Dataset Information

A Case-Control Study of the Genetic Variability in Reactive Oxygen Species-Metabolizing Enzymes in Melanoma Risk.

ABSTRACT: Recent studies have shown that ultraviolet (UV)-induced chemiexcitation of melanin fragments leads to DNA damage; and chemiexcitation of melanin fragments requires reactive oxygen species (ROS), as ROS excite an electron in the melanin fragments. In addition, ROS also cause DNA damages on their own. We hypothesized that ROS producing and metabolizing enzymes were major contributors in UV-driven melanomas. In this case-control study of 349 participants, we genotyped 23 prioritized single nucleotide polymorphisms (SNPs) in nicotinamide adenine dinucleotide phosphate (NADPH) oxidases 1 and 4 (NOX1 and NOX4, respectively), CYBA, RAC1, superoxide dismutases (SOD1, SOD2, and SOD3) and catalase (CAT), and analyzed their associated melanoma risk. Five SNPs, namely rs1049255 (CYBA), rs4673 (CYBA), rs10951982 (RAC1), rs8031 (SOD2), and rs2536512 (SOD3), exhibited significant genotypic frequency differences between melanoma cases and healthy controls. In simple logistic regression, RAC1 rs10951982 (odds ratio (OR) 8.98, 95% confidence interval (CI): 5.08 to 16.44; p < 0.001) reached universal significance (p = 0.002) and the minor alleles were associated with increased risk of melanoma. In contrast, minor alleles in SOD2 rs8031 (OR 0.16, 95% CI: 0.06 to 0.39; p < 0.001) and SOD3 rs2536512 (OR 0.08, 95% CI: 0.01 to 0.31; p = 0.001) were associated with reduced risk of melanoma. In multivariate logistic regression, RAC1 rs10951982 (OR 6.15, 95% CI: 2.98 to 13.41; p < 0.001) remained significantly associated with increased risk of melanoma. Our results highlighted the importance of RAC1, SOD2, and SOD3 variants in the risk of melanoma.

SUBMITTER: Yuan TA

PROVIDER: S-EPMC5796190 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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A Case-Control Study of the Genetic Variability in Reactive Oxygen Species-Metabolizing Enzymes in Melanoma Risk.

Yuan Tze-An TA Yourk Vandy V Farhat Ali A Ziogas Argyrios A Meyskens Frank L FL Anton-Culver Hoda H Liu-Smith Feng F

International journal of molecular sciences 20180114 1

Recent studies have shown that ultraviolet (UV)-induced chemiexcitation of melanin fragments leads to DNA damage; and chemiexcitation of melanin fragments requires reactive oxygen species (ROS), as ROS excite an electron in the melanin fragments. In addition, ROS also cause DNA damages on their own. We hypothesized that ROS producing and metabolizing enzymes were major contributors in UV-driven melanomas. In this case-control study of 349 participants, we genotyped 23 prioritized single nucleoti ...[more]

PMID: 29342889

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Project description:Biological production and decay of the reactive oxygen species (ROS) hydrogen peroxide (H2O2) and superoxide (O[Formula: see text]) likely have significant effects on the cycling of trace metals and carbon in marine systems. In this study, extracellular production rates of H2O2 and O[Formula: see text] were determined for five species of marine diatoms in the presence and absence of light. Production of both ROS was measured in parallel by suspending cells on filters and measuring the ROS downstream using chemiluminescence probes. In addition, the ability of these organisms to break down O[Formula: see text] and H2O2 was examined by measuring recovery of O[Formula: see text] and H2O2 added to the influent medium. O[Formula: see text] production rates ranged from undetectable to 7.3 × 10(-16) mol cell(-1) h(-1), while H2O2 production rates ranged from undetectable to 3.4 × 10(-16) mol cell(-1) h(-1). Results suggest that extracellular ROS production occurs through a variety of pathways even amongst organisms of the same genus. Thalassiosira spp. produced more O[Formula: see text] in light than dark, even when the organisms were killed, indicating that O[Formula: see text] is produced via a passive photochemical process on the cell surface. The ratio of H2O2 to O[Formula: see text] production rates was consistent with production of H2O2 solely through dismutation of O[Formula: see text] for T. oceanica, while T. pseudonana made much more H2O2 than O[Formula: see text]. T. weissflogii only produced H2O2 when stressed or killed. P. tricornutum cells did not make cell-associated ROS, but did secrete H2O2-producing substances into the growth medium. In all organisms, recovery rates for killed cultures (94-100% H2O2; 10-80% O[Formula: see text]) were consistently higher than those for live cultures (65-95% H2O2; 10-50% O[Formula: see text]). While recovery rates for killed cultures in H2O2 indicate that nearly all H2O2 was degraded by active cell processes, O[Formula: see text] decay appeared to occur via a combination of active and passive processes. Overall, this study shows that the rates and pathways for ROS production and decay vary greatly among diatom species, even between those that are closely related, and as a function of light conditions.

