Polymorphism in TGFB1 is associated with worse non-relapse mortality and overall survival after stem cell transplantation with unrelated donors

Abstract

Hematopoietic stem cell transplantation (HSCT) is a medical procedure used to treat malignant and non-malignant diseases of the blood, as well as solid tumors. The outcome of HSCT is influenced both by clinical and genetic factors. Compatibility between the recipient and the donor in terms of HLA is a wellknown limiting factor for the success of allogeneic HSCT.1 In addition, genes other than those of the HLA system, in particular those that are highly polymorphic, have been proposed as potential factors affecting the success of this therapy. T ransforming growth factor β-1, encoded by the TGFB1 gene, is a cytokine that plays a central role in many physiological and pathogenic processes. We have sequenced TGFB1 regulatory region and assigned allelic genotypes in a large cohort of hematopoietic stem cell transplantation patients and donors. In this study, we analyzed 522 unrelated donor-patient pairs and examined the combined effect of all the common polymorphisms in this genomic region. In univariate analysis, we found that patients carrying a specific allele, 'p001', showed significantly reduced overall survival (5-year overall survival 30.7% for p001/p001 patients vs. 41.6% others; P=0.032) and increased non-relapse mortality (1-year nonrelapse mortality: 39.0% vs. 25.4%; P=0.039) after transplantation. In multivariate analysis, the presence of a p001/p001 genotype in patients was confirmed as an independent factor for reduced overall survival [hazard ratio=1.53 (1.04-2.24); P=0.031], and increased non-relapse mortality [hazard ratio=1.73 (1.06-2.83); P=0.030]. In functional experiments we found a trend towards a higher percentage of surface transforming growth factor β-1-positive regulatory T cells after activation when the cells had a p001 allele (P=0.07). Higher or lower production of transforming growth factor β-1 in the inflammatory context of hematopoietic stem cell transplantation may influence the development of complications in these patients. Findings indicate that TGFB1 genotype could potentially be of use as a prognostic factor in hematopoietic stem cell transplantation risk assessment algorithms. ©2016 Ferrata Storti Foundation

Replication and validation of genetic polymorphisms associated with survival after allogeneic blood or marrow transplant

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14] Of the 7 articles whose findings we attempted to replicate, 2 articles tested multiallelic models in NOD2/CARD15 5 and CCR5 Figure 2; supplemental Table 3). Figure 2.…”

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

“…A recent publication from Anthony Nolan showed that the p001 haplotype including the C allele at +29 position, so called 'high producers' patients, had a significant reduction in OS due to an increase in NRM. 49 Our study has strengths. It is one of the largest cohorts reported in this topic.…”

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

“…For this reason we We had to take into consideration that genetic TGFB1 variants are arranged in well-defined haplotypes: −1347T (rs1800469) allele is linked to +29C (rs1982073, +29T>C; L10P), and +74G (rs1800471; +74G>C; R25P), forming the second most common TGFB1 haplotype (called p001, frequency: 30%). Serum TGFβ1 levels and surface expression on regulatory T-cells as latency associated peptide are reported generally higher in the presence of −1347T and +29C variants [16,21]. The haplotype known as p003 [−1347C, +29T, +74G] is the most common among Caucasians with a frequency of 54% [16,21].…”

“…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.…”

“…Haplotype p001 correlated with increased transplant-related mortality and reduced overall survival (OS) in a large HSCT cohort transplanted with matched unrelated donors (MUD), if the variant was present in the recipient [16]. This haplotype showed the closest linkage association with −1347C>T variant and homozygous carriers of the −1347T variant displayed increased TGFβ1 transcription and higher plasma levels in healthy individuals [16,21,22]. The aim of our study was to investigate the role of TGFB1 −1347C>T genotypes in context of complications and the outcome of HSCT.…”