Stress-related Gene Polymorphisms Research Articles

SNP analysis of stress-related genes reveals significant correlations with drug addiction in Jordan

ObjectiveDrug addiction is a complex disorder caused by multiple factors, including environmental and genetic factors. Stress-related genes such as Galanin (GAL) and Oxytocin (OXT) have been linked to the reward pathways that contribute to the development and progression of substance addiction. This study aimed to explore the correlation between several polymorphisms of stress-related genes and drug addiction among Jordanian males. MethodsThe study included 500 participants, consisting of both healthy controls and drug-addicted Jordanian males. The genetic material and clinical data were collected, and 18 SNPs in four candidate genes were genotyped using the Sequenom MassARRAY® system. Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) version 25.0 and the SNPStats website. ResultsThe study identified a significant correlation between three SNPs of the GAL gene and drug addiction, specifically rs3136544, rs3136541, and rs694066. The study also found that different genotypes of these variants were significantly associated with drug addiction. Furthermore, different haplotypes of the GAL, GALR1, and OXTR polymorphisms were also significantly correlated with drug addiction. The study also identified a correlation between several drug addiction features and the studied variants, including the association of rs2717162 of Galanin receptor 1 (GALR1) with age at use onset and the association of rs3136541 of GAL with the type of substance and number of substances used. ConclusionStress-related genes can play a significant role in the development and progression of addiction among the Jordanian population, and further investigations are necessary to understand the underlying mechanisms better and improve future treatment strategies.

Association Between Antioxidant Nutrients, Oxidative Stress-Related Gene Polymorphism and Skeletal Fluorosis in Guizhou, China.

BackgroundOxidative stress plays an important role in the pathogenesis of endemic fluorosis. We analyzed associations between oxidative stress-related gene polymorphisms (PON1 rs662, CAT rs769217, rs2300182, and SOD2 rs11968525) and skeletal fluorosis, and examined potential gene–environment interactions with dietary vitamin C, vitamin E, zinc, and selenium intake.MethodsA cross-sectional study was conducted in the Zhijin County, Guizhou Province of China. Skeletal fluorosis was identified according to the Chinese Diagnostic Criteria of Endemic Skeletal Fluorosis. Dietary information was assessed through face-to-face interviews by trained interviewers using a 75-item food frequency questionnaire. The genotype was detected by high throughput TaqMan-MGB RT-PCR technology. Odds ratios (ORs) and 95% CIs were calculated using an unconditional logistic regression model.ResultsIntake of vitamin E, zinc, and selenium was found to be inversely associated with the risk of skeletal fluorosis. The multivariable-adjusted ORs were 0.438 (95% CI: 0.268 to 0.715, P-trend < 0.001) for vitamin E, 0.490 (95% CI: 0.298 to 0.805, P-trend = 0.001) for zinc, and 0.532 (95% CI: 0.324 to 0.873, P-trend = 0.010) for selenium when comparing the highest with the lowest quartile. The relationship for vitamin C was not observed after adjustment for risk factors. Furthermore, participants with PON1 rs662 AA genotype had a significantly decreased risk of skeletal fluorosis compared with those with the GG genotype (OR = 0.438, 95% CI: 0.231 to 0.830). GG + AG genotype carriers were 2.212 times more likely to have skeletal fluorosis than AA carriers (OR = 2.212, 95% CI: 1.197 to 4.090). Compared with AA carriers, AG carriers had a 2.182 times higher risk of skeletal fluorosis (OR = 2.182, 95% CI: 1.143 to 4.163). Although we observed the risk of skeletal fluorosis was higher with a lower intake of antioxidant nutrients, the potential interactions between nutrient intake and genetic polymorphisms were not observed.ConclusionParticipants with a higher intake of vitamin E, zinc, and selenium have a lower likelihood of skeletal fluorosis. In addition, the PON1 rs662 polymorphism is related to skeletal fluorosis.

