Differential regulation of the interferon response in systemic lupus erythematosus distinguishes patients of Asian ancestry.
Differential regulation of the interferon response in systemic lupus erythematosus distinguishes patients of Asian ancestry.
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DOI：
10.1136/rmdopen-2023-003475
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发表时间：
2023-09
期刊：
影响因子：
6.2
通讯作者：
Lipsky, Peter E.
中科院分区：
文献类型：
--
作者：
Rector, Ian;Owen, Katherine A.;Bachali, Prathyusha;Hubbard, Erika;Yazdany, Jinoos;Dall'era, Maria;Grammer, Amrie C.;Lipsky, Peter E.
I型干扰素（IFN）在系统性红斑狼疮（SLE）的发病机制中起作用，但对不同祖先群体之间IFN应答的差异关注不够。在这里，我们探讨了欧洲血统（EA）和亚洲血统（阿萨A）的SLE患者中干扰素基因特征（IGSs）的表达。我们使用了基因集变异分析和多种IGS，包括分离的CD 14+单核细胞、CD 19 +B细胞、CD 4 +T细胞和自然杀伤（NK）细胞中对1型和2型IFN的反应，这些细胞来自于根据自我确定的祖先分层的SLE患者。还检查了IGS上游基因的表达和狼疮相关风险等位基因的影响。最后，我们使用机器学习（ML）模型来评估按疾病活动分类患者的最重要特征。与EA患者相比，SLE阿萨患者在所有检查的细胞类型中以及在存在和不存在自身抗体的情况下，在IFN核心和IFNA2 IGS中表现出更大的富集。总的来说，阿萨SLE患者IGS上游基因表达高于EA患者。ML的特征重要性分析表明，NK细胞中的IGS表达、抗dsDNA、补体水平和阿萨状态有助于疾病活动。在所有细胞类型中，无论自身抗体状态如何，SLE阿萨患者的IGS均高于EA患者，IGS上游遗传相关基因的表达增强可能起作用。阿萨沿着NK细胞中的IGS、抗dsDNA和补体一起独立地影响SLE疾病活动。
Type I interferon (IFN) plays a role in the pathogenesis of systemic lupus erythematosus (SLE), but insufficient attention has been directed to the differences in IFN responses between ancestral populations. Here, we explored the expression of the interferon gene signatures (IGSs) in SLE patients of European ancestry (EA) and Asian ancestry (AsA). We used gene set variation analysis with multiple IGS encompassing the response to both type 1 and type 2 IFN in isolated CD14+ monocytes, CD19+B cells, CD4+T cells and Natural Killer (NK) cells from patients with SLE stratified by self-identified ancestry. The expression of genes upstream of the IGS and influenced by lupus-associated risk alleles was also examined. Lastly, we employed machine learning (ML) models to assess the most important features classifying patients by disease activity. AsA patients with SLE exhibited greater enrichment in the IFN core and IFNA2 IGS compared with EA patients in all cell types examined and, in the presence and absence of autoantibodies. Overall, AsA patients with SLE demonstrated higher expression of genes upstream of the IGS than EA counterparts. ML with feature importance analysis indicated that IGS expression in NK cells, anti-dsDNA, complement levels and AsA status contributed to disease activity. AsA patients with SLE exhibited higher IGS than EA patients in all cell types regardless of autoantibody status, with enhanced expression of genetically associated genes upstream of the IGS potentially contributing. AsA, along with the IGS in NK cells, anti-dsDNA and complement, independently influenced SLE disease activity.
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影响因子：
27.4
作者：
Mease, Philip J.;Deodhar, Atul A.;van der Heijde, Desiree;Behrens, Frank;Kivitz, Alan J.;Neal, Jeffrey;Kim, Jonghyeon;Singhal, Shalabh;Nowak, Miroslawa;Banerjee, Subhashis
通讯作者：
Banerjee, Subhashis
影响因子：
8
作者：
Catalina, Michelle D.;Bachali, Prathyusha;Lipsky, Peter E.
通讯作者：
Lipsky, Peter E.
影响因子：
9.8
作者：
Owen, Katherine A.;Price, Andrew;Lipsky, Peter E.
通讯作者：
Lipsky, Peter E.
影响因子：
4
作者：
Paz, Ehud;Adawi, Muhammed;Mader, Reuven
通讯作者：
Mader, Reuven
影响因子：
27.4
作者：
Landolt-Marticorena, C.;Bonventi, G.;Wither, J.
通讯作者：
Wither, J.