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The −509C/T polymorphism of transforming growth factor‐β1 is associated with increased risk for development of chronic idiopathic neutropenia
Author(s) -
Eliopoulos Dimitrios G.,
Mavroudi Irene,
Pontikoglou Charalampos,
Ximeri Maria,
Stavroulaki Emily,
Pyrovolaki Katerina,
Velegraki Maria,
Spanoudakis Michael,
Goulielmos George,
Papadaki Helen A.
Publication year - 2009
Publication title -
european journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 84
eISSN - 1600-0609
pISSN - 0902-4441
DOI - 10.1111/j.1600-0609.2009.01319.x
Subject(s) - genotype , transforming growth factor , neutropenia , medicine , tumor necrosis factor alpha , immunology , cytokine , gastroenterology , allele , biology , gene , genetics , toxicity
Objective: 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)‐α, transforming growth factor (TGF)‐β1, and Fas‐Ligand (Fas‐L). In this study, we evaluated the frequency of TNF‐α, TGF‐β1 and Fas‐L gene polymorphisms in CIN patients and explored their role in excessive cytokine production and their association with CIN development. Methods: The TNF‐α−308G/A, TGF‐β1 −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. Results: The mutant genotype C/T or T/T of TGF‐β1 −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‐β1 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‐α−308G/A, TGF‐β1 +869T/C and +915G/C and Fas‐L ‐844T/C polymorphisms. Conclusions: The TGF‐β1 −509C/T polymorphism is associated with increased risk for CIN and contributes to the pathophysiology of the disorder by inducing TGF‐β1 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.