Identification of IRAK1 as a risk gene with critical role in the pathogenesis of systemic lupus erythematosus
Identification of IRAK1 as a risk gene with critical role in the pathogenesis of systemic lupus erythematosus
复制标题
DOI：
10.1073/pnas.0901181106
复制
发表时间：
2009-04-14
影响因子：
11.1
通讯作者：
Mohan, Chandra
中科院分区：
文献类型：
--
作者：
Jacob, Chaim O.;Zhu, Jiankun;Mohan, Chandra
采用正向遗传和反向遗传相结合的方法，检测IRAK1(白细胞介素1受体相关激酶-1)作为X染色体编码的系统性红斑狼疮(SLE)风险因子的可能性。在对大约5,000名受试者和健康对照的研究中，5个跨越IRAK1基因的SNP在4个不同种族的成人和儿童发病的SLE中都显示出疾病关联(P值达到10(-10)，优势比>；1.5)，其中4个SNP单倍型(GGGG)与疾病密切相关。接下来，通过携带Sle1或Sle3致病基因的同源小鼠模型，研究了IRAK1的功能作用。在两种模型中，IRAK1缺乏均可消除所有与狼疮相关的表型，包括IgM和Ig G自身抗体、淋巴细胞活化和肾脏疾病。此外，IRAK1的缺失逆转了与Sle3相关的树突状细胞的“过度活跃”。人类SLE的前瞻遗传学研究和小鼠模型的机制研究共同证实，IRAK1是狼疮的疾病基因，能够调节疾病发展中的至少两个关键检查点。这一证明表明，X染色体基因是人类SLE的疾病易感因素，这增加了SLE的性别差异可能部分归因于性染色体基因。
A combined forward and reverse genetic approach was undertaken to test the candidacy of IRAK1 (interleukin-1 receptor associated kinase-1) as an X chromosome-encoded risk factor for systemic lupus erythematosus (SLE). In studying approximate to 5,000 subjects and healthy controls, 5 SNPs spanning the IRAK1 gene showed disease association ( P values reaching 10(-10), odds ratio > 1.5) in both adult- and childhood-onset SLE, in 4 different ethnic groups, with a 4 SNP haplotype ( GGGG) being strongly associated with the disease. The functional role of IRAK1 was next examined by using congenic mouse models bearing the disease loci: Sle1 or Sle3. IRAK1 deficiency abrogated all lupus-associated phenotypes, including IgM and IgG autoantibodies, lymphocytic activation, and renal disease in both models. In addition, the absence of IRAK1 reversed the dendritic cell "hyperactivity'' associated with Sle3. Collectively, the forward genetic studies in human SLE and the mechanistic studies in mouse models establish IRAK1 as a disease gene in lupus, capable of modulating at least 2 key checkpoints in disease development. This demonstration of an X chromosome gene as a disease susceptibility factor in human SLE raises the possibility that the gender difference in SLE may in part be attributed to sex chromosome genes.