Project description:BackgroundInterindividual genetic variations contribute to differences in patients' response to drugs as well as to the development of certain disorders. Patients who use non-steroidal anti-inflammatory drugs (NSAIDs) may develop serious gastrointestinal disorders, mainly upper gastrointestinal haemorrhage (UGIH). Studies about the interaction between NSAIDs and genetic variations on the risk of UGIH are scarce. Therefore, we investigated the effect of 16 single nucleotide polymorphisms (SNPs) involved in drug metabolism on the risk of NSAIDs-induced UGIH.Materials and methodsWe conducted a multicenter case-control study of 326 cases and 748 controls. Participants were sub-grouped into four categories according to NSAID exposure and genetic profile. We estimated odds ratios (ORs) and their 95% confidence intervals (CI) using generalized linear mixed models for dependent binomial variables and then calculated the measures of interaction, synergism index (S), and relative excess risk due to interaction (RERI). We undertook stratified analyses by the type of NSAID (aspirin, non-aspirin).ResultsWe observed an excess risk of UGIH due to an interaction between any NSAID, non-aspirin NSAIDs or aspirin and carrying certain SNPs. The greatest excess risk was observed for carriers of: rs2180314:C>G [any NSAID: S = 3.30 (95%CI: 1.24-8.80), RERI = 4.39 (95%CI: 0.70-8.07); non-aspirin NSAIDs: S = 3.42 (95%CI: 1.12-10.47), RERI = 3.97 (95%CI: 0.44-7.50)], and rs4809957:A>G [any NSAID: S = 2.11 (95%CI: 0.90-4.97), RERI = 3.46 (95%CI: -0.40-7.31)]. Aspirin use by carriers of rs6664:C>T is also associated with increased risk of UGIH [ORaspirin(+),wild-type: 2.22 (95%CI: 0.69-7.17) vs. ORaspirin(+),genetic-variation: 7.72 (95%CI: 2.75-21.68)], yet larger sample size is needed to confirm this observation.ConclusionsThe joint effect of the SNPs s2180314:C>G and rs4809957:A>G and NSAIDs are more than three times higher than the sum of their individual effects. Personalized prescriptions based on genotyping would permit a better weighing of risks and benefits from NSAID consumption.KEY MESSAGESMulticenter case-control study of the effect of genetic variations involved in drug metabolism on upper gastrointestinal haemorrhage (UGIH) induced by NSAIDs (aspirin and non-aspirin).There is a statistically significant additive synergism interaction between certain genetic polymorphisms and NSAIDs on UGIH: rs2180314:C>G and rs4809957:A>G. The joint effect of each of these single nucleotide polymorphisms and NSAIDs on UGIH is more than three times higher than the sum of their individual effects.Genetic profiling and personalized prescriptions would be useful in managing the risks and benefits associated with NSAIDs.

Dataset Information

A Case-Control Study of the Genetic Variability in Reactive Oxygen Species-Metabolizing Enzymes in Melanoma Risk.

Publications

A Case-Control Study of the Genetic Variability in Reactive Oxygen Species-Metabolizing Enzymes in Melanoma Risk.

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