系统性红斑狼疮与C8orf13–BLK 、ITGAM–ITGAX的关联
Association of Systemic Lupus Erythematosus with C8orf13–BLK and ITGAM–ITGAXABSTRACT
Background
Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease in which the risk of disease is influenced by complex genetic and environmental contributions. Alleles of HLA-DRB1, IRF5, and STAT4 are established susceptibility genes; there is strong evidence for the existence of additional risk loci.
Methods
We genotyped more than 500,000 single-nucleotide polymorphisms (SNPs) in DNA samples from 1311 case subjects with SLE and 1783 control subjects; all subjects were North Americans of European descent. Genotypes from 1557 additional control subjects were obtained from public data repositories. We measured the association between the SNPs and SLE after applying strict quality-control filters to reduce technical artifacts and to correct for the presence of population stratification. Replication of the top loci was performed in 793 case subjects and 857 control subjects from Sweden.
Results
Genetic variation in the region upstream from the transcription initiation site of the gene encoding B lymphoid tyrosine kinase (BLK) and C8orf13 (chromosome 8p23.1) was associated with disease risk in both the U.S. and Swedish case–control series (rs13277113; odds ratio, 1.39; P=1x10–10) and also with altered levels of messenger RNA in B-cell lines. In addition, variants on chromosome 16p11.22, near the genes encoding integrin alpha M (ITGAM, or CD11b) and integrin alpha X (ITGAX), were associated with SLE in the combined sample (rs11574637; odds ratio, 1.33; P=3x10–11).
Conclusions
We identified and then confirmed through replication two new genetic loci for SLE: a promoter-region allele associated with reduced expression of BLK and increased expression of C8orf13 and variants in the ITGAM–ITGAX region
背景
系统性红斑狼疮是一种异质性疾病，其发病风险受多基因和环境因素影响。现已确定等位基因HLA-DRB1, IRF5和 STAT4是SLE的易感基因，有证据强烈提示了其他风险位点的存在。
方法
我们对来自1311位SLE患者和1783位健康对照者的DNA中超过500,000个单核苷酸多态(SNPs)进行基因研究,所有受检者均来自欧洲后裔的北美人。另外1557个对照组基因型由公共数据库提供。为了减少技术上的误差和纠正人群层次，我们在严格筛选病例组后检测了SNPs和SLE之间的相关性。我们复制了来自瑞典的793个病例和857个对照的主要位点。
结果
编码B淋巴酪氨酸激酶(BLK)和C8orf13(染色体8p23.1)的转录起始位点上游基因的变异与美国和瑞典病例组及对照组的疾病风险均有关联(rs13277113;机会比率,1.39;P=1x10–10)，也与B细胞系中信使RNA的变异水平相关联。此外，在所有样品中，位于编码整合素α M (ITGAM或CD11b)和整合素α X (ITGAX)附近的染色体16p11.22的变异与SLE相关联(rs11574637; 机会比率, 1.33; P=3x10–11).
结论
我们通过复制两个新的SLE基因位点鉴定并证实了：在ITGAM–ITGAX区域中一个启动区等位基因与BLK表达的减少和C8orf13表达的增加相关联。
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