. CTA and TTG haplotypes formed from three SNPs of the IL1RN gene (rs419598, rs315952, rs9005) were assessed for association with radiographic severity, and risk for incident radiographic OA (rOA) in a nested case-control cohort. These IL1RN haplotypes were also assessed for association with disease activity (DAS28) and plasma inflammatory markers in patients with RA.Results Carriage of the IL1RN TTG haplotype was associated with increased odds of more severe rOA compared with age-matched, sex-matched and body mass index-matched individuals. Examination of the osteoarthritis initiative Incidence Subcohort demonstrated that carriage of the TTG haplotype was associated with 4.1-fold (p=0.001) increased odds of incident rOA. Plasma IL-1Ra levels were lower in TTG carriers, while chondrocytes from TTG carriers exhibited decreased secretion of IL-1Ra. In patients with RA, the TTG haplotype was associated with increased DAS28, decreased plasma IL-1Ra and elevations of plasma inflammatory markers (hsCRP, interleukin 6 (IL-6)).Conclusion Carriage of the IL1RN TTG haplotype is associated with more severe rOA, increased risk for incident OA, and increased evidence of inflammation in RA. These data suggest that the IL1RN TTG risk haplotype, associated with decreased IL-1Ra plasma levels, impairs endogenous 'anti-inflammatory' mechanisms.