AQUAPORIN-3 AND CYBA GENETIC POLYMORPHISMS MAY PREDICT RISK OF DEVELOPING HYPERTENSION

Objective: Preeclampsia, a placentation disorder, affects 7% of pregnancies in Europe. It influences future cardiovascular disease, such as hypertension. Preeclampsia and hypertension have been associated with oxidative stress, therefore, key proteins in redox signaling may be involved with the development of hypertensive disorders during/after pregnancy. This study aimed at determining associations between oxidative stress-related gene polymorphisms (AQP3-rs2231231 and CYBA-rs4673) with the development of preeclampsia and the risk for future hypertension. Design and method: A cohort of 150pregnant Caucasian women, aged 35.24 ± 5.47 years, 60(40%) normotensive and 90(60%) preeclamptic, was evaluated. Based on a prospective study(2–16 years later), these women were evaluated for the development of hypertension and classified as normotensive 98(67%) or hypertensive 48(33%). The influence of genetic polymorphisms on the susceptibility for cardiovascular disease was evaluated. In this cohort, anthropometric/haemodynamic parameters were studied. For statistical analysis chi-square and Student t-test were used. Results: During pregnancy, no differences between the distribution of studied genetic polymorphisms in preeclampsia were found. However, based on the AQP3 dominant model of A, our data showed that AA+AC genotypes were more frequent (73.3%;p = 0.014) in hypertensive individuals. Moreover, allele A, the allele of risk, was associated with a 3.405-fold higher risk (p = 0.016,OR = 3.405,95%CI[1.26–9.19]) to develop hypertension after pregnancy. In addition, a higher systolic(p = 0.017) and diastolic(p = 0.008) pressure were also observed in women carrying the AA+AC genotype. Furthermore, based on CYBA dominant model of C, TT genotype of polymorphism was also correlated with the development of hypertension(100.0%;p = 0.007) after pregnancy. On the other hand, looking at the recessive model of C, CT+TT genotype was associated with the development of hypertension. Allele T, the allele of risk, was associated with 6.5-fold risk (p = 0,024,OR = 6.500,95%CI[1.28–33.03] to develop hypertension. Moreover, CT+TT genotypes of CYBA genetic polymorphism were more associated with increased weight (p = 0.014), higher waist circumference(p = 0.010), hip(p = 0.008) and systolic(p &lt; 0.001) and diastolic blood pressure(p &lt; 0.001). Conclusions: In this study, AQP3 genetic polymorphism was found associated with the hypertensive disorders after pregnancy for the first time. In addition, CYBA was also associated with the development of essential hypertension. These results open new perspectives in the development of new approaches for cardiovascular disease prevention.

Interaction between three stress-related gene polymorphisms and food addiction increases the risk to develop obesity in a sample of Mexican people attending a nutrition clinic

Chronic stress exposure impacts negatively in individuals leading to food addiction, overweight or obesity. Stress-genes and their translation products are responsible for the responses of humans to adverse environments. Alterations in stress-genes expression or protein function may induce behaviors as compulsive eating of high-energy containing food, which decreases stress-induced negative feelings. However, chronic stress is not assessed in Mexican population. We analyzed here the association between polymorphisms of CRH, CRHR2 and glucocorticoids (GR, NR3C1) receptor genes with food addiction and obesity and overweight in Mexican patients of a Nutrition Clinic. We recruited 508 individuals of both genders, who accepted to participate in the study at their first visit to the clinic, obtaining their fat mass percentage and a blood sample for the genetic analysis. Participants answered the Yale’s food addiction scale and were subjected to a Trier social test, as an acute stressful stimulus. Pre and post-test saliva samples were obtained to evaluate cortisol levels and adrenal axis’ response to the acute stress. The 63% of participants classified as stressed (S); 6.5% of normal-weight individuals showed food-addiction, whereas 63% of participants with food-addiction were also stressed. The fat mass percentage was greater in stress-addiction than in stressed non-addiction participants. The best interaction model for obesity development risk comprehended the presence of polymorphisms of the three genes that in combination with food addiction increased the risk for developing obesity 2.8–4-fold. Thus, frequent stress exposure favors food-addiction, which along with genetic susceptibility seems to add up to Mexican obesity/overweight rates.

Polymorphisms in Stress-Related Genes Are Associated with Reduced Cocaine Abuse and Longer Retention in Methadone Maintenance Treatment for Opioid Use Disorder

