Polymorphisms in the base excision repair pathway and graft-versus-host disease

Abstract

Graft-versus-host disease (GVHD) is a frequent complication after hematopoietic cell transplant (HCT). Tissue damage as a result of chemo-radiation injury is the initiating event in the pathogenesis of acute GVHD. Variations in DNA repair can influence the amount of tissue damage in response to alkylating agents and ionizing radiation used as conditioning during HCT. Since DNA damage caused by these agents is repaired by the Base Excision Repair (BER) pathway, we hypothesized that single nucleotide polymorphisms (SNPs) in BER pathway will be associated with GVHD after HCT. Hence, we analyzed 179 SNPs in BER pathway in 470 recipients of allogeneic HCT for association with acute and chronic GVHD. In multivariate analysis, one SNP (rs6844176) in RFC1 gene was independently associated with a higher risk of grade II-IV acute GVHD (RR:1.39, 95% CI:1.14-1.70, p=0.001), and showed a trend towards higher risk of grade III-IV acute GVHD (RR:1.33, 95% CI:0.95-1.85, p=0.09). One SNP in PARP1 gene (rs1805410) was associated with a higher risk of chronic GVHD (RR:1.81, 95% CI:1.29-2.54, p=0.001). These results show that SNPs in the BER pathway can be used as genetic biomarkers to predict those at high risk for GVHD towards whom novel prophylactic strategies could be targeted.