Single Nucleotide Polymorphisms in CD40L Predict Endothelial Complications and Mortality After Allogeneic Stem-Cell...

Area of Science:

• Immunogenetics
• Transplantation immunology
• Vascular biology

Background:

• Endothelial vulnerability is a risk factor for complications following allogeneic stem-cell transplantation (alloSCT).
• The CD40/CD40 ligand (CD40L) axis is implicated in inflammatory processes and is upregulated in activated endothelial cells, suggesting a role in alloSCT.
• Genetic variations in the CD40L gene may influence alloSCT outcomes.

Purpose of the Study:

• To investigate the association between single nucleotide polymorphisms (SNPs) in the CD40L gene and alloSCT complications.
• To evaluate the predictive value of CD40L SNPs for transplant-associated thrombotic microangiopathy and nonrelapse mortality (NRM).
• To assess the interaction between CD40L SNPs, thrombomodulin (THBD) gene polymorphisms, and the efficacy of statin-based endothelial prophylaxis (SEP).

Main Methods:

• Analysis of three CD40L SNPs (rs3092920, rs3092952, rs3092936) in 294 alloSCT recipients without SEP.
• Comparison of significant CD40L genotypes with established THBD gene polymorphisms.
• Validation in an independent cohort without SEP and in 344 patients who received SEP.

Main Results:

• The rs3092936 CC/CT genotype in the CD40L gene was associated with increased risk of transplant-associated thrombotic microangiopathy (P = .001), overall NRM (P = .03), and NRM after acute graft-versus-host disease (P = .01).
• Both CD40L and THBD SNPs predicted adverse overall survival (OS) and overall NRM similarly in cohorts without SEP.
• SEP completely abolished the negative impact of high-risk CD40L and THBD SNPs on mortality (P = .40).

Conclusions:

• Recipient genetic markers, specifically CD40L SNPs, can predict an increased risk of endothelial complications before alloSCT.
• The use of SEP normalizes mortality risks in patients with high-risk genotypes, suggesting a potential therapeutic strategy.
• These findings warrant further clinical validation to confirm the predictive and therapeutic implications of genetic screening and SEP in alloSCT.