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Association between genetic variants in the base excision repair pathway and outcomes after hematopoietic cell transplantations.

ABSTRACT: Alkylating agents with or without ionizing radiation are frequently used in pretransplant conditioning regimens. Damage induced by these agents is commonly repaired by the base excision repair (BER) pathway. Hence, we hypothesized that genetic polymorphisms in the BER pathway will be associated with posthematopoietic cell transplant (HCT) outcomes. We evaluated the association between single nucleotide polymorphisms (SNPs) (n = 179) in the BER pathway with treatment-related mortality (TRM) at 1 year and disease relapse in a cohort of 470 recipients who underwent allogeneic HCT for treatment of hematologic malignancies at the University of Minnesota. After adjustment for age at transplant, donor type, race, and conditioning regimen, 4 SNPs in OGGI, LIG3, and MUTYH genes (rs159153, rs3135974, rs3219463, and rs3219476) were associated with increased risk of TRM, whereas 2 SNPs in the TDG gene (rs167715 and rs2374327) were associated with decreased risk of TRM at 1 year (P or=4 deleterious alleles versus 14% for

SUBMITTER: Thyagarajan B

PROVIDER: S-EPMC2905878 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Association between genetic variants in the base excision repair pathway and outcomes after hematopoietic cell transplantations.

Thyagarajan Bharat B Lindgren Bruce B Basu Saonli S Nagaraj Sriharsha S Gross Myron D MD Weisdorf Daniel J DJ Arora Mukta M

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 20100311 8

Alkylating agents with or without ionizing radiation are frequently used in pretransplant conditioning regimens. Damage induced by these agents is commonly repaired by the base excision repair (BER) pathway. Hence, we hypothesized that genetic polymorphisms in the BER pathway will be associated with posthematopoietic cell transplant (HCT) outcomes. We evaluated the association between single nucleotide polymorphisms (SNPs) (n = 179) in the BER pathway with treatment-related mortality (TRM) at 1 ...[more]

PMID: 20226869

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Project description:BACKGROUND:Previous research indicates increased prostate cancer risk for pesticide applicators and pesticide manufacturing workers. Although underlying mechanisms are unknown, evidence suggests a role of oxidative DNA damage. OBJECTIVES:Because base excision repair (BER) is the predominant pathway involved in repairing oxidative damage, we evaluated interactions between 39 pesticides and 394 tag single-nucleotide polymorphisms (SNPs) for 31 BER genes among 776 prostate cancer cases and 1,444 male controls in a nested case-control study of white Agricultural Health Study (AHS) pesticide applicators. METHODS:We used likelihood ratio tests from logistic regression models to determine p-values for interactions between three-level pesticide exposure variables (none/low/high) and SNPs (assuming a dominant model), and the false discovery rate (FDR) multiple comparison adjustment approach. RESULTS:The interaction between fonofos and rs1983132 in NEIL3 [nei endonuclease VIII-like 3 (Escherichia coli)], which encodes a glycosylase that can initiate BER, was the most significant overall [interaction p-value (pinteract) = 9.3 × 10-6; FDR-adjusted p-value = 0.01]. Fonofos exposure was associated with a monotonic increase in prostate cancer risk among men with CT/TT genotypes for rs1983132 [odds ratios (95% confidence intervals) for low and high use compared with no use were 1.65 (0.91, 3.01) and 3.25 (1.78, 5.92), respectively], whereas fonofos was not associated with prostate cancer risk among men with the CC genotype. Carbofuran and S-ethyl dipropylthiocarbamate (EPTC) interacted similarly with rs1983132; however, these interactions did not meet an FDR < 0.2. CONCLUSIONS:Our significant finding regarding fonofos is consistent with previous AHS findings of increased prostate cancer risk with fonofos exposure among those with a family history of prostate cancer. Although requiring replication, our findings suggest a role of BER genetic variation in pesticide-associated prostate cancer risk.

Project description:Base excision repair (BER) defects and concomitant oxidative DNA damage accumulation play a role in the etiology and progression of late-onset Alzheimer's disease (LOAD). However, it is not known whether genetic variant(s) of specific BER genes contribute to reduced BER activity in LOAD patients and whether they are associated with risk, development and/or progression of LOAD. Therefore, we performed targeted next generation sequencing for three BER genes, uracil glycosylase (UNG), endonuclease VIII-like DNA glycosylase 1 (NEIL1) and polymerase β (POLβ) including promoter, exonic and intronic regions in peripheral blood samples and postmortem brain tissues (temporal cortex, TC and cerebellum, CE) from LOAD patients, high-pathology control and cognitively normal age-matched controls. In addition, the known LOAD risk factor, APOE was included in this study to test whether any BER gene variants associate with APOE variants, particularly APOE ε4. We show that UNG carry five significant variants (rs1610925, rs2268406, rs80001089, rs1018782 and rs1018783) in blood samples of Turkish LOAD patients compared to age-matched controls and one of them (UNG rs80001089) is also significant in TC from Brazilian LOAD patients (p<0.05). The significant variants present only in CE and TC from LOAD are UNG rs2569987 and POLβ rs1012381950, respectively. There is also significant epistatic relationship (p = 0.0410) between UNG rs80001089 and NEIL1 rs7182283 in TC from LOAD subjects. Our results suggest that significant BER gene variants may be associated with the risk of LOAD in non-APOE ε4 carriers. On the other hand, there are no significant UNG, NEIL1 and POLβ variants that could affect their protein level and function, suggesting that there may be other factors such as post-transcriptional or-translational modifications responsible for the reduced activities and protein levels of these genes in LOAD pathogenesis. Further studies with increased sample size are needed to confirm the relationship between BER variants and LOAD risk.

Dataset Information

Association between genetic variants in the base excision repair pathway and outcomes after hematopoietic cell transplantations.

Publications

Association between genetic variants in the base excision repair pathway and outcomes after hematopoietic cell transplantations.

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