Modeling of clinical phenotypes in systemic lupus erythematosus based on the platelet transcriptome and FCGR2a genotype.
Modeling of clinical phenotypes in systemic lupus erythematosus based on the platelet transcriptome and FCGR2a genotype.
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DOI：
10.1186/s12967-023-04059-w
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发表时间：
2023-04-07
影响因子：
7.4
通讯作者：
Berger, Jeffrey S.
中科院分区：
文献类型：
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作者：
Cornwell, MacIntosh G.;El Bannoudi, Hanane;Luttrell-Williams, Elliot;Engel, Alexis;Barrett, Tessa J.;Myndzar, Khrystyna;Izmirly, Peter;Belmont, H. Michael;Clancy, Robert;Ruggles, Kelly, V;Buyon, Jill P.;Berger, Jeffrey S.
在我们努力提供最佳治疗的同时，SLE 的临床异质性及其复杂的发病机制仍然具有挑战性。血小板对血管内稳态、炎症和免疫调节的贡献凸显了它们在 SLE 中的潜在重要性。我们小组之前的工作表明，Fcγ IIa 型受体 (FcγRIIa)–R/H131 双等位基因多态性与 SLE 患者血小板活性增加和心血管风险相关。该研究旨在调查 SLE 患者的血小板转录组，并评估其与 FcγRIIa 基因型和不同临床特征的关联。纳入了 51 名符合 SLE 既定标准的患者（平均年龄 = 41.1 ± 12.3，100% 女性，45% 西班牙裔，24% 黑人，22% 亚洲人，51% 白人，基线时平均 SLEDAI = 4.4 ± 4.2），并与 18 个人口统计学匹配的对照样本进行比较。对每个样本的 FCGR2a 受体进行基因分型，并对分离的去白细胞血小板进行 RNA 测序。转录组数据用于创建模块化景观，以探索 SLE 患者和对照之间的差异以及 FCGR2a 基因型背景下的各种临床参数。当比较 SLE 样本与对照时，有 2290 个差异表达基因富集于涉及干扰素信号传导、免疫激活和凝血的通路。在分析蛋白尿患者时，与氧化磷酸化和血小板活性相关的模块意外下降。此外，在SLE和蛋白尿患者中增加的基因在免疫效应过程中富集，而在SLE中增加但在蛋白尿患者中减少的基因在凝血和细胞粘附方面富集。低结合 FCG2Ra 等位基因 (R131) 与 FCR 激活减少相关，这进一步与血小板和免疫激活途径的增加相关。最后，我们能够创建临床活动性疾病的转录组学特征，该特征在区分患有活动性临床疾病的 SLE 患者和患有非活动性临床疾病的 SLE 患者方面表现显着。总的来说，这些数据表明血小板转录组可以深入了解狼疮发病机制和疾病活动，并显示出作为使用液体活检评估这种复杂疾病的手段的潜在用途。在线版本包含可在 10.1186/s12967-023-04059-w 获取的补充材料。
The clinical heterogeneity of SLE with its complex pathogenesis remains challenging as we strive to provide optimal management. The contribution of platelets to endovascular homeostasis, inflammation and immune regulation highlights their potential importance in SLE. Prior work from our group showed that the Fcγ receptor type IIa (FcγRIIa)–R/H131 biallelic polymorphism is associated with increased platelet activity and cardiovascular risk in SLE. The study was initiated to investigate the platelet transcriptome in patients with SLE and evaluate its association across FcγRIIa genotypes and distinct clinical features. Fifty-one patients fulfilling established criteria for SLE (mean age = 41.1 ± 12.3, 100% female, 45% Hispanic, 24% black, 22% Asian, 51% white, mean SLEDAI = 4.4 ± 4.2 at baseline) were enrolled and compared with 18 demographically matched control samples. The FCGR2a receptor was genotyped for each sample, and RNA-seq was performed on isolated, leukocyte-depleted platelets. Transcriptomic data were used to create a modular landscape to explore the differences between SLE patients and controls and various clinical parameters in the context of FCGR2a genotypes. There were 2290 differentially expressed genes enriched for pathways involved in interferon signaling, immune activation, and coagulation when comparing SLE samples vs controls. When analyzing patients with proteinuria, modules associated with oxidative phosphorylation and platelet activity were unexpectedly decreased. Furthermore, genes that were increased in SLE and in patients with proteinuria were enriched for immune effector processes, while genes increased in SLE but decreased in proteinuria were enriched for coagulation and cell adhesion. A low-binding FCG2Ra allele (R131) was associated with decreases in FCR activation, which further correlated with increases in platelet and immune activation pathways. Finally, we were able to create a transcriptomic signature of clinically active disease that performed significantly well in discerning SLE patients with active clinical disease form those with inactive clinical disease. In aggregate, these data demonstrate the platelet transcriptome provides insight into lupus pathogenesis and disease activity, and shows potential use as means of assessing this complex disease using a liquid biopsy. The online version contains supplementary material available at 10.1186/s12967-023-04059-w.
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影响因子：
5.8
作者：
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通讯作者：
Schlesner, Matthias
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通讯作者：
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影响因子：
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