Identification of a New Susceptibility Locus for Systemic Lupus Erythematosus on Chromosome 12 in Individuals of European Ancestry.
Identification of a New Susceptibility Locus for Systemic Lupus Erythematosus on Chromosome 12 in Individuals of European Ancestry.
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DOI：
10.1002/art.39403
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发表时间：
2016-01
期刊：
影响因子：
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通讯作者：
Kamboh MI
中科院分区：
文献类型：
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作者：
Demirci FY;Wang X;Kelly JA;Morris DL;Barmada MM;Feingold E;Kao AH;Sivils KL;Bernatsky S;Pineau C;Clarke AE;Ramsey-Goldman R;Vyse TJ;Gaffney PM;Manzi S;Kamboh MI
欧洲血统个体的全基因组关联研究（GWAS）使用早期版本的高密度基因分型平台确定了许多系统性红斑狼疮（SLE）易感基因位点。对暗示性GWAS区域的随访研究使用了更大的样本和更多的标记物，在欧洲血统受试者中发现了额外的SLE位点。在这里，我们报告的结果，我们进行了多阶段的研究，以确定新的SLE基因座。在第1阶段，我们在欧洲血统的北美病例对照样本（n= 1，166）中进行了一项新的SLE GWAS，该样本在Affytron全基因组人类SNP阵列6.0上进行了基因分型。在第2阶段，我们使用欧洲血统受试者（> 2，500人）的额外数据集通过计算机模拟评估和荟萃分析进一步研究了最新的提示性GWAS命中，然后在第3阶段复制另一个欧洲血统受试者（> 10，000人）数据集中的最佳荟萃分析结果。正如预期的那样，我们的GWAS揭示了主要组织相容性复合体位点（6p 21）的最显著关联，这很容易超过全基因组显著性阈值（P<5×10−8）。在第1阶段发现样本中也支持了先前在高加索人和/或亚洲人中涉及的其他几个SLE信号/位点，在2 q32/STAT 4（P=3.6×10−7）和8 p23/BLK（P=8.1×10−6）观察到最强信号。第2阶段荟萃分析在12 q12（Meta P=3.1×10−8）确定了一个新的全基因组显著性SLE位点，该位点在第3阶段重复。我们的多阶段研究确定并复制了一个新的SLE位点，需要在其他研究中进一步随访。公开数据库表明，这种新的SLE信号福尔斯落在功能相关的基因组区域内，并靠近生物学上重要的基因。
Genome-wide association studies (GWASs) in individuals of European ancestry identified a number of systemic lupus erythematosus (SLE) susceptibility loci using earlier versions of high-density genotyping platforms. Follow-up studies on suggestive GWAS regions using larger samples and more markers identified additional SLE loci in European-descent subjects. Here we report the results of a multi-stage study that we performed to identify novel SLE loci. In Stage 1, we conducted a new GWAS of SLE in a North American case-control sample of European ancestry (n=1,166) genotyped on Affymetrix Genome-Wide Human SNP Array 6.0. In Stage 2, we further investigated top new suggestive GWAS hits by in silico evaluation and meta-analysis using an additional dataset of European-descent subjects (>2,500 individuals), followed by replication of top meta-analysis findings in another dataset of European-descent subjects (>10,000 individuals) in Stage 3. As expected, our GWAS revealed most significant associations at the major histocompatibility complex locus (6p21), which easily surpassed genome-wide significance threshold (P<5×10−8). Several other SLE signals/loci previously implicated in Caucasians and/or Asians were also supported in Stage 1 discovery sample and strongest signals were observed at 2q32/STAT4 (P=3.6×10−7) and at 8p23/BLK (P=8.1×10−6). Stage 2 meta-analyses identified a new genome-wide significant SLE locus at 12q12 (meta P=3.1×10−8), which was replicated in Stage 3. Our multi-stage study identified and replicated a new SLE locus that warrants further follow-up in additional studies. Publicly available databases suggest that this new SLE signal falls within a functionally relevant genomic region and near biologically important genes.