High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry.
High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry.
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免疫相关位点的高密度基因分型识别出亚洲血统个体中新的 SLE 风险变异
DOI：
10.1038/ng.3496
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发表时间：
2016-03
期刊：
影响因子：
30.8
通讯作者：
Nath SK
中科院分区：
文献类型：
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作者：
Sun C;Molineros JE;Looger LL;Zhou XJ;Kim K;Okada Y;Ma J;Qi YY;Kim-Howard X;Motghare P;Bhattarai K;Adler A;Bang SY;Lee HS;Kim TH;Kang YM;Suh CH;Chung WT;Park YB;Choe JY;Shim SC;Kochi Y;Suzuki A;Kubo M;Sumida T;Yamamoto K;Lee SS;Kim YJ;Han BG;Dozmorov M;Kaufman KM;Wren JD;Harley JB;Shen N;Chua KH;Zhang H;Bae SC;Nath SK
系统性红斑狼疮（SLE）有一个强大但不完全了解的遗传结构。我们对来自6个东亚队列的4478例SLE病例和12656例对照进行了一项关联研究，以确定新的SLE易感位点并更好地定位已知位点。我们发现了10个新的位点，并确认了20个已知的具有全基因组意义的位点。在新发现的基因座中，最显著的基因座是gtf2ird1 - gtf2iat 7q11.23 (rs73366469,Pmeta= 3.75 × 10−117，比值比(OR) = 2.38)，其次是def6、IL12B、TCF7、TERT、CD226、PCNXL3、RASGRP1、syngr1和siglec6。通过分析表观遗传标记和基因表达数据，我们确定了每个位点上最可能的功能变异。已知有10个候选变异可以改变门牙内体细胞的基因表达。富集分析强调了这些基因座在B细胞和T细胞生物学中的重要性。这些新的基因座与先前已知的基因座一起，将SLE的解释遗传率提高到24%。新的基因座与先前报道的基因座具有相同的功能和本体论特征，可能是SLE治疗的药物靶点。
Systemic lupus erythematosus (SLE) has a strong but incompletely understood genetic architecture. We conducted an association study with replication in 4,478 SLE cases and 12,656 controls from six East Asian cohorts to identify new SLE susceptibility loci and better localize known loci. We identified ten new loci and confirmed 20 known loci with genome-wide significance. Among the new loci, the most significant locus wasGTF2IRD1-GTF2Iat 7q11.23 (rs73366469,Pmeta= 3.75 × 10−117, odds ratio (OR) = 2.38), followed byDEF6,IL12B,TCF7,TERT,CD226,PCNXL3,RASGRP1,SYNGR1andSIGLEC6. We identified the most likely functional variants at each locus by analyzing epigenetic marks and gene expression data. Ten candidate variants are known to alter gene expression incisor intrans. Enrichment analysis highlights the importance of these loci in B cell and T cell biology. The new loci, together with previously known loci, increase the explained heritability of SLE to 24%. The new loci share functional and ontological characteristics with previously reported loci and are possible drug targets for SLE therapeutics.