Background: As CRH-binding protein (CRHBP) SNP rs1500 was associated with reduced cocaine abuse after 1 year in methadone maintenance treatment (MMT) for heroin addiction, we evaluated the association of additional 28 selected SNPs, in 17 stress-related genes, with MMT outcome. Methods: The distribution of genotypes of each SNP by cocaine abuse after 1 year in MMT was assessed under the dominant and recessive models using χ². Cumulative retention (up to 26.5 years) was studied using Kaplan-Meier analyses. Logistic regression and Cox model were used for multivariate analyses. Results: Of a nonselective sample of 404 patients, 25 patients with <50% Europeans/Middle Eastern ancestry were excluded. Of the remaining 379 patients, 330 (87.1%) stayed at least 1 year in treatment. Four SNPs were associated with cocaine abuse after 1 year in MMT. A lower proportion of cocaine abusers was found in the groups of subjects with the following genotypes: arginine vasopressin (AVP) SNP rs2282018 CC, CRHBP rs7728378 TT, galanin rs3136541 TT/TC, and neuropeptide Y receptor Y1 (NPY1R) rs4518200 AA. The following independent variables were associated with lack of cocaine in urine after 1 year (multivariate analyses): CRHBP rs7728378 TT, NPY1R rs4518200 AA, no cocaine in urine on admission, as well as opiate and benzodiazepine use after 1 year in MMT. Cumulative retention (n = 379) was longer in carriers of AVP rs2282018 CC (13.7 years, 95% CI 11.1–16.2) versus TT/TC genotypes (10.5, 95% CI 9.4–11.5) (p = 0.0230) Conclusions: The study suggests that a reduction in cocaine abuse and longer retention among MMT patients is mediated in part by variants in stress-related genes and is a step toward precision medicine.

Oxidative Stress-Related Gene Polymorphisms Are Associated With Hepatitis B Virus-Induced Liver Disease in the Northern Chinese Han Population.

Oxidative stress is closely related to the occurrence and development of various diseases such as cancer, diabetes, and cardiovascular and infectious diseases. We identified six critical genetic variants related to oxidative stress, and evaluated their main effects and their interaction effects on hepatitis B virus (HBV)-induced liver diseases. We enrolled 3,128 Han Chinese subjects into five groups: healthy controls, chronic hepatitis B (CHB), liver cirrhosis (LC), hepatocellular carcinoma (HCC), and natural clearance. We then determined the genotypes in each group for CYBA-rs4673, NCF4-rs1883112, NOX4-rs1836882, rs3017887, SOD2-rs4880, and GCLM-rs41303970, and evaluated the association between these variants and HBV-induced liver diseases. Gene-gene interactions were evaluated using generalized multifactor dimensionality reduction, logistic regression, and four-by-two tables. Significant associations were observed between healthy controls and the CIB group (CHB+LC+HCC). The CYBA-rs4673AG genotype was associated with a 1.356 rate of susceptibility of HBV-induced liver disease compared to the wild type GG genotype. The NCF4-rs1883112G allele occurred more frequently in healthy controls than in the CIB group in all three models (dominant, codominant, and recessive). Nox4-rs1836882 TC showed a protective association, being more frequent in healthy controls compared to the wild type TT genotype. GCLM-rs41303970A was associated with HBV-induced liver disease. The overall best model by multifactor dimensionality reduction was a five factor interaction model that had the highest cross validation consistency (10/10) and test accuracy (0.5669), P = 0.001. Oxidative stress-related gene polymorphisms are likely to be associated with HBV-induced liver disease, suggesting that information on these variations is useful for risk assessment of HBV-induced liver disease.

Interaction Between Stress and Addiction: Contributions From Latin-American Neuroscience.

Drug addiction is a chronic neuropsychiatric disorder that escalates from an initial exposure to drugs of abuse, such as cocaine, cannabis, or heroin, to compulsive drug-seeking and intake, reduced ability to inhibit craving-induced behaviors, and repeated cycles of abstinence and relapse. It is well-known that chronic changes in the brain’s reward system play an important role in the neurobiology of addiction. Notably, environmental factors such as acute or chronic stress affect this system, and increase the risk for drug consumption and relapse. Indeed, the HPA axis, the autonomic nervous system, and the extended amygdala, among other brain stress systems, interact with the brain’s reward circuit involved in addictive behaviors. There has been a growing interest in studying the molecular, cellular, and behavioral mechanisms of stress and addiction in Latin-America over the last decade. Nonetheless, these contributions may not be as strongly acknowledged by the broad scientific audience as studies coming from developed countries. In this review, we compile for the first time a series of studies conducted by Latin American-based neuroscientists, who have devoted their careers to studying the interaction between stress and addiction, from a neurobiological and clinical perspective. Specific contributions about this interaction include the study of CRF receptors in the lateral septum, investigations on the neural mechanisms of cross-sensitization for psychostimulants and ethanol, the identification of the Wnt/β-catenin pathway as a critical neural substrate for stress and addiction, and the emergence of the cannabinoid system as a promising therapeutic target. We highlight animal and human studies, including for instance, reports coming from Latin American laboratories on single nucleotide polymorphisms in stress-related genes and potential biomarkers of vulnerability to addiction, that aim to bridge the knowledge from basic science to clinical research.

