Prediction of Graft-Versus-Host Disease in Humans by Donor Gene-Expression Profiling

Baron, Chantal; Somogyi, Roland; Greller, Larry D.; Rineau, Vincent; Wilkinson, Peter; Cho, Carolyn R.; Cameron, Mark J.; Kelvin, David J.; Chagnon, Pierre; Roy, Denis‐Claude; Busque, Lambert; Sékaly, Rafick‐Pierre; Perreault, Claude

doi:10.1371/journal.pmed.0040023

Cited by 93 publications

(90 citation statements)

References 82 publications

(70 reference statements)

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“…Likewise, although not statistically significant, the probability of death due to hepatic veno-occlusive disease/thrombotic thrombocytopenic purpura was also increased, coinciding with previous findings of an association between veno-occlusive disease and TGF-β1 secretion. 34 In agreement with a study by Baron et al, who demonstrated that the donor gene-expression profile, in particular the TGF-β1 pathway, has a dominant influence on the development of GvHD, 35 we also found that the presence of the SNP at codon 10 in donors, as well as in patientdonor pairs, was associated with a higher incidence of acute GvHD and its clinically significant forms. This agrees with observations by Hattori et al, 25 who found that the wild-type donor genotype (TT) was protective for acute GvHD in an HLA-identical sibling donor pediatric cohort.…”

Section: Ii-iv (%) Iii-iv (%)supporting

confidence: 92%

Association of functional polymorphisms of the transforming growth factor B1 gene with survival and graft-versus-host disease after unrelated donor hematopoietic stem cell transplantation

Berro¹,

Mayor²,

Maldonado-Torres³

et al. 2009

Haematologica

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BackgroundMany genetic factors play major roles in the outcome of hematopoietic stem cell transplants from unrelated donors. Transforming growth factor β1 is a member of a highly pleiotrophic family of growth factors involved in the regulation of numerous immunomodulatory processes. Design and MethodsWe investigated the impact of single nucleotide polymorphisms at codons 10 and 25 of TGFB1, the gene encoding for transforming growth factor β1, on outcomes in 427 myeloablative-conditioned transplanted patients. In addition, transforming growth factor β1 plasma levels were measured in 263 patients and 327 donors. ResultsPatients homozygous for the single nucleotide polymorphism at codon 10 had increased non-relapse mortality (at 3 years: 46.8% versus 29.4%, P=0.014) and reduced overall survival (at 5 years 29.3% versus 42.2%, P=0.013); the differences remained statistically significant in multivariate analysis. Donor genotype alone had no impact, although multiple single nucleotide polymorphisms within the pair were significantly associated with higher non-relapse mortality (at 3 years: 44% versus 29%, P=0.021) and decreased overall survival (at 5 years: 33.8% versus 41.9%, P=0.033). In the 10/10 HLA matched transplants (n=280), recipients of non-wild type grafts tended to have a higher incidence of acute graft-versus-host disease grades II-IV (P=0.052). In multivariate analysis, when analyzed with patients' genotype, the incidences of both overall and grades II-IV acute graft-versushost disease were increased (P=0.025 and P=0.009, respectively) in non-wild-type pairs. ConclusionsWe conclude that increasing numbers of single nucleotide polymorphisms in codon 10 of TGFB1 in patients and donors are associated with a worse outcome following hematopoietic stem cell transplantation from unrelated donors.Key words: stem cell transplantation, TGF-β1, polymorphisms, survival, graft-versus-host disease.Citation: Berro M, Mayor NP, Maldonado-Torres H, Cooke L, Kusminsky G, Marsh SGE, Madrigal JA, and Shaw BE. Association of functional polymorphisms of the transforming growth factor B1 gene with survival and graft-versus-host disease after unrelated donor hematopoietic stem cell transplantation. Haematologica. 2010; 95:276-283. doi:10.3324/haematol.2009 This is an open-access paper.Association of functional polymorphisms of the transforming growth factor B1 gene with survival and graft-versus-host disease after unrelated donor hematopoietic stem cell transplantation

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Section: Ii-iv (%) Iii-iv (%)supporting

confidence: 92%

Association of functional polymorphisms of the transforming growth factor B1 gene with survival and graft-versus-host disease after unrelated donor hematopoietic stem cell transplantation

Berro¹,

Mayor²,

Maldonado-Torres³

et al. 2009

Haematologica

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“…We found that pre-AHCT gene-expression profiling segregates donors whose recipient suffered from GVHD or not. 19 The 'dangerous donor' trait (GVHD þ recipient) is under polygenic control and is shaped by the activity of genes that regulate TGF-b signaling and cell proliferation. The gene with the best GVHD predictive accuracy in our studies was SMAD3.…”

