Association between single-nucleotide polymorphisms in the SEC8L1 gene, which encodes a subunit of the exocyst complex, and rheumatoid arthritis in a Japanese population
Association between single-nucleotide polymorphisms in the SEC8L1 gene, which encodes a subunit of the exocyst complex, and rheumatoid arthritis in a Japanese population
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DOI：
10.1002/art.21013
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发表时间：
2005-05-01
影响因子：
--
通讯作者：
Itakura, M
中科院分区：
文献类型：
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作者：
Hamada, D;Takata, Y;Itakura, M
Objective.通过对53个日本家庭进行初步全基因组扫描，确定了一个候选易感基因，并对染色体7 q31 -34进行了大规模病例对照关联分析和连锁不平衡（LD）作图，以确定日本人群中类风湿关节炎（RA）的易感基因。我们在染色体7 q31 -34上的每个基因座中制备了728个密集、均匀间隔的SNP，其中次要等位基因频率> 0.15。使用这些SNPs，对760例RA患者（157例男性和603例女性）和806例非RA对照（189例男性和617例女性）进行了2阶段病例对照分析。对380名正常对照进行单倍型和LD作图。在第一组DNA样本（380例RA病例和380例非RA对照;第一阶段分析）中，48个SNP显示等位基因关联（P < 0.05）。对于SEC 8L 1基因中的4个SNPs，在第二组独立的DNA样本（另外380例RA病例和380例非RA对照;第二阶段分析）中复制了相关性（P < 0.05）。当两组的数据相结合时，观察到与SNP 4411（SEC 8L 1基因的内含子SNP）最显著的等位基因关联（P = 0.000059）。具有显着等位基因关联的SEC 8L 1 SNP均位于单个保守LD区块（区块4）中。单倍型分析揭示了疾病风险（P = 0.0015）和疾病保护（P = 0.0000062）单倍型。对块4内编码外显子的重测序未鉴定出任何非同义SNP。实时荧光定量聚合酶链反应显示SEC 8L 1在人组织中广泛表达，包括RA患者的成纤维细胞样滑膜细胞。我们的全基因座关联和LD分析确定了与RA密切相关的SEC 8L 1基因的内含子SNP和单倍型。我们建议，SEC 8L 1，它编码的外囊复合物的一个组成部分，是一个候选的易感基因RA在日本人口。
Objective. To identify rheumatoid arthritis (RA) susceptibility genes in a Japanese population by conducting a large-scale case-control association analysis and linkage disequilibrium (LD) mapping on chromosome 7q31-34, a candidate susceptibility locus identified in a preliminary genome-wide scan in 53 Japanese families, using single-nucleotide polymorphisms (SNPs).Methods. We prepared 728 dense, evenly spaced SNPs with a minor allele frequency > 0.15 in each gene locus on chromosome 7q31-34. Using these SNPs, a 2-stage case-control analysis was performed on 760 RA patients (157 men and 603 women) and 806 non-RA controls (189 men and 617 women). Haplotypes and LD mapping results were assessed based on SNP genotypes in 380 controls.Results. Forty-eight SNPs showed allele associations (P < 0.05) in the first set of DNA samples (380 RA cases and 380 non-RA controls; first-stage analysis). For 4 of the SNPs in the SEC8L1 gene, the association was replicated (P < 0.05) in the second, independent set of DNA samples (an additional 380 RA cases and 380 non-RA controls; second-stage analysis). When data from the 2 groups were combined, the most significant allele association was observed with SNP 4411, an intronic SNP of the SEC8L1 gene (P = 0.000059). The SEC8L1 SNPs with significant allele associations were all located in a single conserved LD block (block 4). Haplotype analysis revealed the disease-risk (P = 0.0015) and disease-protective (P = 0.0000062) haplotypes. Resequencing of coding exons within block 4 did not identify any nonsynonymous SNPs. Real-time quantitative polymerase chain reaction revealed that SEC8L1 was expressed ubiquitously in human tissues, including fibroblast-like synoviocytes from RA patients.Conclusion. Our locus-wide association and LD analyses identified intronic SNPs and haplotypes in the SEC8L1 gene that are strongly associated with RA. We propose that SEC8L1, which encodes a component of the exocyst complex, is a candidate susceptibility gene for RA in the Japanese population.