Identification of single nucleotide polymorphisms (SNPs) associated with chronic graft-versus-host disease in patients undergoing allogeneic hematopoietic cell transplantation.

Autor: Mougeot, Jean-Luc C., Beckman, Micaela F., Hovan, Allan J., Hasséus, Bengt, Legert, Karin Garming, Johansson, Jan-Erik, von Bültzingslöwen, Inger, Brennan, Michael T., Bahrani Mougeot, Farah
Zdroj: Supportive Care in Cancer; Oct2023, Vol. 31 Issue 10, p1-15, 15p
Abstrakt: 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. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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