Vitamin D Modifies the Incidence of Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation Depending on the Vitamin D Receptor (VDR) Polymorphisms

Carrillo‐Cruz, Estrella; García-Lozano, José R.; Márquez-Malaver, Francisco J.; Sánchez‐Guijo, Fermín; Cuadrado, Isabel Montero; Coll, Christelle Ferra i; Valcárcel, David; López‐Godino, Oriana; Cuesta, Marian; Parody, Rocío; López-Corral, Lucía; Alcoceba, Miguel; Caballero‐Velázquez, Teresa; Rodríguez-Gil, Alfonso; Bejarano-García, José A.; Ramos, Teresa Lopes; Pérez‐Simón, José A.

doi:10.1158/1078-0432.ccr-18-3875

Cited by 10 publications

(17 citation statements)

References 30 publications

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“…In an HSCT setting, vitamin D deficiency is considered a common complaint that may affect the treatment outcome (62). Genetic polymorphisms of the VDR have been shown to alter the immunomodulatory effect of vitamin D (63). Consistent with these observations, our results suggest a role for VDR in aGvHD-pathogenesis and present 24 VDR-associated biological processes.…”

Section: Discussionsupporting

confidence: 86%

Meta-Analysis of Genome-Wide Association and Gene Expression Studies Implicates Donor T Cell Function and Cytokine Pathways in Acute GvHD

et al. 2020

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Graft-vs.-host disease (GvHD) is a major complication after allogeneic hematopoietic stem cell transplantation that causes mortality and severe morbidity. Genetic disparities in human leukocyte antigens between the recipient and donor are known contributors to the risk of the disease. However, the overall impact of genetic component is complex, and consistent findings across different populations and studies remain sparse. To gain a comprehensive understanding of the genes responsible for GvHD, we combined genome-wide association studies (GWAS) from two distinct populations with previously published gene expression studies on GvHD in a single gene-level meta-analysis. We hypothesized that genes driving GvHD should be associated in both data modalities and therefore could be detected more readily through their combined effects in the integrated analysis rather than in separate analyses. The meta-analysis yielded a total of 51 acute GvHD-associated genes (false detection rate [FDR] <0.1). In support of our hypothesis, this number was significantly higher than that in a permutation meta-analysis involving the whole data set, as well as in separate meta-analyses on the GWAS and gene expression data sets. The genes indicated by the meta-analysis were significantly enriched in 277 Gene Ontology terms (FDR < 0.05), such as T cell function and cytokine-mediated signaling pathways, and the results highlighted several established immune mediators, such as interleukins and JAK-STAT signaling, and presented TRAF6 and TERT as potential effector candidates. Altogether, the results support the chosen methodological approach, implicate a role of gene-level variation in donors' key immunological regulators predisposing patients to acute GVHD, and present potential targets for therapeutic intervention.

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Section: Discussionsupporting

confidence: 86%

Meta-Analysis of Genome-Wide Association and Gene Expression Studies Implicates Donor T Cell Function and Cytokine Pathways in Acute GvHD

et al. 2020

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“…Further evidence for a causal link is provided by the fact that vitamin D receptor (VDR) gene polymorphisms are associated with development of aGvHD in humans [11]. In line, a recent study reported a decreased incidence of cGvHD upon vitamin D supplementation of patients with a certain VDR genotype [12]. Interestingly, VDR gene polymorphisms have also been characterized as risk factors for graft rejection after liver Tx [36].…”

Section: Discussionmentioning

confidence: 98%

“…A number of reports has described insufficiency for 25-hydroxyvitamin-D3 in patients undergoing allogeneic HSCT [2,5,6,19]. As a consequence, we and others used different approaches to increase vitamin D levels in patients undergoing HSCT [7,12,[20][21][22]. At present, the role of 25-hydroxyvitamin-D3 for survival after HSCT has been examined in eight studies [3-5, 7, 18, 23-25].…”

Section: Discussionmentioning

confidence: 99%

“…In humans, polymorphisms of the vitamin D receptor, mediating the biological activity of 1,25-dihydroxyvitamin-D3, were shown to correlate with survival and aGvHD in HLAmatched sibling allogeneic HSCT [11]. Recently, Carrillo-Cruz et al reported a reduced incidence of cGvHD in response to vitamin D supplementation of patients with a certain VDR genotype [12].…”

Section: Introductionmentioning

confidence: 99%

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1,25-dihydroxyvitamin-D3 but not the clinically applied marker 25-hydroxyvitamin-D3 predicts survival after stem cell transplantation

