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

Arora M, Lindgren B, Basu S, Nagaraj S, Gross M, Weisdorf D, Thyagarajan B - Leukemia (2010)

Bottom Line: Tissue damage as a result of chemoradiation injury is the initiating event in the pathogenesis of acute GVHD.In multivariate analysis, one SNP (rs6844176) in RFC1 (replication factor C (activator 1)) gene was independently associated with a higher risk of grade II-IV acute GVHD (relative risk (RR): 1.39, 95% confidence interval (CI): 1.14-1.70, P=0.001), and showed a trend toward 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).

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA. arora005@umn.edu

ABSTRACT
Graft-versus-host disease (GVHD) is a frequent complication after hematopoietic cell transplant (HCT). Tissue damage as a result of chemoradiation 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. As 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 (replication factor C (activator 1)) gene was independently associated with a higher risk of grade II-IV acute GVHD (relative risk (RR): 1.39, 95% confidence interval (CI): 1.14-1.70, P=0.001), and showed a trend toward 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 toward whom novel prophylactic strategies could be targeted.

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Cumulative Incidence of grade II-IV acute GVHD in those with homozygous major, heterozygous or homozygous minor genotype for SNP rs6844176Footnote: Shown are the proportion of patients with grade II-IV acute GVHD across the three categories of SNP rs6844176.
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Figure 2: Cumulative Incidence of grade II-IV acute GVHD in those with homozygous major, heterozygous or homozygous minor genotype for SNP rs6844176Footnote: Shown are the proportion of patients with grade II-IV acute GVHD across the three categories of SNP rs6844176.

Mentions: In multivariate analysis (table 4a), one SNP (rs6844176) remained independently associated with a higher risk of grade II-IV acute GVHD (RR 1.39, 95% CI 1.14-1.70, p=0.001). Other significant variables included donor type, diagnosis and disease status at transplant. The model was also evaluated for interactions between SNP and significant clinical co-variates. A significant interaction was noted between disease status at transplant and the SNP rs6844176. The SNP, rs6844176, was significantly associated with higher risk of grade II-IV acute GVHD in patients with relapse or primary induction failure at transplant (p=0.03), but not in those without relapse or primary induction failure (p=0.15). No other SNP-clinical covariate interactions were observed (all p>0.05). The cumulative incidence of grade II-IV acute GVHD was 47% (95% CI 37-56.9%) in 115 patients with homozygous minor genotype versus 42% (95% CI 34.9-49.1%) in 219 patients with heterozygous genotype versus 32.3% (95% CI 24-40.7%) in 133 patients with homozygous major genotype (p =0.06) (Figure 2).


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

Arora M, Lindgren B, Basu S, Nagaraj S, Gross M, Weisdorf D, Thyagarajan B - Leukemia (2010)

Cumulative Incidence of grade II-IV acute GVHD in those with homozygous major, heterozygous or homozygous minor genotype for SNP rs6844176Footnote: Shown are the proportion of patients with grade II-IV acute GVHD across the three categories of SNP rs6844176.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2921004&req=5

Figure 2: Cumulative Incidence of grade II-IV acute GVHD in those with homozygous major, heterozygous or homozygous minor genotype for SNP rs6844176Footnote: Shown are the proportion of patients with grade II-IV acute GVHD across the three categories of SNP rs6844176.
Mentions: In multivariate analysis (table 4a), one SNP (rs6844176) remained independently associated with a higher risk of grade II-IV acute GVHD (RR 1.39, 95% CI 1.14-1.70, p=0.001). Other significant variables included donor type, diagnosis and disease status at transplant. The model was also evaluated for interactions between SNP and significant clinical co-variates. A significant interaction was noted between disease status at transplant and the SNP rs6844176. The SNP, rs6844176, was significantly associated with higher risk of grade II-IV acute GVHD in patients with relapse or primary induction failure at transplant (p=0.03), but not in those without relapse or primary induction failure (p=0.15). No other SNP-clinical covariate interactions were observed (all p>0.05). The cumulative incidence of grade II-IV acute GVHD was 47% (95% CI 37-56.9%) in 115 patients with homozygous minor genotype versus 42% (95% CI 34.9-49.1%) in 219 patients with heterozygous genotype versus 32.3% (95% CI 24-40.7%) in 133 patients with homozygous major genotype (p =0.06) (Figure 2).

Bottom Line: Tissue damage as a result of chemoradiation injury is the initiating event in the pathogenesis of acute GVHD.In multivariate analysis, one SNP (rs6844176) in RFC1 (replication factor C (activator 1)) gene was independently associated with a higher risk of grade II-IV acute GVHD (relative risk (RR): 1.39, 95% confidence interval (CI): 1.14-1.70, P=0.001), and showed a trend toward 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).

View Article: PubMed Central - PubMed

Affiliation: Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA. arora005@umn.edu

ABSTRACT
Graft-versus-host disease (GVHD) is a frequent complication after hematopoietic cell transplant (HCT). Tissue damage as a result of chemoradiation 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. As 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 (replication factor C (activator 1)) gene was independently associated with a higher risk of grade II-IV acute GVHD (relative risk (RR): 1.39, 95% confidence interval (CI): 1.14-1.70, P=0.001), and showed a trend toward 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 toward whom novel prophylactic strategies could be targeted.

Show MeSH
Related in: MedlinePlus