Department of Medical and Molecular Genetics, Division of Genetics and Molecular Medicine, School of Medicine, King's College London, London, United Kingdom.
PLoS Genet. 2011 Oct;7(10):e1002341. doi: 10.1371/journal.pgen.1002341. Epub 2011 Oct 27.
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 (P(comb)<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.
系统性红斑狼疮（SLE）是一种复杂的特征，其特征是产生一系列自身抗体和多样化的临床表型。目前，在欧洲人中，约有 8%的 SLE 遗传贡献是已知的，这是在发表了几项中等规模的全基因组（GW）关联研究之后得出的，这些研究确定了具有强效应（OR>1.3）的基因座。为了确定增加 SLE 易感性的其他基因，我们在一个英国数据集（870 例病例，5551 例对照）中对 23 个变体进行了复制研究，这些变体在以前的研究中显示出中度狼疮风险。在英国数据集的关联分析以及随后与已发表数据的荟萃分析确定了五个 SLE 易感性基因达到全基因组显著水平（P(comb)<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)), 和 TYK2 (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，该通路已知在 SLE 的发病机制中发挥关键作用。这些结果将已确立的狼疮易感性基因数量增加到约 30 个，并验证了使用大数据集来确认中度增加疾病风险的基因座关联的重要性。
