title: The -509C/T polymorphism of transforming growth factor-beta1 is associated with increased risk for development of chronic idiopathic neutropenia.
abstract: 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)-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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Haematology, University of Crete School of Medicine, Heraklion, Crete.
authors.forename: Dimitrios G
authors.initials: DG
authors.lastname: Eliopoulos
authors.forename: Irene
authors.initials: I
authors.lastname: Mavroudi
authors.forename: Charalampos
authors.initials: C
authors.lastname: Pontikoglou
authors.forename: Maria
authors.initials: M
authors.lastname: Ximeri
authors.forename: Emily
authors.initials: E
authors.lastname: Stavroulaki
authors.forename: Katerina
authors.initials: K
authors.lastname: Pyrovolaki
authors.forename: Maria
authors.initials: M
authors.lastname: Velegraki
authors.forename: Michael
authors.initials: M
authors.lastname: Spanoudakis
authors.forename: George
authors.initials: G
authors.lastname: Goulielmos
authors.forename: Helen A
authors.initials: HA
authors.lastname: Papadaki
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D002908:Chronic Disease; D053222:Fas Ligand Protein / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006115:Greece / Q000453:epidemiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000097:blood / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D015854:Up-Regulation; D055815:Young Adult
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha