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Antioxidant genes, diabetes and dietary antioxidants in association with risk of pancreatic cancer.

ABSTRACT: To test the hypothesis that polymorphic variants of antioxidant genes modify the risk of pancreatic cancer, we examined seven single-nucleotide polymorphisms (SNPs) of genes coding for superoxide dismutase (SOD) 2, glutathione S-transferase alpha 4 (GSTA4), catalase and glutathione peroxidase in 575 patients with pancreatic adenocarcinoma and 648 healthy controls in a case-control study. Information on risk factors was collected by personal interview and dietary information was collected by a self-administered food frequency questionnaire. Genotypes were determined using the Taqman method. Adjusted odds ratio (AOR) and 95% confidence interval (CI) were estimated by unconditional logistic regression. No significant main effect of genotype was observed. A borderline significant interaction between diabetes and SOD2 Ex2+24T>C CT/TT genotype was observed (P(interaction) = 0.051); the AORs (95% CI) were 0.98 (0.73-1.32) for non-diabetics carrying the CT/TT genotype, 1.73 (0.94-3.18) for diabetics carrying the CC genotype and 3.49 (2.22-5.49) for diabetics carrying the CT/TT genotype compared with non-diabetics carrying the CC genotype. Moreover, the SOD2 -1221G>A AA genotype carriers had a significantly increased risk for pancreatic cancer among those with a low dietary vitamin E intake but decreased risk among those with a high vitamin E intake (P(interaction) = 0.002). There was a non-significant interaction between diabetes and GSTA4 Ex5-64G>A genotypes (P(interaction) = 0.078). No significant interaction between genotype with cigarette smoking or vitamin C intake was observed. These data suggest that genetic variations in antioxidant defenses modify the risk of pancreatic cancer in diabetics or individuals with a low dietary vitamin E intake.

SUBMITTER: Tang H

PROVIDER: S-EPMC2847085 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Antioxidant genes, diabetes and dietary antioxidants in association with risk of pancreatic cancer.

Tang Hongwei H Dong Xiaoqun X Day R Sue RS Hassan Manal M MM Li Donghui D

Carcinogenesis 20100122 4

To test the hypothesis that polymorphic variants of antioxidant genes modify the risk of pancreatic cancer, we examined seven single-nucleotide polymorphisms (SNPs) of genes coding for superoxide dismutase (SOD) 2, glutathione S-transferase alpha 4 (GSTA4), catalase and glutathione peroxidase in 575 patients with pancreatic adenocarcinoma and 648 healthy controls in a case-control study. Information on risk factors was collected by personal interview and dietary information was collected by a se ...[more]

PMID: 20097730

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Project description:Importance:Individuals genetically predisposed to pancreatic cancer may benefit from early detection. Genes that predispose to pancreatic cancer and the risks of pancreatic cancer associated with mutations in these genes are not well defined. Objective:To determine whether inherited germline mutations in cancer predisposition genes are associated with increased risks of pancreatic cancer. Design, Setting, and Participants:Case-control analysis to identify pancreatic cancer predisposition genes; longitudinal analysis of patients with pancreatic cancer for prognosis. The study included 3030 adults diagnosed as having pancreatic cancer and enrolled in a Mayo Clinic registry between October 12, 2000, and March 31, 2016, with last follow-up on June 22, 2017. Reference controls were 123?136 individuals with exome sequence data in the public Genome Aggregation Database and 53?105 in the Exome Aggregation Consortium database. Exposures:Individuals were classified based on carrying a deleterious mutation in cancer predisposition genes and having a personal or family history of cancer. Main Outcomes and Measures:Germline mutations in coding regions of 21 cancer predisposition genes were identified by sequencing of products from a custom multiplex polymerase chain reaction-based panel; associations of genes with pancreatic cancer were assessed by comparing frequency of mutations in genes of pancreatic cancer patients with those of reference controls. Results:Comparing 3030 case patients with pancreatic cancer (43.2% female; 95.6% non-Hispanic white; mean age at diagnosis, 65.3 [SD, 10.7] years) with reference controls, significant associations were observed between pancreatic cancer and mutations in CDKN2A (0.3% of cases and 0.02% of controls; odds ratio [OR], 12.33; 95% CI, 5.43-25.61); TP53 (0.2% of cases and 0.02% of controls; OR, 6.70; 95% CI, 2.52-14.95); MLH1 (0.13% of cases and 0.02% of controls; OR, 6.66; 95% CI, 1.94-17.53); BRCA2 (1.9% of cases and 0.3% of controls; OR, 6.20; 95% CI, 4.62-8.17); ATM (2.3% of cases and 0.37% of controls; OR, 5.71; 95% CI, 4.38-7.33); and BRCA1 (0.6% of cases and 0.2% of controls; OR, 2.58; 95% CI, 1.54-4.05). Conclusions and Relevance:In this case-control study, mutations in 6 genes associated with pancreatic cancer were found in 5.5% of all pancreatic cancer patients, including 7.9% of patients with a family history of pancreatic cancer and 5.2% of patients without a family history of pancreatic cancer. Further research is needed for replication in other populations.

Project description:Synopsis Ecologically relevant factors such as exercise and diet quality can directly influence how physiological systems work including those involved in maintaining oxidative balance; however, to our knowledge, no studies to date have focused on how such factors directly affect expression of key components of the endogenous antioxidant system (i.e., transcription factors, select antioxidant genes, and corresponding antioxidant enzymes) in several metabolically active tissues of a migratory songbird. We conducted a three-factor experiment that tested the following hypotheses: (H1) Daily flying over several weeks increases the expression of transcription factors NRF2 and PPARs as well as endogenous antioxidant genes (i.e., CAT, SOD1, SOD2, GPX1, GPX4), and upregulates endogenous antioxidant enzyme activities (i.e., CAT, SOD, GPx). (H2) Songbirds fed diets composed of more 18:2n-6 PUFA are more susceptible to oxidative damage and thus upregulate their endogenous antioxidant system compared with when fed diets with less PUFA. (H3) Songbirds fed dietary anthocyanins gain additional antioxidant protection and thus upregulate their endogenous antioxidant system less compared with songbirds not fed anthocyanins. Flight training increased the expression of 3 of the 6 antioxidant genes and transcription factors measured in the liver, consistent with H1, but for only one gene (SOD2) in the pectoralis. Dietary fat quality had no effect on antioxidant pathways (H2), whereas dietary anthocyanins increased the expression of select antioxidant enzymes in the pectoralis, but not in the liver (H3). These tissue-specific differences in response to flying and dietary antioxidants are likely explained by functional differences between tissues as well as fundamental differences in their turnover rates. The consumption of dietary antioxidants along with regular flying enables birds during migration to stimulate the expression of genes involved in antioxidant protection likely through increasing the transcriptional activity of NRF2 and PPARs, and thereby demonstrates for the first time that these relevant ecological factors affect the regulation of key antioxidant pathways in wild birds. What remains to be demonstrated is how the extent of these ecological factors (i.e., intensity or duration of flight, amounts of dietary antioxidants) influences the regulation of these antioxidant pathways and thus oxidative balance.

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Antioxidant genes, diabetes and dietary antioxidants in association with risk of pancreatic cancer.

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Antioxidant genes, diabetes and dietary antioxidants in association with risk of pancreatic cancer.

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