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.

中文翻译：

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白细胞介素 1 受体拮抗剂 (IL1RN) 基因变异可预测膝骨关节炎的影像学严重程度和发病风险


目的 在这些研究中，我们检查了 IL1RN 基因的单核苷酸多态性 (SNP) 与症状性膝骨关节炎 (SKOA) 的放射学严重程度以及发生 OA 的风险之间的关系。我们还探索了新发类风湿性关节炎（RA）患者的这些基因多态性。方法 从美国国立卫生研究院 (NIH) 资助的三个独立队列中选出 1000 多名符合美国风湿病学会胫股骨 OA 标准的受试者。在嵌套病例对照队列中，评估了由 IL1RN 基因的三个 SNP（rs419598、rs315952、rs9005）形成的 CTA 和 TTG 单倍型与放射学严重程度和放射学 OA (rOA) 事件风险的关联。还评估了这些 IL1RN 单倍型与 RA 患者疾病活动性 (DAS28) 和血浆炎症标志物的关联。结果 与年龄匹配、性别匹配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 几率增加相关。对骨关节炎主动发病率子队列的检查表明，携带 TTG 单倍型与 4.1 倍 (p=0.001) 增加的 rOA 发病几率相关。 TTG 携带者的血浆 IL-1Ra 水平较低，而 TTG 携带者的软骨细胞则表现出 IL-1Ra 分泌减少。在 RA 患者中，TTG 单倍型与 DAS28 升高、血浆 IL-1Ra 降低和血浆炎症标志物（hsCRP、白细胞介素 6 (IL-6)）升高相关。结论 IL1RN TTG 单倍型的携带与更严重的 rOA、发生 OA 的风险增加以及 RA 炎症证据的增加相关。 这些数据表明，IL1RN TTG 风险单倍型与 IL-1Ra 血浆水平降低相关，会损害内源性“抗炎”机制。