Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with systemic lupus erythematosus.
Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with systemic lupus erythematosus.
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DOI：
10.1371/journal.pgen.1002341
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发表时间：
2011-10
期刊：
影响因子：
4.5
通讯作者：
Vyse TJ
中科院分区：
文献类型：
--
作者：
Cunninghame Graham DS;Morris DL;Bhangale TR;Criswell LA;Syvänen AC;Rönnblom L;Behrens TW;Graham RR;Vyse TJ
系统性红斑狼疮（SLE）是一种复杂的性状，其特征在于产生一系列自身抗体和多种临床表型。目前，在几项中等规模的全基因组（GW）关联研究发表后，欧洲人SLE的遗传贡献率为1.8%，这些研究确定了具有强效应（OR>1.3）的基因座。为了确定其他有助于SLE易感性的基因，我们在英国数据集（870例病例，5，551例对照）中进行了一项复制研究，该数据集包含23种变异，这些变异在以前的研究中显示出中度狼疮风险。英国数据集的关联分析和随后对已发表数据的荟萃分析确定了五个SLE易感基因达到全基因组显著性水平（Pcomb<5×10−8）：NCF 2（P comb = 2.87×10−11），IKZF 1（P comb = 2.33×10−9），IRF 8（P comb = 1.24×10−8），IFIH 1（P comb = 1.63×10−8）和TYK 2（P comb = 3.88×10−8）。 这里确定的五个新基因座中的每一个都可以映射到干扰素信号通路中，这是已知的在SLE的发病机制中发挥关键作用。这些结果增加了已建立的狼疮易感基因的数量，并验证了使用大型数据集来确认适度增加疾病风险的基因座关联的重要性。全基因组关联研究彻底改变了我们识别系统性红斑狼疮（SLE）常见易感等位基因的能力。在SLE等复杂疾病中，许多不同的基因对疾病易感性的贡献不大，因此有必要进行大规模的关联研究，将多个数据集的结果联合收割机结合起来，以便有足够的能力识别高度显著的新基因座（P<5×10−8）。使用870例英国SLE病例和5，551例英国未受影响个体的大型SLE收集，我们首先从3，273例SLE病例和12，188例健康对照的美国-瑞典研究中复制了10个中度风险等位基因（P<0.05）。结合我们的研究结果与美国-瑞典的数据，确定了五个新的基因座，其跨越了全基因组意义的水平：NCF 2（中性粒细胞胞质因子2），IKZF 1（Ikaros家族锌指1），IRF 8（干扰素调节因子8），IFIH 1（干扰素诱导的解旋酶C结构域蛋白1）和TYK 2（酪氨酸激酶2）。这五个基因中的每一个都调节免疫反应的不同方面，并有助于I型和II型干扰素的产生。虽然需要进一步的研究来确定这些基因座内的致病等位基因，但五个新的狼疮易感基因的确认使我们对SLE遗传贡献的理解向前迈出了重要一步。
Systemic lupus erythematosus (SLE) is a complex trait characterised by the production of a range of auto-antibodies and a diverse set of clinical phenotypes. Currently, ∼8% of the genetic contribution to SLE in Europeans is known, following publication of several moderate-sized genome-wide (GW) association studies, which identified loci with a strong effect (OR>1.3). In order to identify additional genes contributing to SLE susceptibility, we conducted a replication study in a UK dataset (870 cases, 5,551 controls) of 23 variants that showed moderate-risk for lupus in previous studies. Association analysis in the UK dataset and subsequent meta-analysis with the published data identified five SLE susceptibility genes reaching genome-wide levels of significance (Pcomb<5×10−8): NCF2 (P comb = 2.87×10−11), IKZF1 (P comb = 2.33×10−9), IRF8 (P comb = 1.24×10−8), IFIH1 (P comb = 1.63×10−8), and TYK2 (P comb = 3.88×10−8). Each of the five new loci identified here can be mapped into interferon signalling pathways, which are known to play a key role in the pathogenesis of SLE. These results increase the number of established susceptibility genes for lupus to ∼30 and validate the importance of using large datasets to confirm associations of loci which moderately increase the risk for disease. Genome-wide association studies have revolutionised our ability to identify common susceptibility alleles for systemic lupus erythematosus (SLE). In complex diseases such as SLE, where many different genes make a modest contribution to disease susceptibility, it is necessary to perform large-scale association studies to combine results from several datasets, to have sufficient power to identify highly significant novel loci (P<5×10−8). Using a large SLE collection of 870 UK SLE cases and 5,551 UK unaffected individuals, we firstly replicated ten moderate-risk alleles (P<0.05) from a US–Swedish study of 3,273 SLE cases and 12,188 healthy controls. Combining our results with the US-Swedish data identified five new loci, which crossed the level for genome-wide significance: NCF2 (neutrophil cytosolic factor 2), IKZF1 (Ikaros family zinc-finger 1), IRF8 (interferon regulatory factor 8), IFIH1 (interferon-induced helicase C domain-containing protein 1), and TYK2 (tyrosine kinase 2). Each of these five genes regulates a different aspect of the immune response and contributes to the production of type-I and type-II interferons. Although further studies will be required to identify the causal alleles within these loci, the confirmation of five new susceptibility genes for lupus makes a significant step forward in our understanding of the genetic contribution to SLE.
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影响因子：
30.8
作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
30.8
作者：
Han, Jian-Wen;Zheng, Hou-Feng;Zhang, Xue-Jun
通讯作者：
Zhang, Xue-Jun
影响因子：
2.6
作者：
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