A genome-wide association study identified AFF1 as a susceptibility locus for systemic lupus eyrthematosus in Japanese.
A genome-wide association study identified AFF1 as a susceptibility locus for systemic lupus eyrthematosus in Japanese.
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DOI：
10.1371/journal.pgen.1002455
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发表时间：
2012-01
期刊：
影响因子：
4.5
通讯作者：
Yamamoto K
中科院分区：
文献类型：
--
作者：
Okada Y;Shimane K;Kochi Y;Tahira T;Suzuki A;Higasa K;Takahashi A;Horita T;Atsumi T;Ishii T;Okamoto A;Fujio K;Hirakata M;Amano H;Kondo Y;Ito S;Takada K;Mimori A;Saito K;Kamachi M;Kawaguchi Y;Ikari K;Mohammed OW;Matsuda K;Terao C;Ohmura K;Myouzen K;Hosono N;Tsunoda T;Nishimoto N;Mimori T;Matsuda F;Tanaka Y;Sumida T;Yamanaka H;Takasaki Y;Koike T;Horiuchi T;Hayashi K;Kubo M;Kamatani N;Yamada R;Nakamura Y;Yamamoto K
系统性红斑狼疮（SLE）是一种自身免疫性疾病，导致多器官损害。虽然最近的全基因组关联研究（GWAS）有助于发现SLE易感基因，但很少有研究在亚洲人群中进行。在这里，我们报告了一项SLE的GWAS，检查了891例SLE病例和3，384例对照，并在日本受试者中进行了多阶段重复研究，检查了1，387例SLE病例和28，564例对照。考虑到表达数量性状基因座（eQTL）与自身免疫性疾病的遗传风险有关，我们将eQTL研究整合到GWAS的结果中。我们观察到，与全基因组SNP（6.9%）相比，在已知的SLE易感基因座中，顺式eQTL阳性基因座（30.8%）富集。此外，我们还发现了AF 4/FMR 2家族成员1（AFF 1）基因4 q21的一个变异体与SLE易感性的新关联（rs340630; P = 8.3×10−9，比值比= 1.21）。 rs340630的risk A等位基因对AFF 1基因表达有显著影响（P<0.05）。由于AFF 1转录本在CD 4+和CD 19+外周血淋巴细胞中显著表达，因此AFF 1的上调可能导致这些淋巴细胞的异常，从而导致疾病的发生。虽然最近的全基因组关联研究（GWAS）方法已经成功地为疾病基因的发现做出了贡献，但由于多重假设检验的严格显著性阈值，许多易感性位点仍然未被捕获。因此，建议通过纳入其他信息对GWAS结果进行优先排序。系统性红斑狼疮（SLE）是一种自身免疫性疾病，导致多器官损害。考虑到B细胞活性异常在SLE中起重要作用，基于B细胞表达数量性状基因座（eQTL）研究的优先排序将是一种有前途的方法。在这项研究中，我们报告了一项GWAS和SLE的多阶段重复研究，在日本受试者中检查了2，278例SLE病例和31，948例对照。我们将eQTL研究整合到GWAS的结果中，并将AFF 1鉴定为一个新的SLE易感基因座。我们还证实了该位点对AFF 1转录本的顺式调节作用。我们的研究将是使用eQTL研究检测新的遗传位点的初步成功之一，它应该有助于我们理解标准GWAS方法未捕获的遗传位点。
Systemic lupus erythematosus (SLE) is an autoimmune disease that causes multiple organ damage. Although recent genome-wide association studies (GWAS) have contributed to discovery of SLE susceptibility genes, few studies has been performed in Asian populations. Here, we report a GWAS for SLE examining 891 SLE cases and 3,384 controls and multi-stage replication studies examining 1,387 SLE cases and 28,564 controls in Japanese subjects. Considering that expression quantitative trait loci (eQTLs) have been implicated in genetic risks for autoimmune diseases, we integrated an eQTL study into the results of the GWAS. We observed enrichments of cis-eQTL positive loci among the known SLE susceptibility loci (30.8%) compared to the genome-wide SNPs (6.9%). In addition, we identified a novel association of a variant in the AF4/FMR2 family, member 1 (AFF1) gene at 4q21 with SLE susceptibility (rs340630; P = 8.3×10−9, odds ratio = 1.21). The risk A allele of rs340630 demonstrated a cis-eQTL effect on the AFF1 transcript with enhanced expression levels (P<0.05). As AFF1 transcripts were prominently expressed in CD4+ and CD19+ peripheral blood lymphocytes, up-regulation of AFF1 may cause the abnormality in these lymphocytes, leading to disease onset. Although recent genome-wide association study (GWAS) approaches have successfully contributed to disease gene discovery, many susceptibility loci are known to be still uncaptured due to strict significance threshold for multiple hypothesis testing. Therefore, prioritization of GWAS results by incorporating additional information is recommended. Systemic lupus erythematosus (SLE) is an autoimmune disease that causes multiple organ damage. Considering that abnormalities in B cell activity play essential roles in SLE, prioritization based on an expression quantitative trait loci (eQTLs) study for B cells would be a promising approach. In this study, we report a GWAS and multi-stage replication studies for SLE examining 2,278 SLE cases and 31,948 controls in Japanese subjects. We integrated eQTL study into the results of the GWAS and identified AFF1 as a novel SLE susceptibility loci. We also confirmed cis-regulatory effect of the locus on the AFF1 transcript. Our study would be one of the initial successes for detecting novel genetic locus using the eQTL study, and it should contribute to our understanding of the genetic loci being uncaptured by standard GWAS approaches.
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64.8
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影响因子：
30.8
作者：
Han, Jian-Wen;Zheng, Hou-Feng;Zhang, Xue-Jun
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影响因子：
30.8
作者：
Graham, Robert R.;Cotsapas, Chris;Davies, Leela;Hackett, Rachel;Lessard, Christopher J.;Leon, Joanlise M.;Burtt, Noel P.;Guiducci, Candace;Parkin, Melissa;Gates, Casey;Plenge, Robert M.;Behrens, Timothy W.;Wither, Joan E.;Rioux, John D.;Fortin, Paul R.;Graham, Deborah Cunninghame;Wong, Andrew K.;Vyse, Timothy J.;Daly, Mark J.;Altshuler, David;Moser, Kathy L.;Gaffney, Patrick M.
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