IL1RN Variation Influences Both Disease Susceptibility and Response to Recombinant Human Interleukin-1 Receptor Antagonist Therapy in Systemic Juvenile Idiopathic Arthritis.
IL1RN Variation Influences Both Disease Susceptibility and Response to Recombinant Human Interleukin-1 Receptor Antagonist Therapy in Systemic Juvenile Idiopathic Arthritis.
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DOI：
10.1002/art.40498
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发表时间：
2018-08
期刊：
影响因子：
--
通讯作者：
Ombrello MJ
中科院分区：
文献类型：
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作者：
Arthur VL;Shuldiner E;Remmers EF;Hinks A;Grom AA;Foell D;Martini A;Gattorno M;Özen S;Prahalad S;Zeft AS;Bohnsack JF;Ilowite NT;Mellins ED;Russo R;Len C;Oliveira S;Yeung RSM;Rosenberg AM;Wedderburn LR;Anton J;Haas JP;Rösen-Wolff A;Minden K;Szymanski AM;INCHARGE Consortium;Thomson W;Kastner DL;Woo P;Ombrello MJ
在迄今为止最大的研究人群中，确定通过候选基因研究确定的全身性幼年特发性关节炎（sJIA）易感基因位点是否与sJIA相关。在包括770例sJIA病例和6947例对照者在内的9个人群中检测了11个已报道的sJIA危险基因座的单核苷酸多态性（SNPs）。sJIA相关SNP对基因表达的影响通过计算机模拟在来自373名欧洲1000基因组计划受试者的淋巴母细胞系（LCL）的配对全基因组和RNA测序数据中进行评估。在38例有治疗反应数据的美国患者中评价sJIA相关SNPs与阿那白滞素治疗反应之间的关系。我们没有发现先前报道的26个SNPs与sJIA相关。对包含26个SNP的区域的扩展分析仅揭示了一个显著关联，即IL 1 RN的启动子区域（p<1 E-4）。sJIA相关SNPs与LCL中IL 1 RN表达相关，sJIA风险与IL 1 RN表达呈负相关。纯合子IL 1 RN高表达等位基因的存在与阿那白滞素治疗无应答密切相关（OR 28.7 [3.2，255.8]）。IL 1 RN是本研究中唯一与sJIA相关的候选位点。相关的SNP是IL 1 RN和IL 1 RA水平最强的已知决定因素之一，将低表达与sJIA风险增加联系起来。纯合子高表达等位基因预测阿那白滞素治疗无应答，提名它们作为候选生物标志物来指导sJIA治疗。这是迈向sJIA个性化治疗的重要第一步。
To determine whether systemic juvenile idiopathic arthritis (sJIA) susceptibility loci identified by candidate gene studies demonstrated association with sJIA in the largest study population assembled to date. Single nucleotide polymorphisms (SNPs) from 11 previously reported sJIA risk loci were examined for association in 9 populations, including 770 sJIA cases and 6947 control subjects. The effect of sJIA-associated SNPs on gene expression was evaluated in silico in paired whole genome and RNA sequencing data from lymphoblastoid cell lines (LCL) of 373 European 1000 Genomes Project subjects. The relationship between sJIA-associated SNPs and response to anakinra treatment was evaluated in 38 US patients for whom treatment response data were available. We found no association of the 26 SNPs previously reported as sJIA-associated. Expanded analysis of the regions containing the 26 SNPs revealed only one significant association, the promoter region of IL1RN (p<1E-4). sJIA-associated SNPs correlated with IL1RN expression in LCLs, with an inverse correlation between sJIA risk and IL1RN expression. The presence of homozygous IL1RN high expression alleles correlated strongly with non-response to anakinra therapy (OR 28.7 [3.2, 255.8]). IL1RN was the only candidate locus associated with sJIA in our study. The implicated SNPs are among the strongest known determinants of IL1RN and IL1RA levels, linking low expression with increased sJIA risk. Homozygous high expression alleles predicted non-response to anakinra therapy, nominating them as candidate biomarkers to guide sJIA treatment. This is an important first step towards the personalized treatment of sJIA.
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影响因子：
30.8
作者：
Marchini, Jonathan;Howie, Bryan;Donnelly, Peter
通讯作者：
Donnelly, Peter
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
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作者：
Ogilvie, Emma Mary;Khan, Arshad;Woo, Patricia
通讯作者：
Woo, Patricia
DOI：
10.1038/nrrheum.2011.68
发表时间：
2011-06-07
期刊：
Nature reviews. Rheumatology
影响因子：
--
作者：
通讯作者：
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影响因子：
11
作者：
Farrell, M. S.;Werge, T.;Sklar, P.;Owen, M. J.;Ophoff, R. A.;O'Donovan, M. C.;Corvin, A.;Cichon, S.;Sullivan, P. F.
通讯作者：
Sullivan, P. F.