信号转导和转录激活因子4与类风湿性关节炎及系统性红斑狼疮的风险
STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus.
作者信息
Remmers Elaine F, Plenge Robert M, Lee Annette T, Graham Robert R, Hom Geoffrey, Behrens Timothy W, de Bakker Paul I W, Le Julie M, Lee Hye-Soon, Batliwalla Franak, Li Wentian, Masters Seth L, Booty Matthew G, Carulli John P, Padyukov Leonid, Alfredsson Lars, Klareskog Lars, Chen Wei V, Amos Christopher I, Criswell Lindsey A, Seldin Michael F, Kastner Daniel L, Gregersen Peter K
机构信息
National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, USA.
出版信息
N Engl J Med. 2007 Sep 6;357(10):977-86. doi: 10.1056/NEJMoa073003.
BACKGROUND
Rheumatoid arthritis is a chronic inflammatory disease with a substantial genetic component. Susceptibility to disease has been linked with a region on chromosome 2q.
METHODS
We 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.
RESULTS
A 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=2.81x10(-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=1.87x10(-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.
CONCLUSIONS
A haplotype of STAT4 is associated with increased risk for both rheumatoid arthritis and systemic lupus erythematosus, suggesting a shared pathway for these illnesses.
背景
类风湿性关节炎是一种具有重要遗传成分的慢性炎症性疾病。疾病易感性与2号染色体上的一个区域相关。
方法
我们检测了先前关联的2号染色体区域内及周围13个候选基因中的单核苷酸多态性（SNP）与类风湿性关节炎的关联性。然后我们对总共1620例确诊类风湿性关节炎患者和2635例对照进行了STAT1-STAT4区域的精细定位，所有病例和对照均来自北美。在另一个独立的病例对照系列中，我们对1529例早期类风湿性关节炎患者和881例对照（均来自瑞典）以及来自三个系统性红斑狼疮患者系列的总共1039例病例和1248例对照进一步检测了相关SNP。
结果
STAT4第三个内含子中的一个SNP单倍型与类风湿性关节炎和系统性红斑狼疮的易感性均相关。确诊类风湿性关节炎患者的染色体中，该单倍型定义SNP的次要等位基因在27%的染色体上出现，而对照中为22%（对于SNP rs7574865，P = 2.81×10⁻⁷；患者染色体中具有风险等位基因与对照染色体的比值比，1.32）。该关联在瑞典近期发病的类风湿性关节炎患者（P = 0.02）及匹配对照中得到重复验证。由rs7574865标记的单倍型与狼疮强烈相关，病例患者染色体的31%上存在该单倍型，对照中为22%（P = 1.87×10⁻⁹；患者染色体中具有风险等位基因与对照染色体的比值比，1.55）。与不存在该等位基因相比，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性关节炎风险增加60%相关。
结论
STAT4的一个单倍型与类风湿性关节炎和系统性红斑狼疮的风险增加相关，提示这两种疾病存在共同途径。
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