Peter

Siska

Roider

et al. 2020

Bone Marrow Transplant

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The serum level of 25-hydroxyvitamin-D3 is accepted as marker for a person’s vitamin D status but its role for the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) is controversially discussed. The impact of 1,25-dihydroxyvitamin-D3 on HSCT outcome, however, has never been studied. In a discovery cohort of 143 HSCT patients we repeatedly (day −16 to 100) measured 1,25-dihydroxyvitamin-D3 and in comparison the well-established marker for serum vitamin D status 25-hydroxyvitamin-D3. Only lower 1,25-dihydroxyvitamin-D3 levels around HSCT (day −2 to 7, peritransplant) were significantly associated with higher 1-year treatment-related mortality (TRM) risk (Mann–Whitney U test, P = 0.001). This was confirmed by Cox-model regression without and with adjustment for baseline risk factors and severe acute Graft-versus-Host disease (aGvHD; unadjusted P = 0.001, adjusted P = 0.005). The optimal threshold for 1,25-dihydroxyvitamin-D3 to identify patients at high risk was 139.5 pM. Also in three replication cohorts consisting of altogether 365 patients 1,25-dihydroxyvitamin-D3 levels below 139.5 pM had a 3.3-fold increased risk of TRM independent of severe aGvHD compared to patients above 139.5 pM (Cox-model unadjusted P < 0.0005, adjusted P = 0.001). Our data highlight peritransplant 1,25-dihydroxyvitamin-D3 levels but not the commonly monitored 25-hydroxyvitamin-D3 levels as potent predictor of 1-year TRM and suggest to monitor both vitamin D metabolites in HSCT patients.

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“…The association of VDR gene polymorphisms with major clinical outcomes following HSCT has been investigated in different studies with inconclusive results (116,143,(146)(147)(148)(149)(150). Therefore, further research in this field is warranted with larger study samples, including more recipients of different donor types (unrelated, haploidentical).…”

Section: Vdr As Biomarker In Hsctmentioning

confidence: 99%

Insights Into the Role of Vitamin D as a Biomarker in Stem Cell Transplantation

et al. 2020

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Vitamin D was discovered 100 years ago and since then multiple studies have consistently proved its effect on bone health and mineral metabolism. Further research has also explored its so-called "non-classical" biological effects, encompassing immune regulation and control of cell proliferation and differentiation. Vitamin D downregulates pro-inflammatory immune cells and subsequently their cytokine production, while enhancing the anti-inflammatory subsets, thus mediating inflammation and fostering a more tolerogenic environment. Its biological action is exerted through the vitamin D receptor, a nuclear receptor that mediates gene transcription and is expressed in most cells from the innate and adaptive immunity. Owing to its immune-modulatory properties, its role in cancer pathophysiology, hematology disorders and stem cell transplantation has also been investigated. Vitamin D deficiency causes immune imbalance and cytokine dysregulation, contributing to some autoimmune diseases. In the hematopoietic stem cell transplant setting this could lead to complications such as acute and chronic graft-versus-host disease, ultimately impacting transplant outcomes. Other factors have also been linked to this, including specific polymorphisms of the vitamin D receptor in both stem cell donors and recipients. Nevertheless, studies thus far have shown conflicting results and the use of vitamin D or its receptor as biomarkers has not been validated yet, therefore there are no evidence-based consensus guidelines to guide clinicians in their day-today practice. To gain more insight in this topic, we have reviewed the existent literature and gathered the current evidence. This is an overview of the role of serum vitamin D and its receptor as biomarkers for clinical outcomes in patients undergoing hematopoietic stem cell transplantation. Further prospective studies with larger cohorts are warranted to validate the viability of using serum vitamin D, and its receptor, as biomarkers in potential stem cell donors and patients, to identify those at risk of post-transplant complications and enable early therapeutic interventions.

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Vitamin D Modifies the Incidence of Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation Depending on the Vitamin D Receptor (VDR) Polymorphisms

Cited by 10 publications

References 30 publications

Meta-Analysis of Genome-Wide Association and Gene Expression Studies Implicates Donor T Cell Function and Cytokine Pathways in Acute GvHD

Meta-Analysis of Genome-Wide Association and Gene Expression Studies Implicates Donor T Cell Function and Cytokine Pathways in Acute GvHD

1,25-dihydroxyvitamin-D3 but not the clinically applied marker 25-hydroxyvitamin-D3 predicts survival after stem cell transplantation

Insights Into the Role of Vitamin D as a Biomarker in Stem Cell Transplantation

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