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Polymorphisms in CXCR3 ligands predict early CXCL9 recovery and severe chronic GVHD

Chronic graft-versus-host disease (cGVHD) is a major cause of mortality and morbidity after allogeneic stem cell transplantation (alloSCT). The individual risk of severe cGVHD remains difficult to predict and may involve CXCR3 ligands. This study investigated the role of single-nucleotide polymorphi...

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Autores principales: Dai, Hao, Rachakonda, Sivaramakrishna P., Penack, Olaf, Blau, Igor W., Blau, Olga, Radujkovic, Aleksandar, Müller-Tidow, Carsten, Dreger, Peter, Kumar, Rajiv, Luft, Thomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914250/
https://www.ncbi.nlm.nih.gov/pubmed/33640906
http://dx.doi.org/10.1038/s41408-021-00434-2
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author Dai, Hao
Rachakonda, Sivaramakrishna P.
Penack, Olaf
Blau, Igor W.
Blau, Olga
Radujkovic, Aleksandar
Müller-Tidow, Carsten
Dreger, Peter
Kumar, Rajiv
Luft, Thomas
author_facet Dai, Hao
Rachakonda, Sivaramakrishna P.
Penack, Olaf
Blau, Igor W.
Blau, Olga
Radujkovic, Aleksandar
Müller-Tidow, Carsten
Dreger, Peter
Kumar, Rajiv
Luft, Thomas
author_sort Dai, Hao
collection PubMed
description Chronic graft-versus-host disease (cGVHD) is a major cause of mortality and morbidity after allogeneic stem cell transplantation (alloSCT). The individual risk of severe cGVHD remains difficult to predict and may involve CXCR3 ligands. This study investigated the role of single-nucleotide polymorphisms (SNPs) of CXCL4, CXCL9, CXCL10, and CXCL11, and their day +28 serum levels, in cGVHD pathogenesis. Eighteen CXCR3 and CXCL4, CXCL9–11 SNPs as well as peri-transplant CXCL9–11 serum levels were analyzed in 688 patients without (training cohort; n = 287) or with statin-based endothelial protection cohort (n = 401). Clinical outcomes were correlated to serum levels and SNP status. Significant polymorphisms were further analyzed by luciferase reporter assays. Findings were validated in an independent cohort (n = 202). A combined genetic risk comprising four CXCR3 ligand SNPs was significantly associated with increased risk of severe cGVHD in both training cohort (hazard ratio (HR) 2.48, 95% confidence interval (CI) 1.33–4.64, P = 0.004) and validation cohort (HR 2.95, 95% CI 1.56–5.58, P = 0.001). In reporter assays, significantly reduced suppressive effects of calcineurin inhibitors in constructs with variant alleles of rs884304 (P < 0.001) and rs884004 (P < 0.001) were observed. CXCL9 serum levels at day +28 after alloSCT correlated with both genetic risk and risk of severe cGVHD (HR 1.38, 95% CI 1.10–1.73, P = 0.006). This study identifies patients with high genetic risk to develop severe cGVHD.
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spelling pubmed-79142502021-03-04 Polymorphisms in CXCR3 ligands predict early CXCL9 recovery and severe chronic GVHD Dai, Hao Rachakonda, Sivaramakrishna P. Penack, Olaf Blau, Igor W. Blau, Olga Radujkovic, Aleksandar Müller-Tidow, Carsten Dreger, Peter Kumar, Rajiv Luft, Thomas Blood Cancer J Article Chronic graft-versus-host disease (cGVHD) is a major cause of mortality and morbidity after allogeneic stem cell transplantation (alloSCT). The individual risk of severe cGVHD remains difficult to predict and may involve CXCR3 ligands. This study investigated the role of single-nucleotide polymorphisms (SNPs) of CXCL4, CXCL9, CXCL10, and CXCL11, and their day +28 serum levels, in cGVHD pathogenesis. Eighteen CXCR3 and CXCL4, CXCL9–11 SNPs as well as peri-transplant CXCL9–11 serum levels were analyzed in 688 patients without (training cohort; n = 287) or with statin-based endothelial protection cohort (n = 401). Clinical outcomes were correlated to serum levels and SNP status. Significant polymorphisms were further analyzed by luciferase reporter assays. Findings were validated in an independent cohort (n = 202). A combined genetic risk comprising four CXCR3 ligand SNPs was significantly associated with increased risk of severe cGVHD in both training cohort (hazard ratio (HR) 2.48, 95% confidence interval (CI) 1.33–4.64, P = 0.004) and validation cohort (HR 2.95, 95% CI 1.56–5.58, P = 0.001). In reporter assays, significantly reduced suppressive effects of calcineurin inhibitors in constructs with variant alleles of rs884304 (P < 0.001) and rs884004 (P < 0.001) were observed. CXCL9 serum levels at day +28 after alloSCT correlated with both genetic risk and risk of severe cGVHD (HR 1.38, 95% CI 1.10–1.73, P = 0.006). This study identifies patients with high genetic risk to develop severe cGVHD. Nature Publishing Group UK 2021-02-27 /pmc/articles/PMC7914250/ /pubmed/33640906 http://dx.doi.org/10.1038/s41408-021-00434-2 Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Dai, Hao
Rachakonda, Sivaramakrishna P.
Penack, Olaf
Blau, Igor W.
Blau, Olga
Radujkovic, Aleksandar
Müller-Tidow, Carsten
Dreger, Peter
Kumar, Rajiv
Luft, Thomas
Polymorphisms in CXCR3 ligands predict early CXCL9 recovery and severe chronic GVHD
title Polymorphisms in CXCR3 ligands predict early CXCL9 recovery and severe chronic GVHD
title_full Polymorphisms in CXCR3 ligands predict early CXCL9 recovery and severe chronic GVHD
title_fullStr Polymorphisms in CXCR3 ligands predict early CXCL9 recovery and severe chronic GVHD
title_full_unstemmed Polymorphisms in CXCR3 ligands predict early CXCL9 recovery and severe chronic GVHD
title_short Polymorphisms in CXCR3 ligands predict early CXCL9 recovery and severe chronic GVHD
title_sort polymorphisms in cxcr3 ligands predict early cxcl9 recovery and severe chronic gvhd
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914250/
https://www.ncbi.nlm.nih.gov/pubmed/33640906
http://dx.doi.org/10.1038/s41408-021-00434-2
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