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

Authors :
Hao Dai
Sivaramakrishna P. Rachakonda
Olaf Penack
Igor W. Blau
Olga Blau
Aleksandar Radujkovic
Carsten Müller-Tidow
Peter Dreger
Rajiv Kumar
Thomas Luft
Source :
Blood Cancer Journal, Vol 11, Iss 2, Pp 1-12 (2021)
Publication Year :
2021
Publisher :
Nature Publishing Group, 2021.

Abstract

Abstract 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

Details

Language :
English
ISSN :
20445385
Volume :
11
Issue :
2
Database :
Directory of Open Access Journals
Journal :
Blood Cancer Journal
Publication Type :
Academic Journal
Accession number :
edsdoj.971e0d0bb95d481495b6e90192e86eeb
Document Type :
article
Full Text :
https://doi.org/10.1038/s41408-021-00434-2