Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus
Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus
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DOI：
10.1086/428480
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发表时间：
2005-03-01
影响因子：
9.8
通讯作者：
Syvänen, AC
中科院分区：
文献类型：
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作者：
Sigurdsson, S;Nordmark, G;Syvänen, AC
系统性红斑狼疮（SLE）是一种由遗传和环境因素共同引起的复杂的系统性自身免疫性疾病。SLE家族的基因组扫描表明，多个潜在的染色体区域存在SLE易感基因，不同人群的相关研究表明，SLE有几个易感等位基因。I型干扰素（IFN）的产生和IFN诱导基因的表达增加在SLE中是常见的，可能是疾病分子发病机制的关键。我们分析了679名瑞典、芬兰和冰岛SLE患者、798名未受影响的家庭成员和438名无血缘关系的对照个体中来自I型IFN通路的13个基因的44个单核苷酸多态性（snp），以研究与SLE的联合连锁和关联。在两个基因——酪氨酸激酶2 （TYK2）和IFN调节因子5 （IRF5）基因中，我们在与SLE的连锁和关联的联合分析中发现了显示出强信号的snp（未经调整的P < 10(-7)）。TYK2与I型IFN受体复合物结合，IRF5是I型IFN基因表达的调节因子。因此，我们的研究结果支持SLE的疾病机制涉及I型IFN系统的关键成分。
Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease caused by both genetic and environmental factors. Genome scans in families with SLE point to multiple potential chromosomal regions that harbor SLE susceptibility genes, and association studies in different populations have suggested several susceptibility alleles for SLE. Increased production of type I interferon (IFN) and expression of IFN-inducible genes is commonly observed in SLE and may be pivotal in the molecular pathogenesis of the disease. We analyzed 44 single-nucleotide polymorphisms ( SNPs) in 13 genes from the type I IFN pathway in 679 Swedish, Finnish, and Icelandic patients with SLE, in 798 unaffected family members, and in 438 unrelated control individuals for joint linkage and association with SLE. In two of the genes - the tyrosine kinase 2 (TYK2) and IFN regulatory factor 5 (IRF5) genes - we identified SNPs that displayed strong signals in joint analysis of linkage and association (unadjusted P < 10(-7)) with SLE. TYK2 binds to the type I IFN receptor complex and IRF5 is a regulator of type I IFN gene expression. Thus, our results support a disease mechanism in SLE that involves key components of the type I IFN system.