Increase of urinary malondialdehyde level by bisphenol A exposure: a longitudinal panel study

BackgroundTo verify oxidative stress as a possible mechanism that establishes a relationship between exposure to bisphenol A (BPA) and adverse health outcomes in the elderly Korean population, we evaluated the relation between visit-to-visit variations in urinary BPA and oxidative stress biomarker.MethodsTo assess the relation between BPA and urinary malondialdehyde (MDA) as an oxidative stress biomarker, we used a mixed effect model after controlling for age, sex, BMI, drinking status, exercise, urinary cotinine level, PM10 on lag day 2, and mean temperature and dew point on the day. The relation between exposure to BPA and MDA level by sex of participants and polymorphisms of oxidative stress-related genes (COX2, EPHX1, HSP70-hom, PON1, eNOS, CAT, DRD2, SOD2, and MPO) was also evaluated.ResultsA significant association was found for BPA with MDA in both male and female elderly participants (male, β = 0.19 and p = 0.0003; female, β = 0.18 and p < .0001; and total, β = 0.18 and p < .0001). Furthermore, the association of BPA with MDA was found regardless of any genotype of the nine oxidative stress-related genes.ConclusionsThe results of our study suggest a strong association of BPA with oxidative stress, not related with sex and oxidative stress-related gene polymorphisms.

73 Genetic variability in oxidative stress-related gene polymorphisms (GSTM1, GSTT1, NOS3 and MTHFR) in preeclampsia and future cardiovascular risk

Introduction Preeclampsia (PE) may affect the risk for future cardiovascular disease. Oxidative stress and genetic polymorphisms associated to this pathway may modulate that risk through the antioxidant and anti-inflammatory differential effects of their genotypes. Objectives To study the association between oxidative stress-related gene polymorphisms (GSTM1, GSTT1, NOS3 and MTHFR) with the risk for preeclampsia and future cardiovascular risk. Methods We evaluated 222 women, aged 35.11±5.51years, 124 (55.9%) with normal blood pressure in pregnancy and 98 (44.1%) with preeclampsia (PE). In a sub-sample of these, we also evaluated in a prospective study, 88 (62.9%) women that had previous PE 2 to 16 years ago. The GSTM1, GSTT1 and NOS3 a/b polymorphisms were determined by PCR and MTHFR C677T was determined by PCR-RFLP. In the prospective cohort, we studied demographic, anthropometric, and haemodynamic biomarkers such as C-reactive protein, myeloperoxidase, and nitric oxide metabolites (total and nitrites), and others associated with liver function (AST and ALT) and lipid profile (total LDL and cholesterol HDL, non-HDL and apolipoproteins A and B). For statistical analysis Student t -test and binary regression logistic were used. P Results We found lower PE risk associated to GSTT1 null (OR=0.48; 95% CI=0.25–0.96; P =0.038) and an increased PE risk associated to MTHFR C carriers (OR=4.18; 95% CI=1.36–12.81; P =0.012). The latter was also significantly associated to PE risk in a multivariate analysis (OR=4.43; 95% CI=1.41–3.14; P =0.011). The two-way combination of GSTT1 non-null and MTHFR C carriers, adjusted for age, resulted in almost 3-fold increased PE risk (OR=2.74; 95% CI=1.20–6.69; P =0.018). In the prospective cohort, for the GSTT1 non-null and MTHFR C carriers risk genotypes, we found that PE women that developed later hypertension, presented significantly higher levels of LDL in relation to those that became normotensive (138.53±45.20 versus 104.16±30.81; P =0.025). NOS3 and GSTM1 polymorphisms were not associated to risk for PE. Conclusions The present study indicates that oxidative stress-related gene polymorphisms, namely, the association of GSTT1 non-null and MTHFR C carriers genotypes may be involved in susceptibility for preeclampsia. For this risk genetic model and according with the previously history of PE, these women may be more susceptible to future cardiovascular risk in premenopausal.

092 Polymorphisms in Stress-Related Genes Affect Body Weights of Angus-Based Crossbred Cows at Weaning

092 Polymorphisms in Stress-Related Genes Affect Body Weights of Angus-Based Crossbred Cows at Weaning

Metabolic Parameters and Polymorphisms of Stress-related Genes

Metabolic Parameters and Polymorphisms of Stress-related Genes

Interactions of early adversity with stress-related gene polymorphisms impact regional brain structure in females.

