Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX
Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX
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DOI：
10.1056/nejmoa0707865
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发表时间：
2008-02-28
影响因子：
158.5
通讯作者：
Behrens, Timothy W.
中科院分区：
文献类型：
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作者：
Hom, Geoffrey;Graham, Robert R.;Behrens, Timothy W.
系统性红斑狼疮（SLE）是一种临床异质性疾病，其发病风险受到复杂的遗传和环境因素的影响。等位基因的HLA-DRB 1，IRF 5，和STAT 4建立易感基因，有强有力的证据存在额外的风险locites.Methods我们基因型超过500,000单核苷酸多态性（SNPs）的DNA样本从1311例受试者SLE和1783对照组，所有受试者都是欧洲血统的北美人。另外1557名对照受试者的基因型来自公共数据库。在应用严格的质量控制过滤器以减少技术伪影并校正人群分层的存在后，我们测量了SNPs与SLE之间的关联。结果在编码B淋巴酪氨酸激酶（BLK）和C8 orf 13基因的转录起始位点上游区域存在遗传变异，在美国和瑞典的病例对照系列中，染色体8p23.1与疾病风险相关（rs 13277113;比值比，1.39; P=1 × 10（-10）），并且在B细胞系中也具有改变的信使RNA水平。此外，染色体16p11.22上的变体，靠近编码整合素α M的基因，（ITGAM，或CD 11b）和整合素α X（ITGAX）与合并样本中的SLE相关。（rs 11574637;比值比，1.33; P=3 × 1（-11））。结论我们鉴定并通过重复实验证实了SLE的两个新的基因位点：启动子区等位基因与BLK表达降低和C8 orf 13表达增加相关，以及ITGAM-ITGAX区的变体。
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=1 x 10(-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=3 x 1 (-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.