STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus
STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus
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DOI：
10.1056/nejmoa073003
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发表时间：
2007-09-06
影响因子：
158.5
通讯作者：
Gregersen, Peter K.
中科院分区：
文献类型：
--
作者：
Remmers, Elaine F.;Plenge, Robert M.;Gregersen, Peter K.
背景类风湿性关节炎是一种具有显着遗传成分的慢性炎症性疾病。疾病易感性与 2q 染色体上的一个区域有关。方法我们测试了先前关联的 2q 染色体区域内及其周围 13 个候选基因的单核苷酸多态性 (SNP)，以了解与类风湿性关节炎的关联。然后，我们对 1620 名患有类风湿性关节炎的患者和 2635 名对照患者（全部来自北美）的 STAT1-STAT4 区域进行了精细定位。在一个独立的病例对照系列中进一步测试了相关的 SNP，该系列包括 1529 名早期类风湿性关节炎患者和 881 名对照者（全部来自瑞典），以及来自三个系列的系统性红斑狼疮患者的总共 1039 名病例患者和 1248 名对照者。结果 STAT4 第三个内含子中的 SNP 单倍型与类风湿性关节炎和系统性红斑狼疮的易感性相关。 红斑狼疮。确定单倍型的 SNP 的次要等位基因存在于已确诊的类风湿性关节炎患者的 27% 染色体中，而对照组的这一比例为 22%（对于 SNP rs7574865，P=2.81 x 10(-7)；患者与对照染色体中存在风险等位基因的比值比为 1.32）。这种关联在瑞典新发类风湿性关节炎患者（P = 0.02）和匹配的对照组中得到了复制。 rs7574865标记的单倍型与狼疮密切相关，存在于病例患者染色体的31%和对照染色体的22%上（P=1.87 x 10(-9)；患者染色体与对照染色体中存在风险等位基因的优势比为1.55）。与不存在等位基因相比，风险等位基因的纯合性与狼疮风险增加一倍以上以及类风湿关节炎风险增加 60% 相关。 结论 STAT4 的单倍型与类风湿关节炎和系统性红斑狼疮风险增加相关，表明这些疾病存在共同的途径。
BackgroundRheumatoid arthritis is a chronic inflammatory disease with a substantial genetic component. Susceptibility to disease has been linked with a region on chromosome 2q.MethodsWe tested single-nucleotide polymorphisms (SNPs) in and around 13 candidate genes within the previously linked chromosome 2q region for association with rheumatoid arthritis. We then performed fine mapping of the STAT1-STAT4 region in a total of 1620 case patients with established rheumatoid arthritis and 2635 controls, all from North America. Implicated SNPs were further tested in an independent case-control series of 1529 patients with early rheumatoid arthritis and 881 controls, all from Sweden, and in a total of 1039 case patients and 1248 controls from three series of patients with systemic lupus erythematosus.ResultsA SNP haplotype in the third intron of STAT4 was associated with susceptibility to both rheumatoid arthritis and systemic lupus erythematosus. The minor alleles of the haplotype-defining SNPs were present in 27% of chromosomes of patients with established rheumatoid arthritis, as compared with 22% of those of controls (for the SNP rs7574865, P=2.81 x 10(-7); odds ratio for having the risk allele in chromosomes of patients vs. those of controls, 1.32). The association was replicated in Swedish patients with recent-onset rheumatoid arthritis (P=0.02) and matched controls. The haplotype marked by rs7574865 was strongly associated with lupus, being present on 31% of chromosomes of case patients and 22% of those of controls (P=1.87 x 10(-9); odds ratio for having the risk allele in chromosomes of patients vs. those of controls, 1.55). Homozygosity of the risk allele, as compared with absence of the allele, was associated with a more than doubled risk for lupus and a 60% increased risk for rheumatoid arthritis.ConclusionsA haplotype of STAT4 is associated with increased risk for both rheumatoid arthritis and systemic lupus erythematosus, suggesting a shared pathway for these illnesses.