Early adverse life events (EALs) have been associated with regional thinning of the subgenual cingulate cortex (sgACC), a brain region implicated in the development of disorders of mood and affect, and often comorbid functional pain disorders, such as irritable bowel syndrome (IBS). Regional neuroinflammation related to chronic stress system activation has been suggested as a possible mechanism underlying these neuroplastic changes. However, the interaction of genetic and environmental factors in these changes is poorly understood. The current study aimed to evaluate the interactions of EALs and candidate gene polymorphisms in influencing thickness of the sgACC. 210 female subjects (137 healthy controls; 73 IBS) were genotyped for stress and inflammation-related gene polymorphisms. Genetic variation with EALs, and diagnosis on sgACC thickness was examined, while controlling for race, age, and total brain volume. Compared to HCs, IBS had significantly reduced sgACC thickness (p = 0.03). Regardless of disease group (IBS vs. HC), thinning of the left sgACC was associated with a significant gene-gene environment interaction between the IL-1β genotype, the NR3C1 haplotype, and a history of EALs (p = 0.05). Reduced sgACC thickness in women with the minor IL-1β allele, was associated with EAL total scores regardless of NR3C1 haplotype status (p = 0.02). In subjects homozygous for the major IL-1β allele, reduced sgACC with increasing levels of EALs was seen only with the less common NR3C1 haplotype (p = 0.02). These findings support an interaction between polymorphisms related to stress and inflammation and early adverse life events in modulating a key region of the emotion arousal circuit.

Lack of association between oxidative stress-related gene polymorphisms and chronic migraine in an Italian population

Migraine patients present increased risks of vascular diseases such as high blood pressure, insulin resistance, metabolic syndrome, stroke and coronary heart disease. Oxidative stress (OS) is increasingly being studied in relation to the pathophysiology of migraine, stimulated by the described association with the most frequent migraine comorbidities. Because many of the gene-encoded players of the OS balance are characterized by functional polymorphisms, it is supposed that the individual genomic profile could affect susceptibility to OS and to related pathophysiological conditions. This study aimed to characterize a panel of 10 polymorphisms in 8 OS-related genes in a chronic migraine (CM) population and healthy controls, to recognize a genetic risk in the process of migraine chronification. The sample consisted of 45 healthy women and 96 women diagnosed with CM. No deviations from the Hardy-Weinberg equilibrium were detected, or in the overall population, or in the CM group or in the control group.

The stress systems in depression: a postmortem study

After trauma, depressive disorders are among the most frequent emerging diagnoses. However, although the symptoms of depression are well characterized, the molecular mechanisms underlying this disorder are largely unknown. Factors involved in the heterogeneous pathogenesis of depression include polymorphisms in stress-related genes, gender, age, developmental history, and environmental (traumatic) stressors such as epigenetic factors. These factors may make different parts of the stress-related brain systems more vulnerable to different stressful or traumatic life events or psychological stresses, causing alterations in a network of neurotransmitters and neuromodulators including amines, amino acids, nitric oxide (NO), and neuropeptides, and finally make individuals at risk for depression. The hypothalamo–pituitary–adrenal (HPA) axis has a prominent position in this network. With the postmortem brain material obtained from the Netherlands Brain Bank, we have carried on a series of studies with the aim to elucidate the specific changes in these systems in relation to special subtypes of depression. Our final destination is to set up tailor-made treatment for depressive patients on the basis of his/her developmental history, genetic and epigenetic background, and the vulnerability in particular neurobiological systems. This presentation is a review of our findings of changes in systems of sex steroids, receptors in the hypothalamic paraventricular nucleus, corticotrophin-releasing hormone, orexin, γ-aminobutyric acid, and NO in the etiology of depression, in relation to HPA activity, sex differences, and suicide.

Association of Polymorphisms in Stress-Related TNFα and NPY Genes with the Metabolic Syndrome in Han and Hui Ethnic Groups

