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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...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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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. |
format | Online Article Text |
id | pubmed-7914250 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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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