A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus
A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus
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DOI：
10.1038/ng1782
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发表时间：
2006-05-01
期刊：
影响因子：
30.8
通讯作者：
Alarcón-Riquelme, ME
中科院分区：
文献类型：
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作者：
Graham, RR;Kozyrev, SV;Alarcón-Riquelme, ME
全身性红斑狼疮（SLE）是一种复杂的自身免疫性疾病（1），其特征是激活I型干扰素（IFN）途径（2-4）。在这里，我们在四个独立的病例对照组中（p = 4.4 x 10（-16））和基于家庭的传输不平衡测试分析（p = 0.0006 restibe contrace conscomplication consumutatory因子5（IRF5）RS2004640 T等位基因与SLE5的相关关联）。 RS2004640 T等位基因在IRF5的替代外显子1中创建了一个5'供体剪接位点，从而表达了几种独特的IRF5同工型。我们还确定了与IRF5表达升高并与外显子1B剪接位点相关的独立顺式作用变体。带有与表达升高和缺乏外显子1B供体部位相关的变体的单倍型不会赋予SLE的风险。因此，IRF5多种独特的同工型的升高表达的常见IRF5单倍型是SLE的重要遗传危险因素，它为人类自身免疫中I型IFN途径基因的因果作用确立了因果作用。
Systemic lupus erythematosus (SLE) is a complex autoimmune disease(1) characterized by activation of the type I interferon (IFN) pathway(2-4). Here we convincingly replicate association of the IFN regulatory factor 5 (IRF5) rs2004640 T allele with SLE5 in four independent case-control cohorts (P = 4.4 x 10(-16)) and by family-based transmission disequilibrium test analysis (P = 0.0006). The rs2004640 T allele creates a 5' donor splice site in an alternate exon 1 of IRF5, allowing expression of several unique IRF5 isoforms. We also identify an independent cis-acting variant associated with elevated expression of IRF5 and linked to the exon 1B splice site. Haplotypes carrying the variant associated with elevated expression and lacking the exon 1B donor site do not confer risk of SLE. Thus, a common IRF5 haplotype driving elevated expression of multiple unique isoforms of IRF5 is an important genetic risk factor for SLE, establishing a causal role for type I IFN pathway genes in human autoimmunity.