Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus.
Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus.
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DOI：
10.1038/ng.3434
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发表时间：
2015-12
期刊：
影响因子：
30.8
通讯作者：
Vyse TJ
中科院分区：
文献类型：
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作者：
Bentham J;Morris DL;Graham DSC;Pinder CL;Tombleson P;Behrens TW;Martín J;Fairfax BP;Knight JC;Chen L;Replogle J;Syvänen AC;Rönnblom L;Graham RR;Wither JE;Rioux JD;Alarcón-Riquelme ME;Vyse TJ
系统性红斑狼疮（SLE; OMIM 152700）是一种遗传复杂的自身免疫性疾病，其特征是对核和细胞表面抗原的免疫耐受丧失。以前的全基因组关联研究（GWAS）样本量不大，降低了它们的范围和可靠性。我们的研究包括7219例病例和15991例对照欧洲血统：一项新的GWAS，荟萃分析与已发表的GWAS和一项重复研究。我们绘制了43个易感位点，包括10个新的关联。在密集的基因组覆盖的帮助下，imputation提供了支持8个基因关联的错义变异的证据。通过检测一系列体外免疫细胞中顺式作用的相关等位基因，确定了其他可能的致病基因。我们发现在SLE易感基因中转录因子的代表性过高（n=16）。这支持了这样一种观点，即先天和适应性免疫反应中多种细胞类型中基因表达网络的异常调节与SLE的发生风险有关。
Systemic lupus erythematosus (SLE; OMIM 152700) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry: a new GWAS, meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including 10 novel associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n=16) of transcription factors among SLE susceptibility genes. This supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE.