Oxidative Stress-related Gene Polymorphisms Research Articles

Genetic Polymorphisms In Oxidative Stress-Related Genes Correlated with Outcome Following Anthracycline-Based Therapy for Aggressive B-Cell Non-Hodgkin Lymphomas

AbstractAbstract 321Gene expression profiling of newly diagnosed diffuse large B-cell lymphomas shows a correlation between the expression of oxidative stress-related genes and patient prognosis following chemotherapy. Anthracyclines and cyclophosphamide used in lymphoma therapy are known to work, at least in part, through oxidative stress. We hypothesized that single nucleotide polymorphisms (SNPs) in oxidative stress-related genes may contribute to clinical outcomes and/or the development of hematologic toxicities for patients treated with curative intent anthracycline-based therapies for aggressive B-cell Non-Hodgkin lymphomas. Our study involved 473 patients enrolled in 7 prior Phase II or Phase III Southwest Oncology Group clinical trials. DNA for the SNP analyses was obtained from banked, paraffin-embedded diagnostic tissue. Genotyping was performed for 72 SNPs in 33 oxidative stress-related genes. After excluding pathologically or clinically ineligible patients and those with SNP call rates <85%, 345 patients were included in the analysis. All analyses were stratified on clinical trial and adjusted by IPI score. We found polymorphic alleles in aldo-keto reductase family 1 member C3 (AKR1C3), inducible nitric oxide synthase (NOS2) and myeloperoxidase (MPO) were associated with patient outcomes (see table below). AKR1C3 is a member of a superfamily of oxidoreductases. The diverse reactions catalyzed by these enzymes include the conversion of steroid hormones (e.g., glucocorticoids) to more potent forms and the repair of oxidative damage to proteins and lipids. The AKR1C3 SNP rs10508293, located in intron 4 of the gene, is of unknown functional significance. NOS2 produces nitric oxide, which is an important signaling molecule. However, nitric oxide can also increase oxidative stress by reacting with superoxide to produce the potent oxidant, peroxynitrite. The NOS2 polymorphism rs1060826 relevant to this study is located in exon 22. It does not change the amino acid sequence in the protein. MPO is found in neutrophils and macrophages where it produces hypochlorous acid. This enzyme can also activate xenobiotics and its products can cause protein oxidation. For our analysis of the MPO gene, we chose the -764A/G SNP (rs2243828) as a proxy for the -463G/A SNP (rs2333227). The latter polymorphism affects the transcription rate of the gene. Importantly, it has been linked to survival rates for breast cancer patients treated with cyclophosphamide. The -764A/G SNP was used due to technical difficulty genotyping the -463G/A SNP. There is 100% genotype concordance between these two SNPs. We found that patients with at least 1 copy of the AKR1C3 T allele had better overall and progression-free survival than those with the CC genotype. We also found that patients who were homozygous for the NOS2 G allele had better overall and progression-free survival than those with the AA genotype. In complete agreement with the study of breast cancer patients, the MPO GG genotype was associated with worse overall and progression-free survival, as compared to the AA genotype. Our additional tests for polymorphisms associated with hematologic toxicity identified the -212A/G SNP (rs1883112) in NCF4. This gene encodes p40-phox, a regulatory subunit of NAD(P)H oxidase. The NCF4 GG genotype has previously been linked to a two-fold reduction in the risk of anthracycline-induced cardiotoxicity among Non-Hodgkin lymphoma patients. We now report a similar reduction in hematologic toxicity for patients homozygous for the G allele, as compared to those with the AA genotype (hazard ratio, 0.48; 95% confidence interval, 0.19–0.95; unadjusted P = 0.038). This is the first report linking polymorphisms in AKR1C3, NOS2, MPO and NCF4 with outcome in aggressive lymphomas. Further work is needed to elucidate the mechanism(s) by which the SNP genotypes would influence treatment outcome. Disclosures:No relevant conflicts of interest to declare.

Synergistic effect of two oxidative stress‐related genes (heme oxygenase‐1 and GSK3β) on the risk of Parkinson’s disease

Oxidative stress is a central factor in the pathogenesis of Parkinson's disease (PD). Heme oxygenase-1 (HO-1) is an antioxidant protein expressed in response to oxidative challenge, and its expression levels are inversely correlated with glycogen synthase kinase-3beta (GSK3beta) activity. Underexpression of HO-1 in concert with an upregulation of GSK3beta would result in a less effective antioxidant response and might increase the risk of PD. We examined two functional polymorphism in the promoter regions of HO-1 (-413, rs2071746) and GSK3beta (-157, rs6438552) in a group of 251 Spanish patients with PD and 234 controls. Subjects carrying both the HO-1 (-413, rs2071746) TT genotype and the GSK3beta (-157, rs6438552) TT genotype had a four times higher risk of developing PD than subjects without these genotypes (adjusted by age and sex OR = 4.12; 95% CI = 1.45-11.71; Bonferroni corrected P = 0.024). Considering synergistic effects between polymorphisms in oxidative stress-related genes may help in determining the risk profile for PD.

