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

Area of Science:

• Immunology
• Transplantation Medicine
• Genetics

Background:

• Chronic graft-versus-host disease (cGVHD) is a significant complication following allogeneic stem cell transplantation (alloSCT), leading to substantial mortality and morbidity.
• Predicting individual risk for severe cGVHD remains challenging, with potential involvement of CXCR3 ligands.

Purpose of the Study:

• To investigate the role of single-nucleotide polymorphisms (SNPs) in CXCL4, CXCL9, CXCL10, and CXCL11, and their serum levels, in the pathogenesis of cGVHD.
• To identify genetic markers and biomarkers that can predict the risk of developing severe cGVHD.

Main Methods:

• Analysis of 18 CXCR3 and CXCL4, CXCL9-11 SNPs and peri-transplant CXCL9-11 serum levels in 688 patients undergoing alloSCT.
• Correlation of clinical outcomes with serum levels and SNP status, including luciferase reporter assays for functional validation.
• Validation of findings in an independent patient cohort.

Main Results:

• A combined genetic risk score from four CXCR3 ligand SNPs was significantly associated with an increased risk of severe cGVHD in both training and validation cohorts.
• Variant alleles in rs884304 and rs884004 showed reduced suppressive effects of calcineurin inhibitors in reporter assays.
• Elevated CXCL9 serum levels at day +28 post-alloSCT correlated with both genetic risk and the risk of severe cGVHD.

Conclusions:

• This study identifies a significant genetic predisposition to severe cGVHD based on specific CXCR3 ligand SNPs.
• CXCL9 serum levels serve as a potential biomarker for predicting cGVHD risk.
• These findings enable the identification of high-risk patients for severe cGVHD.