Department of Haematology, University of Crete School of Medicine, Heraklion, Crete.
Eur J Haematol. 2009 Dec 1;83(6):535-40. doi: 10.1111/j.1600-0609.2009.01319.x. Epub 2009 Jul 14.
Impaired granulopoiesis in chronic idiopathic neutropenia (CIN) has been associated with an inflammatory bone marrow (BM) microenvironment consisting of pro-inflammatory and pro-apoptotic mediators, such as tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1, and Fas-Ligand (Fas-L). In this study, we evaluated the frequency of TNF-alpha, TGF-beta1 and Fas-L gene polymorphisms in CIN patients and explored their role in excessive cytokine production and their association with CIN development.
The TNF-alpha-308G/A, TGF-beta1 -509C/T, +869T/C, +915G/C, and Fas-L -844T/C polymorphisms were studied in 57 CIN patients, and 100 healthy controls from Crete, a well-defined area with genetically homogeneous population, using a polymerase chain reaction-based restriction fragment length polymorphism assay.
The mutant genotype C/T or T/T of TGF-beta1 -509C/T polymorphism was more common in CIN patients than in controls (P = 0.033). Compared to wild-type genotype, the TT genotype was associated with increased risk for CIN development (OR: 5.7; 95% CI: 1.18-27.26; P = 0.033). Compared to controls, patients with CT and TT genotypes displayed increased TGF-beta1 levels in serum (P < 0.0001 and P = 0.0002, respectively) and BM (P < 0.0001 and P = 0.0002, respectively). No significant difference was found between patients and controls in the frequency of TNF-alpha-308G/A, TGF-beta1 +869T/C and +915G/C and Fas-L -844T/C polymorphisms.
The TGF-beta1 -509C/T polymorphism is associated with increased risk for CIN and contributes to the pathophysiology of the disorder by inducing TGF-beta1 overproduction. This is the first study providing evidence that genetic factors may predispose to CIN and may have a role in the pathophysiology of the disorder.
慢性特发性中性粒细胞减少症（CIN）中粒状细胞生成受损与由促炎和促凋亡介质组成的炎症性骨髓（BM）微环境有关，例如肿瘤坏死因子（TNF）-α、转化生长因子（TGF）-β1 和 Fas 配体（Fas-L）。在这项研究中，我们评估了 CIN 患者中 TNF-α、TGF-β1 和 Fas-L 基因多态性的频率，并探讨了它们在过度细胞因子产生中的作用及其与 CIN 发展的关系。
使用聚合酶链反应-基于限制性片段长度多态性分析的方法，在来自克里特岛的 57 名 CIN 患者和 100 名健康对照者中研究了 TNF-α-308G/A、TGF-β1-509C/T、+869T/C、+915G/C 和 Fas-L-844T/C 多态性。克里特岛是一个遗传上同质人群的明确区域。
CIN 患者中 TGF-β1-509C/T 多态性的突变基因型 C/T 或 T/T 比对照组更为常见（P = 0.033）。与野生型基因型相比，TT 基因型与 CIN 发展的风险增加相关（OR：5.7；95%CI：1.18-27.26；P = 0.033）。与对照组相比，CT 和 TT 基因型的患者血清（P < 0.0001 和 P = 0.0002）和 BM（P < 0.0001 和 P = 0.0002）中 TGF-β1 水平升高。TNF-α-308G/A、TGF-β1+869T/C 和+915G/C 以及 Fas-L-844T/C 多态性在患者和对照组之间的频率无显著差异。
TGF-β1-509C/T 多态性与 CIN 风险增加相关，并通过诱导 TGF-β1 过度产生而导致疾病的病理生理学。这是第一项提供遗传因素可能易患 CIN 并可能在疾病的病理生理学中起作用的证据的研究。
