The -509C/T polymorphism of transforming growth factor-beta1 is associated with increased risk for development of chronic idiopathic neutropenia.
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.
Eliopoulos
Dimitrios G
DG
Department of Haematology, University of Crete School of Medicine, Heraklion, Crete.
Mavroudi
Irene
I
Pontikoglou
Charalampos
C
Ximeri
Maria
M
Stavroulaki
Emily
E
Pyrovolaki
Katerina
K
Velegraki
Maria
M
Spanoudakis
Michael
M
Goulielmos
George
G
Papadaki
Helen A
HA
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
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha