Cytokine pathway variants modulate platelet production: IFNA16 is a thrombocytosis susceptibility locus in humans.
Cytokine pathway variants modulate platelet production: IFNA16 is a thrombocytosis susceptibility locus in humans.
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DOI：
10.1182/bloodadvances.2021005648
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发表时间：
2022-08-23
期刊：
影响因子：
7.5
通讯作者：
Bahou, Wadie F.
中科院分区：
文献类型：
--
作者：
V. Gnatenko, Dmitri;Liu, Zhaoyan;Hearing, Patrick;Sohn, Sook-Young;Hu, Yetao;Falanga, Anna;Wu, Song;Malone, Lisa E.;Zhu, Wei;Bahou, Wadie F.
细胞因子途径阵列已经识别出调节应激性血小板增多症中血小板形成的变体和功能性相互作用网络。IFNA 16遗传变异在原发性（但非反应性）血小板增多症中表现为易感基因座，仅限于JAK 2 V617 F阴性队列。炎症刺激对外周血小板计数有不同的影响，尽管血小板减少和血小板增多反应的机制仍然知之甚少。应用靶向血小板生成和细胞因子信号传导途径中富集的326个多态性基因的候选基因方法来鉴定与反应性血小板增多症（RT）或原发性（骨髓增生性肿瘤[MPN]）血小板增多症（ET）队列中血小板反应增强有关的单核苷酸变体（SNV）。ET和RT之间的细胞因子谱包括15个成员的子集、通路拓扑结构和功能性相互作用网络，这与夸大的血小板生成的不同调节通路一致。使用聚集（ET + RT）或ET限制性队列的遗传研究确定了与2个IFNA 16（干扰素-α16）SNV的相关性，并在第二个独立队列中验证了ET相关性（P = .0002）。合并ET队列（n = 105）的比值比为4.92，仅限于JAK 2 V617 F阴性亚组（比值比，5.01）。在16种可定量的细胞因子中，通过变体IFNA 16进行的ET亚层分析显示IFN-α16水平在统计学上显著增加（P = .002）。包含3个连锁的非同义SNV（E65 H95 P133）的重组表达变体IFN-α16保留了与天然IFN-α16（V65 D95 A133）或IFN-α2相当的抗病毒和pSTAT信号传导特征，尽管天然和变体IFN-α16在CD 34+刺激的巨核细胞中均显示出IFN调节基因的阶段限制性差异（与IFN-α2相比）。这些数据暗示IFNA 16（IFN-α16基因产物）是MPN中明显的更广泛的破坏细胞因子网络内的推定易感性位点（驱动因子），并且它们为解剖调节应激或MPN血栓形成的功能性相互作用网络提供了框架。
A cytokine pathway array has identified variants and functional interactive networks regulating platelet formation in stress thrombocytosis. IFNA16 genetic variants behave as susceptibility loci in essential (but not reactive) thrombocytosis, limited to JAK2V617F-negative cohorts. Inflammatory stimuli have divergent effects on peripheral platelet counts, although the mechanisms of thrombocytopenic and thrombocytotic responses remain poorly understood. A candidate gene approach targeting 326 polymorphic genes enriched in thrombopoietic and cytokine signaling pathways was applied to identify single nucleotide variants (SNVs) implicated in enhanced platelet responses in cohorts with reactive thrombocytosis (RT) or essential (myeloproliferative neoplasm [MPN]) thrombocytosis (ET). Cytokine profiles incorporating a 15-member subset, pathway topology, and functional interactive networks were distinct between ET and RT, consistent with distinct regulatory pathways of exaggerated thrombopoiesis. Genetic studies using aggregate (ET + RT) or ET-restricted cohorts identified associations with 2 IFNA16 (interferon-α16) SNVs, and the ET associations were validated in a second independent cohort (P = .0002). Odds ratio of the combined ET cohort (n = 105) was 4.92, restricted to the JAK2V617F-negative subset (odds ratio, 5.01). ET substratification analysis by variant IFNA16 exhibited a statistically significant increase in IFN-α16 levels (P = .002) among 16 quantifiable cytokines. Recombinantly expressed variant IFN-α16 encompassing 3 linked non-synonymous SNVs (E65H95P133) retained comparable antiviral and pSTAT signaling profiles as native IFN-α16 (V65D95A133) or IFN-α2, although both native and variant IFN-α16 showed stage-restricted differences (compared with IFN-α2) of IFN-regulated genes in CD34+-stimulated megakaryocytes. These data implicate IFNA16 (IFN-α16 gene product) as a putative susceptibility locus (driver) within the broader disrupted cytokine network evident in MPNs, and they provide a framework for dissecting functional interactive networks regulating stress or MPN thrombopoiesis.
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Soranzo, Nicole
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15.9
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