Section: Introductionmentioning

confidence: 99%

“…The gene with the best GVHD predictive accuracy in our studies was SMAD3. 19 No AHCT recipients suffered from GVHD when their donor cells expressed high levels of SMAD3 transcripts. 19 These data demonstrate that interindividual variations exist in the levels of SMAD3 transcripts.…”

Section: Introductionmentioning

confidence: 99%

“…19 No AHCT recipients suffered from GVHD when their donor cells expressed high levels of SMAD3 transcripts. 19 These data demonstrate that interindividual variations exist in the levels of SMAD3 transcripts. Moreover, they suggest that, in accordance with its key role in self-tolerance, SMAD3 regulates the development of graft-host tolerance following AHCT.…”

Section: Introductionmentioning

confidence: 99%

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Differential expression of SMAD3 transcripts is not regulated by cis-acting genetic elements but has a gender specificity

et al. 2009

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As a key component of the transforming growth factor-b (TGF-b) pathway, SMAD3 plays an essential role in development and maintenance of self-tolerance. Furthermore, a recent study based on gene-expression profiling in donors of allogeneic hematopoietic cell grafts revealed that the level of expression of several components of the TGF-b pathway can predict the occurrence of graft-versus-host disease (GVHD) in recipients. The gene with the best GVHD predictive accuracy was SMAD3: no recipients suffered from GVHD when their donor cells expressed high levels of SMAD3 transcripts. The present study had two specific aims: to validate differential expression of SMAD3 transcripts in an independent and larger cohort of subjects and to determine whether interindividual differences were dictated by cis-acting genetic elements. In a cohort of 397 subjects, we found that SMAD3 transcript levels varied over a sixfold range. Analyses of SMAD3 single nucleotide polymorphisms and of SMAD3 promoter methylation patterns provide compelling evidence that interindividual differences in SMAD3 transcript levels do not result from in-cis genetic variations. Of note, part of the variance in SMAD3 expression was gender related as women expressed lower levels of SMAD3 transcripts than men.

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“…In addition to identifying signatures or patterns of gene expression that represent a disease state, analyses can be constructed to identify representative pathway genes that might point to novel pathophysiology relevant to the underlying disease state. Peripheral blood gene expression signatures have now been reported in a variety of conditions including rheumatoid arthritis (Lequerré et al 2006;Shou et al 2006), systemic lupus erythematosis (Rus et al 2004), multiple sclerosis (Bomprezzi et al 2003;Singh et al 2007), asthma (Brutsche et al 2002), solid malignancies (Alizadeh et al 2000;Golub et al 1999;Valk et al 2004), solid organ transplantation (Baron et al 2007;Horwitz et al 2004), as well as environmental exposures (Lodovici et al 2007;Wu et al 2003;Dressman et al 2007) (see Table 1). Many of these conditions have an inflammatory component and thus affect immune cells in the vascular compartment.…”

Section: Introductionmentioning

confidence: 99%

Peripheral blood gene expression profiling for cardiovascular disease assessment

Aziz

Zaas

Ginsburg

2007

HUGO J

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Whole blood gene expression profiling has the potential to be informative about dynamic changes in disease states and to provide information on underlying disease mechanisms. Having demonstrated proof of concept in animal models, a number of studies have now tried to tackle the complexity of cardiovascular disease in human hosts to develop better diagnostic and prognostic indicators. These studies show that genomic signatures are capable of classifying patients with cardiovascular diseases into finer categories based on the molecular architecture of a patient's disease and more accurately predict the likelihood of a cardiovascular event than current techniques. To highlight the spectrum of potential applications of whole blood gene expression profiling approach in cardiovascular science, we have chosen to review the findings in a number of complex cardiovascular diseases such as atherosclerosis, hypertension and myocardial infarction as well as thromboembolism, aortic aneurysm, and heart transplant.

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Prediction of Graft-Versus-Host Disease in Humans by Donor Gene-Expression Profiling

Cited by 93 publications

References 82 publications

Association of functional polymorphisms of the transforming growth factor B1 gene with survival and graft-versus-host disease after unrelated donor hematopoietic stem cell transplantation

Association of functional polymorphisms of the transforming growth factor B1 gene with survival and graft-versus-host disease after unrelated donor hematopoietic stem cell transplantation

Differential expression of SMAD3 transcripts is not regulated by cis-acting genetic elements but has a gender specificity

Peripheral blood gene expression profiling for cardiovascular disease assessment

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