IL1RN 变异既影响全身型幼年特发性关节炎的发病易感性，也影响其对重组人白细胞介素-1 受体拮抗剂治疗的反应。
IL1RN Variation Influences Both Disease Susceptibility and Response to Recombinant Human Interleukin-1 Receptor Antagonist Therapy in Systemic Juvenile Idiopathic Arthritis.
机构信息
National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland.
National Human Genome Research Institute, NIH, Bethesda, Maryland.
出版信息
Arthritis Rheumatol. 2018 Aug;70(8):1319-1330. doi: 10.1002/art.40498. Epub 2018 Jun 28.
OBJECTIVE
To determine whether systemic juvenile idiopathic arthritis (JIA) susceptibility loci that were identified by candidate gene studies demonstrate association with systemic JIA in the largest study population assembled to date.
METHODS
Single-nucleotide polymorphisms (SNPs) from 11 previously reported systemic JIA risk loci were examined for association in 9 populations, including 770 patients with systemic JIA and 6,947 controls. The effect of systemic JIA-associated SNPs on gene expression was evaluated in silico in paired whole genome and RNA sequencing data from the lymphoblastoid cell lines (LCLs) of 373 European subjects from the 1000 Genomes Project. Responses of systemic JIA-associated SNPs to anakinra treatment were evaluated in 38 US patients for whom treatment response data were available.
RESULTS
We found no association between the previously reported 26 SNPs and systemic JIA. Expanded analysis of the regions containing the 26 SNPs revealed only 1 significant association: the promoter region of IL1RN (P < 1 × 10 ). Systemic JIA-associated SNPs correlated with IL1RN expression in LCLs, with an inverse correlation between systemic JIA risk and IL1RN expression. The presence of homozygous IL1RN high expression alleles correlated strongly with a lack of response to anakinra therapy (odds ratio 28.7 [95% confidence interval 3.2-255.8]).
CONCLUSION
In our study, IL1RN was the only candidate locus associated with systemic JIA. The implicated SNPs are among the strongest known determinants of IL1RN and interleukin-1 receptor antagonist levels, linking low expression with increased systemic JIA risk. Homozygous high expression alleles predicted nonresponsiveness to anakinra therapy, making them ideal candidate biomarkers to guide systemic JIA treatment. This study is an important first step toward the personalized treatment of systemic JIA.
目的
确定通过候选基因研究确定的全身性幼年特发性关节炎（JIA）易感基因座是否与迄今为止最大的研究人群中的全身性 JIA 相关。
方法
在 9 个群体中检查了 11 个先前报道的全身性 JIA 风险基因座的单核苷酸多态性（SNP）与全身性 JIA 的相关性，这些群体包括 770 名全身性 JIA 患者和 6947 名对照。使用来自 1000 基因组计划的 373 名欧洲个体的淋巴母细胞系（LCL）的全基因组和 RNA 测序数据的计算生物学方法评估了与全身性 JIA 相关的 SNP 对基因表达的影响。对 38 名美国患者的全身性 JIA 相关 SNP 对阿那白滞素治疗的反应进行了评估，这些患者可获得治疗反应数据。
结果
我们未发现先前报道的 26 个 SNP 与全身性 JIA 之间存在关联。对包含 26 个 SNP 的区域的扩展分析仅发现了 1 个显著关联：IL1RN 的启动子区域（P < 1×10 ）。与全身性 JIA 相关的 SNP 与 LCL 中的 IL1RN 表达相关，全身性 JIA 风险与 IL1RN 表达呈负相关。IL1RN 高表达等位基因的纯合子存在与对阿那白滞素治疗无反应密切相关（比值比 28.7 [95%置信区间 3.2-255.8]）。
结论
在我们的研究中，IL1RN 是唯一与全身性 JIA 相关的候选基因座。所涉及的 SNP 是已知最强的 IL1RN 和白细胞介素 1 受体拮抗剂水平的决定因素之一，将低表达与全身性 JIA 风险增加联系起来。纯合的高表达等位基因预测对阿那白滞素治疗无反应，使其成为指导全身性 JIA 治疗的理想候选生物标志物。这项研究是实现全身性 JIA 个体化治疗的重要的第一步。
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