Metabolic syndrome (MS) is a cluster of complicated disorders caused by the interactive influencing factors of heredity and environment, which predisposes to many cnacers. RESULTS from epidemic research indicate that stress is tightly related to the pathogenesis of MS and neoplasia. This paper aims to investigate the association between psychological stress and MS with respect to the tumor necrosis factor alpha (TNFα) and neuropeptide Y (NPY) genes in the Han and Hui ethnic groups. All subjects for this case-control study matched strict enrollment criteria (nationality, gender and age) and lived in the city of Wu Zhong of Ningxia Province in China. The enrolled group contained 102 matched pairs of Hui ethnic individuals and 98 matched pairs of Han ethnic individuals. Enrolled subjects completed the general Symptom Checklist-90 (SCL-90). The TNFα-308G/A variant and NPYrs16147 polymorphism were detected in case (81 males, 119 females) and control (81 males, 119 females) groups by polymerase chain reaction (PCR) amplification. Nine factors of the SCL-90 were found to be statistically different (p<0.05) between case and control groups. The homozygous mutant genotype (AA) and the mutant allele (A) of the TNFα-308G/A gene were less frequently observed in the control population compared to the case group. The odds ratio (95% confidence interval) in "Allele" for MS was 2.28 (1.47-3.53), p=0.0001, while "OR" was 1.11 (0.83-1.47), p=0.15, for the NPYrs16147 gene polymorphism. Psychological stress has been positively associated with MS. A previous study from our group suggested there were differences in the level of psychological stress between Hui and Han ethnic groups. Furthermore, we found that the stress-related TNFα gene was associated with MS for both Han and Hui ethnic groups. In contrast, NPY may be a possible contributor to MS and associated cancer for the Han ethnic group.

Accumulation of oxidative stress-related gene polymorphisms and the risk of coronary heart disease events in patients with type 2 diabetes – An 8-year prospective study

ObjectiveOxidative stress, which is provoked in patients with diabetes, plays critical roles in the pathogenesis of coronary heart disease (CHD). We simultaneously determined 5 relatively common genetic variants related to oxidative stress and evaluated the combined effect on CHD. MethodsWe enrolled 1977 Japanese type 2 diabetic subjects without history of CVD (males 66.1%, 59.5 ± 10.0 years old), determined their genotypes regarding glutamate-cysteine ligase modifier subunit (GCLM) C-588T, manganese superoxide dismutase (SOD2) Val16Ala, endothelial nitric oxide synthase (NOS3) G894T, NAD(P)H oxidase p22phox (CYBA) C242T, and myeloperoxidase (MPO) G-463A polymorphisms, and prospectively evaluated the association between these polymorphisms and CHD events. ResultsThe median follow-up period was 7.5 years and there were 85 new CHD events. The single association analysis revealed that there were no statistically significant associations between each polymorphism and the prevalence of CHD. Interestingly, the risk of CHD event was higher with the increase of the total number of 10 concomitant unfavorable “pro-oxidant alleles” in each subject (p for trend = 0.018, log-rank test). Especially, the carriers of ≥8 pro-oxidant alleles had a significantly increased risk as compared to the carriers of <8 pro-oxidant alleles, whether the other clinical variables were adjusted (HR 2.92 with 95%CI 1.50–5.67, p = 0.002) or not (HR 2.89 with 95%CI 1.49–5.59, p = 0.002).. ConclusionsAccumulation of gene polymorphisms related to oxidative stress is likely associated with the development of CHD in patients with type 2 diabetes, suggesting that the combined information about these variants is useful to assess the risk of CHD.

Oxidative stress-related enzyme gene polymorphisms and susceptibility to breast cancer in non-smoking, non-alcohol-consuming Taiwanese women: a case-control study

Mitochondrial manganese superoxide dismutase (MnSOD) converts superoxide anion into H(2)O(2), which is neutralized sequentially by either catalase (CAT) or glutathione peroxidase 1 (Gpx 1) into water or converted into highly reactive hypochlorous acid by myeloperoxidase (MPO). We hypothesize that gene variants for these enzymes might be associated with the risk of breast cancer in non-smoking, non-alcohol-consuming women. Genotypes of oxidative stress-related enzymes (MnSOD1183T>C, MPO-463G>A, GPx1Pro198Leu and CAT-262C>T) were analysed in 260 non-smoking and non-alcohol-consuming female patients with breast cancer and 224 habit-matched controls. Subjects with the MnSOD1183T>C C carrier or those with the GPx1Pro198Leu CT genotype had significantly decreased age-adjusted risks (odds ratio [OR]: 0.56 and 0.16 with 95% confidence intervals [95% CI]: 0.38-0.83 and 0.08-0.29, respectively) for breast cancer. Certain combined genotypes of the polymorphisms also significantly modulated the age-adjusted risk. We conclude that oxidative stress-related enzyme genetic variants, especially GPx1Pro198Leu CT, modify the risk of breast cancer development in non-smoking and non-alcohol-consuming women. The role of unidentified environmental factors predisposing to breast cancer development through an oxidative stress mechanism merits further investigation.

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.