Replication of GWAS-identified systemic lupus erythematosus susceptibility genes affirms B-cell receptor pathway signalling and strengthens the role of IRF5 in disease susceptibility in a Northern European population
Replication of GWAS-identified systemic lupus erythematosus susceptibility genes affirms B-cell receptor pathway signalling and strengthens the role of IRF5 in disease susceptibility in a Northern European population
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DOI：
10.1093/rheumatology/ker263
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发表时间：
2012-01-01
期刊：
影响因子：
5.5
通讯作者：
Kere, Juha
中科院分区：
文献类型：
--
作者：
Jarvinen, Tiina M.;Hellquist, Anna;Kere, Juha
Objective.大量的基因，包括一些以前没有牵连在SLE易感性，最近已确定或全基因组关联研究（GWAS）证实。在这项研究中，我们试图在芬兰SLE患者（n = 275）和对照个体（n = 356）中复制这些结果。我们在12个最支持的GWAS鉴定的SLE基因和位点中对32个单核苷酸多态性（SNP）进行基因分型。我们进一步研究了基因间的相互作用。在IRF 5-TNPO 3位点发现了最强的相关证据，最显著的P值为2.0 x 10（-7），比值比为1.95（95% CI 1.51，2.50）。SLE与TNFAIP 3、FAM 167 A-BLK、BANK 1和KIAA 1542之间的相关性也得到了证实，尽管其显著性水平较低，对个体风险的贡献也较低。与1q25.1、PXK、ATG 5、ICA 1、XKR 6、林恩和SCUBE 1无明显相关性。此外，未发现明显的基因间相互作用。在不同人群中重复先前的GWAS发现对于验证这些关联并更好地了解SLE易感人群之间的潜在遗传异质性具有重要意义。我们的研究结果证实了B细胞受体途径和IFN信号在SLE发病机制中的重要性。
Objective. A large number of genes, including several not previously implicated in SLE susceptibility, have recently been identified or confirmed by genome-wide association studies (GWAS). In this study, we sought to replicate some of these results in Finnish SLE patients (n = 275) and control individuals (n = 356).Methods. We genotyped 32 single nucleotide polymorphisms (SNPs) in 12 of the best-supported GWAS-identified SLE genes and loci. We further investigated gene-gene interactions between the loci included in the study.Results. The strongest evidence of association was found at the IRF5-TNPO3 locus, with the most significant P-value being 2.0 x 10(-7) and an odds ratio of 1.95 (95% CI 1.51, 2.50). Association between SLE and TNFAIP3, FAM167A-BLK, BANK1 and KIAA1542 was also confirmed, although at a lower significance level and contribution to individual risk. No significant association was found with 1q25.1, PXK, ATG5, ICA1, XKR6, LYN and SCUBE1. Furthermore, no significant gene-gene interactions were detected.Conclusion. Replication of previous GWAS findings across diverse populations is of importance to validate these associations and to get a better understanding of potential genetic heterogeneity between populations in SLE susceptibility. Our results attest the importance of B-cell receptor pathway and IFN signalling in SLE pathogenesis.