Identification of single nucleotide polymorphisms (SNPs) associated with chronic graft-versus-host disease in patients undergoing allogeneic hematopoietic cell transplantation
Related Experiment Video
Updated: Jul 16, 2025
Bone Marrow Transplantation Platform to Investigate the Role of Dendritic Cells in Graft-versus-Host Disease
Published on: March 17, 2020
Jean-Luc C Mougeot1, Micaela F Beckman2, Allan J Hovan3
1Translational Research Laboratories, Department of Oral Medicine/Oral & Maxillofacial Surgery, Atrium Health - Carolinas Medical Center, Charlotte, NC, USA. jean-luc.mougeot@atriumhealth.org.
Insights
Genetic variations in three chromosome 9 genes increase chronic graft-versus-host disease (cGVHD) risk in hematopoietic cell transplant (HCT) patients. These findings may inform new therapeutic strategies targeting STAT3 pathways.
Area of Science:
- Genetics
- Immunology
- Oncology
Background:
- Chronic graft-versus-host disease (cGVHD) is a significant complication following allogeneic hematopoietic cell transplantation (HCT), severely impacting patient quality of life.
- Identifying genetic factors predisposing to cGVHD is crucial for improving patient outcomes and developing targeted therapies.
Purpose of the Study:
- To identify single nucleotide polymorphisms (SNPs) and genes associated with chronic graft-versus-host disease (cGVHD) susceptibility in hematopoietic cell transplantation (HCT) patients.
- To explore the functional implications of identified genetic variants in the context of cGVHD pathogenesis.
Main Methods:
- Whole exome sequencing was performed on saliva samples from 82 HCT patients (16 cGVHD+, 66 cGVHD-).
- Logistic regression and Fisher's exact test were used to identify significant SNPs associated with cGVHD.
- Bioinformatic tools including FUMA (SNP2GENE, GENE2FUNC) and Epilogos were employed for SNP annotation, gene mapping, and functional analysis.
Main Results:
- Logistic regression identified 986 SNPs associated with cGVHD. Analysis revealed three genomic risk loci, four lead SNPs, 48 candidate SNPs, and four mapped genes.
- Fisher's exact test confirmed significant homozygous genotypes for four lead SNPs (p < 0.05).
- Functional analysis implicated KANK1, KDM4C, and PTPRD genes, with lead SNPs associated with these genes.
Conclusions:
- Single nucleotide polymorphisms (SNPs) in three genes on chromosome 9 are associated with genetic susceptibility to cGVHD in HCT recipients.
- These genes appear to modulate STAT3 signaling, a pathway relevant to cancer pathogenesis and targeted by JAK inhibitors in cGVHD treatment.
- The study findings offer potential targets for novel therapeutic interventions aimed at mitigating cGVHD.
Introduction:
Chronic graft-versus-host disease (cGVHD) is a debilitating side effect of allogeneic hematopoietic cell transplantation (HCT), affecting the quality of life of patients. We used whole exome sequencing to identify candidate SNPs and complete a multi-marker gene-level analysis using a cohort of cGVHD( +) (N = 16) and cGVHD( -) (N = 66) HCT patients.
Methods:
Saliva samples were collected from HCT patients (N = 82) pre-conditioning in a multi-center study from March 2011 to May 2018. Exome sequencing was performed and FASTQ files were processed for sequence alignments. Significant SNPs were identified by logistic regression using PLINK2v3.7 and Fisher's exact test. One cGVHD( -) patient sample was excluded from further analysis since no SNP was present in at least 10% of the sample population. The FUMA platform's SNP2GENE was utilized to annotate SNPs and generate a MAGMA output. Chromatin state visualization of lead SNPs was completed using Epilogos tool. FUMA's GENE2FUNC was used to obtain gene function and tissue expression from lead genomic loci.
Results:
Logistic regression classified 986 SNPs associated with cGVHD( +). SNP2GENE returned three genomic risk loci, four lead SNPs, 48 candidate SNPs, seven candidate GWAS tagged SNPs, and four mapped genes. Fisher's exact test identified significant homozygous genotypes of four lead SNPs (p < 0.05). GENE2FUNC analysis of multi-marker SNP sets identified one positional gene set including lead SNPs for KANK1 and KDM4C and two curated gene sets including lead SNPs for PTPRD, KDM4C, and/or KANK1.
Conclusions:
Our data suggest that SNPs in three genes located on chromosome 9 confer genetic susceptibility to cGVHD in HCT patients. These genes modulate STAT3 expression and phosphorylation in cancer pathogenesis. The findings may have implications in the modulation of pathways currently targeted by JAK inhibitors in cGVHD clinical trials.
More Related Videos
11:55Induction of Alloantigen-specific Anergy in Human Peripheral Blood Mononuclear Cells by Alloantigen Stimulation with Co-stimulatory Signal Blockade
Published on: March 14, 2011
06:06Induction and Scoring of Graft-Versus-Host Disease in a Xenogeneic Murine Model and Quantification of Human T Cells in Mouse Tissues using Digital PCR
Published on: May 23, 2019
Related Concept Videos
01:11Genome-wide Association Studies-GWAS
GWAS does not require the identification of the target gene involved in...
01:05Single Nucleotide Polymorphisms-SNPs
01:22Bone Marrow Sampling and Transplants
The transplant begins with high doses of chemotherapy and radiation treatment, which aim to destroy...