The −509C/T polymorphism of transforming growth factor‐β1 is associated with increased risk for development of chronic idiopathic neutropenia

Abstract

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.

Mesenchymal Stem Cells Contribute to the Abnormal Bone Marrow Microenvironment in Patients with Chronic Idiopathic Neutropenia by Overproduction of Transforming Growth Factor-β1

“…5A. Genotype data of this group of CIN patients have been reported previously [32]. We found that the group of CIN patients with the mutant CT (n ¼ 7) or TT (n ¼ 3) genotype displayed significantly increased levels of TGF-b1 in P2, P4, and P6 MSC culture supernatants (1946 AE 1085, 1195 AE 1024, and 652 AE 277 pg=mL, respectively) compared with patients with the wild-type CC genotype (n ¼ 4) (678 AE 227, 327 AE 79, and 233 AE 51 pg=mL, respectively; P ¼ 0.002, P ¼ 0.002, and P ¼ 0.008, respectively) or the healthy controls (858 AE 273, 422 AE 324, and 266 AE 206 pg=mL, respectively; P ¼ 0.0004, P ¼ 0.0029, and P ¼ 0.0005, respectively).…”

“…Previous studies have also shown elevated TGF-b1 levels in patient sera and LTBMCs and this cytokine has been critically involved in the pathophysiology of CIN by affecting several parameters of hematopoiesis [4,5,7,32,33]. It has also been proposed that TGF-b1 overproduction in CIN may be genetically determined because CIN patients display at a high frequency the TGF-b1-509C=T polymorphism, which in turn is associated with the elevated cytokine concentration in peripheral blood and LTBMC supernatants.…”

“…Our previous studies have shown that the -509C=T polymorphism of TGF-b1 is identified at a higher frequency in CIN patients compared with normal individuals [32]. We have also shown that CIN patients with this particular polymorphism display increased levels of the cytokine in serum and long-term bone marrow culture (LTBMC) supernatants [32].…”

“…We have also shown that CIN patients with this particular polymorphism display increased levels of the cytokine in serum and long-term bone marrow culture (LTBMC) supernatants [32]. To investigate whether the -509C=T polymorphism has also a role in the increased TGF-b1 production by patient MSCs, we analyzed cytokine levels on the basis of -509C=T TGF-b1 genotype and the results are shown in Fig.…”

Genetic Associations in Acquired Immune-Mediated Bone Marrow Failure Syndromes: Insights in Aplastic Anemia and Chronic Idiopathic Neutropenia

“…A possible association between the elevated levels of the above soluble mediators and the genetic predisposition for CIN has been investigated by two different groups. Although the −308G/A polymorphism of the TNF- α gene, especially the TNF2 allele, had been previously shown to contribute to increased serum levels of this cytokine in other disease entities [92, 93], no association was identified between this polymorphism with either the occurrence or the severity of neutropenia in CIN subjects [94, 95]. Likewise, no difference in frequency of the −511C/T IL1B and the +3953C/T IL1B SNP or the variable number tandem repeat (VNTR) in intron 2 of IL-1Ra gene (IL1RN) was detected in CIN patients, [95] although these polymorphisms have been associated with IL1B gene expression and increased IL-1 β production [96, 97].…”