Transforming growth factor-β1 functional polymorphisms in myeloablative sibling hematopoietic stem cell transplantation

Abstract

Hematopoietic stem cell transplantation (HSCT) with sibling donors (s.d.) is a life-saving intervention for patients with hematological malignancies. Numerous genetic factors have a role in transplant outcome. Several functional polymorphisms have been identified in TGF-β1 gene, such as single-nucleotide polymorphism (SNP) at +29C>T within exon 1. Two hundred and forty five patient/donor pairs who underwent a s.d. HSCT in our centers were genotyped for this SNP. In the myeloablative cohort, +29CC donors were associated with an increase in severe chronic GvHD (32% vs 16%, hazard ratio (HR) 9.0, P=0.02). Regarding survival outcomes, +29CC patients developed higher non relapse mortality (NRM) (1-5 years CC 28-32% vs TC/TT 7-10%; HR 5.1, P=0.01). Recipients of +29TT donors experienced a higher relapse rate (1-5 years TT 37-51% vs TC 19-25% vs CC 13%-19%; HR 2.4, P=0.01) with a decreased overall survival (OS) (1-5 years TT 69-50% vs TC/CC 77-69%; HR 1.9, P=0.05). Similar to previous myeloablative unrelated donors HSCT results, we confirmed that +29CC patients had higher NRM. In addition we found that +29TT donors might be associated with a higher relapse rate and lower OS. These results should be confirmed in larger series. Identification of these SNPs will allow personalizing transplant conditioning and immunosuppressant regimens, as well as assisting in the choice of the most appropriate donor.

Investigation of TGFB1 −1347C>T variant as a biomarker after allogeneic hematopoietic stem cell transplantation

“…In the previous study, +29CC genotype increased NRM, and reduced OS due to increased infectious death [27]. Another study described that +29CC patients had higher NRM [17]. Whereas, in Canadian HSCT patients (n = 394), −1347TT/TC genotypes in recipients were associated with increased rate of aGvHD, without any effect on NRM or OS [28,29].…”

“…(iii) The favourable effect of the donors' TGFB1 −1347T/+29C variants was noted in the following studies. In a myeloablative HSCT cohort (n = 245) using sibling donors from Argentina, patients with +29TT donors displayed decreased OS due to higher relapse rate [17]. In a large, Japanese, mismatched HSCT cohort (n = 460, only discovery cohort), −1347CC genotype in donors proved to be a risk factor for aGvHD [18].…”

“…Several variants, located in the 5′ regulatory and in the signal peptide regions, are responsible for interindividual variations in cytokine secretion and plasma levels. Several studies investigated the effect of functional TGFB1 polymorphisms on the outcome of HSCT, however results were contradictory [12,[16][17][18][19][20]. Resolving the issue, a fine mapping of TGFB1 promoter haplotype structure was performed recently in Caucasian population.…”

Single nucleotide polymorphisms within HLA region are associated with disease relapse for patients with unrelated cord blood transplantation

“…A genome-wide association study has revealed that rs13202464, instead of rs4349859, within the MHC region represents the main risk effect of HLA-B*27 variants in Han Chinese ( Cortes et al, 2013 ). In addition to the SNPs flanking the HLA loci, many SNPs beyond chromosome 6, where the HLA loci are located, are related to relapse after HSCT ( Dickinson & Charron, 2005 ; Qin et al, 2016 ; Wun et al, 2017 ; Berro et al, 2017 ). The SNPs within the tumor necrosis factor II receptor superfamily member 1B gene and the interleukin 10 gene in human chromosome 1 are associated with improved survival after HSCT ( Dickinson et al, 2010 ).…”

The role of TGF-β1 gene polymorphisms in the development of post-transplant complications

“…В настоящее время известно, что ген TGFВ1 обладает значительным генетическим полиморфизмом, который может служить причиной индивидуального уровня экспрессии белка и быть связан с различными заболеваниями [13][14][15][16][17] и осложнениями после трансплантации органов [16,[18][19][20][21][22].…”