Combined effect of oxidative stress-related gene polymorphisms on atherosclerosis

It is well known that oxidative stress plays critical roles in the pathogenesis of atherosclerosis. In this study, we enrolled 1746 type 2 diabetic subjects, determined 4 common genetic variants related to oxidative stress ( glutamate-cysteine ligase modifier subunit (GCLM) C-588T, myeloperoxidase G-463A, human paraoxonase 1 Gln192Arg and NAD(P)H oxidase p22phox C242T polymorphisms), and measured carotid intima-media thickness (IMT) as a surrogate marker for atherosclerosis. GCLM C-588T polymorphism was associated with average IMT (AveIMT) ( r = 0.090, p = 0.0008), but the association between the other 3 polymorphisms and AveIMT did not reach the statistical significance. However, AveIMT was significantly greater as the total number of 4 concomitant “pro-oxidant alleles” in each subject was increased ( r = 0.108, p < 0.0001). Furthermore, the number of “pro-oxidant alleles” was a risk factor for a high AveIMT independently of conventional risk factors ( p = 0.0003). In conclusion, accumulation of oxidative stress-associated alleles was associated with carotid atherosclerosis in type 2 diabetic patients.

Gene-Diet Interaction on Cancer Risk in Epidemiological Studies

Genetic factors clearly play a role in carcinogenesis, but migrant studies provide unequivocal evidence that environmental factors are critical in defining cancer risk. Therefore, one may expect that the lower availability of substrate for biochemical reactions leads to more genetic changes in enzyme function; for example, most studies have indicated the variant MTHFR genotype 677TT is related to biomarkers, such as homocysteine concentrations or global DNA methylation particularly in a low folate diet. The modification of a phenotype related to a genotype, particularly by dietary habits, could support the notion that some of inconsistencies in findings from molecular epidemiologic studies could be due to differences in the populations studied and unaccounted underlying characteristics mediating the relationship between genetic polymorphisms and the actual phenotypes. Given the evidence that diet can modify cancer risk, gene-diet interactions in cancer etiology would be anticipated. However, much of the evidence in this area comes from observational epidemiology, which limits the causal inference. Thus, the investigation of these interactions is essential to gain a full understanding of the impact of genetic variation on health outcomes. This report reviews current approaches to gene-diet interactions in epidemiological studies. Characteristics of gene and dietary factors are divided into four categories: one carbon metabolism-related gene polymorphisms and dietary factors including folate, vitamin B group and methionines; oxidative stress-related gene polymorphisms and antioxidant nutrients including vegetable and fruit intake; carcinogen-metabolizing gene polymorphisms and meat intake including heterocyclic amins and polycyclic aromatic hydrocarbon; and other gene-diet interactive effect on cancer.

Oxidative stress, telomere length and biomarkers of physical aging in a cohort aged 79 years from the 1932 Scottish Mental Survey

Telomere shortening is a biomarker of cellular senescence and is associated with a wide range of age-related disease. Oxidative stress is also associated with physiological aging and several age-related diseases. Non-human studies suggest that variants in oxidative stress genes may contribute to both telomere shortening and biological aging. We sought to test whether oxidative stress-related gene polymorphisms contribute to variance in both telomere length and physical biomarkers of aging in humans. Telomere lengths were calculated for 190 (82 men, 108 women) participants aged 79 years and associations with 384 SNPs, from 141 oxidative stress genes, identified 9 significant SNPS, of which those from 5 genes ( GSTZ1, MSRA, NDUFA3, NDUFA8, VIM) had robust associations with physical aging biomarkers, respiratory function or grip strength. Replication of associations in a sample of 318 (120 males, 198 females) participants aged 50 years confirmed significant associations for two of the five SNPs ( MSRA rs4841322, p = 0.008; NDUFA8 rs6822, p = 0.048) on telomere length. These data indicate that oxidative stress genes may be involved in pathways that lead to both telomere shortening and physiological aging in humans. Oxidative stress may explain, at least in part, associations between telomere shortening and physiological aging.

Oxidative stress-related gene polymorphisms and susceptibility to Barrett's esophagus

Oxidative stress-related gene polymorphisms and susceptibility to Barrett's esophagus