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.

Recent advances in the management of graft-versus-host disease

“…For example, two single-nucleotide polymorphisms in the heparanase gene associated with high recipient heparanase levels correlated with extensive cGvHD53 and polymorphisms in the PARP1 gene have been associated with a higher risk of cGvHD 54…”

Risk model incorporating donor IL6 and IFNG genotype and gastrointestinal GVHD can discriminate patients at high risk of steroid refractory acute GVHD

“…They have been evaluated for association with several diseases including GVHD. [7][8][9][10] Our group has previously shown a risk model using SNPs to predict patients with high risk of developing aGVHD and hence decreased OS. 11 Other studies have also examined SNPs to predict the onset of GVHD, but not their response to steroid therapy or development of SR aGVHD.…”

DNA repair systems

“…The rela onship between carriership of certain allele variants of genes coding for products with roles in BER and the risk of development of various tumours was established around the same me [214]. Later, it was shown that some polymorphic variants of hOGG1 (the human homologue of Ogg1), MUTYH (the mammalian homologue of MutY, A/G-specific adenine DNA glycosylase) and G/T thymidine glycosylase (TDG)may modulate the transplant-related mortality in recipients of allogeneic haematopoie c stem cells [215,216]. It has been already proven, albeit in animal models only, that muta ons in some of the human genes, coding for AP-lyases are associated with mul factorial disease, such as metabolic syndrome [217].…”

“…The carriership of some polymorphic variants of PARP have been found to play a role in the cons tu on of the risk for development of chronic gra -versus-host dis¬ease a er transplanta on of allogeneic haematopoie c stem cells [215,216]. A polymorphism in a processed pseudogene of PARP1, located on chromosome 13 (13q33) was reported to be associated with increased risk for several common cancers [922].…”