Lack of association of genetic polymorphisms of angiotensin-converting enzyme gene I/D and glutathione-S-transferase enzyme T1 and M1 with retinopathy of prematures

One of the most frequently observed causes of blindness in infancy is the pathogenesis known as retinopathy of prematurity (ROP). Angiotensin-converting enzyme (ACE) is a vital enzyme in the renin-angiotensin-aldosterone system; it is involved in the development of cardiovascular system diseases linked to I/D polymorphism of the ACE gene. Glutathione-S-transferase enzyme (GST) is one of the most important regulating components of the antioxidant system; there are indications that certain polymorphisms of GST genes (GSTT1, GSTM1), especially the null genotypes, increase the tendency for oxidative stress diseases. We investigated a possible correlation between ACE gene I/D and GSTT1 and GSTM1 gene polymorphisms in 56 prematures suffering from ROP and a control group composed of 48 prematures without ROP in a hospital in Turkey. PCR was used to detect the ACE I/D, GSTT1 and GSTM1 gene polymorphisms. Genotype was determined based on bands formed on agarose gel electrophoresis. We found no significant differences in genotype frequency of the ACE I/D, GSTT1 and GSTM1 genes between normal subjects and patients with ROP. Our results do not support an association of ACE I/D, GSTT1 and GSTM1 gene polymorphisms with risk for ROP.     

Relationship between GSTM1 and GSTT1 polymorphisms and schizophrenia: A case–control study in a Tunisian population

There is substantial evidence found in the literature that supports the fact that the presence of oxidative stress may play an important role in the pathophysiology of schizophrenia. The glutathione S-transferases (GSTs) forms one of the major detoxifying groups of enzymes responsible for eliminating products of oxidative stress. Interindividual differences observed in the metabolism of xenobiotics have been attributed to the genetic polymorphism of genes coding for enzymes involved in detoxification. Thus, in this study we investigated the association of glutathione S-transferase Mu-1 (GSTM1) and glutathione S-transferase theta-1 (GSTT1) gene deletion polymorphisms and schizophrenia in a Tunisian population. A case–control study including 138 schizophrenic patients and 123 healthy controls was enrolled. The GSTM1 and GSTT1 polymorphisms were analyzed by multiplex polymerase chain reaction (PCR). No association was found between the GSTM1 genotype and schizophrenia, whereas the prevalence of the GSTT1 active genotype was significantly higher in the schizophrenic patients (57.2%) than in the controls (45.5%) with (OR = 0.6, IC 0.37–0.99, p = 0.039). Thus, we noted a significant association between schizophrenia and GSTT1 active genotype. Furthermore, the combination of the GSTM1 and GSTT1 null genotypes showed a non-significant trend to an increased risk of schizophrenia. The present finding indicated that GSTT1 seems to be a candidate gene for susceptibility to schizophrenia in at least Tunisian population.     

Genetic susceptibility to malignant pleural mesothelioma and other asbestos-associated diseases

Exposure to asbestos fibers is a major risk factor for malignant pleural mesothelioma (MPM), lung cancer, and other non-neoplastic conditions, such as asbestosis and pleural plaques. However, in the last decade many studies have shown that polymorphism in the genes involved in xenobiotic and oxidative metabolism or in DNA repair processes may play an important role in the etiology and pathogenesis of these diseases. To evaluate the association between diseases linked to asbestos and genetic variability we performed a review of studies on this topic included in the PubMed database. One hundred fifty-nine citations were retrieved; 24 of them met the inclusion criteria and were evaluated in the review. The most commonly studied GSTM1 polymorphism showed for all asbestos-linked diseases an increased risk in association with the null genotype, possibly linked to its role in the conjugation of reactive oxygen species. Studies focused on GSTT1 null and SOD2 Ala16Val polymorphisms gave conflicting results, while promising results came from studies on alpha1-antitrypsin in asbestosis and MPO in lung cancer. Among genetic polymorphisms associated to the risk of MPM, the GSTM1 null genotype and two variant alleles of XRCC1 and XRCC3 showed increased risks in a subset of studies. Results for the NAT2 acetylator status, SOD2 polymorphism and EPHX activity were conflicting. Major limitations in the study design, including the small size of study groups, affected the reliability of these studies. Technical improvements such as the use of high-throughput techniques will help to identify molecular pathways regulated by candidate genes.     

Inherited susceptibility to bleomycin-induced micronuclei: correlating polymorphisms in GSTT1, GSTM1 and DNA repair genes with mutagen sensitivity

Susceptibility to DNA damage varies among individuals and sensitivity to bleomycin (BLM) may reflect the inter-individual differences. BLM sensitivity in part may be explained by inherited differences in DNA repair genes. We investigated the association between genetic polymorphisms in the GSTT1, GSTM1, XPD, XRCC1 and XRCC3 genes and the levels of spontaneous and BLM-induced DNA damage in peripheral blood lymphocytes from 200 healthy, unexposed individuals. The investigation of BLM sensitivity on cancer- or disease-free subjects and not occupationally exposed to known mutagen represents the strengths of the present study, as the detection of genetic damage is not biased by any disease- and occupational-related factor. The micronucleus (MN) assay was used to detect the spontaneous and BLM-induced genetic damage whereas, genotype analysis was carried out using methods based on polymerase chain reaction. Poisson regression analysis showed that subject's age, gender and smoking status had no effect on the spontaneous and BLM-induced MN frequencies. Genotype analysis revealed a clear association between GSTT1-null and XPD polymorphisms and both spontaneous and BLM-induced MN frequencies, whereas the effect of the XRCC1 polymorphism was marginally significant only with regard to spontaneous MN frequency. Genotype analysis did not reveal a clear association between the other studied SNPs (GSTM1 and XRCC3) and MN frequencies. Poisson regression analysis revealed no association between the score of protective alleles and the frequency of spontaneous MN. However, an increased number of protective alleles was significantly associated with a lower frequency of BLM-induced MN (P=0.0003). This finding highlights the genetic basis for BLM sensitivity, which could be a valid and useful surrogate for identifying genotypes that might increase susceptibility in population exposed to carcinogens. Further investigations in a large sample size and including more SNPs, reflecting the complexity of DNA repair machinery, might lead to the identification of a genetic profile responsible for the susceptibility to genotoxicants, with a far-reaching long-term impact on primary prevention and early detection of disease associated genes.     

Polymorphism in environment responsive genes and association with Parkinson disease

Attempts were made in the present case-control study to investigate the association of polymorphism in the genes encoding proteins involved in toxication–detoxication and dopaminergic pathways and susceptibility to Parkinson’s disease (PD). Seventy patients suffering from PD and one hundred healthy controls belonging to the same geographical location and same ethnicity were included in the study. PCR-RFLP and allele-specific PCR-based methodology were used to identify the genotypes. Multivariate logistic regression analysis revealed that heterozygous genotypes of cytochrome P4502D6*4(CYP2D6*4), CYP2E1*5B (RsaI) polymorphism and homozygous mutant genotypes of CYP2E1*6 (Dra1) were found to be overrepresented in PD cases when compared to the controls. Risk was also found to be increased in patients carrying glutathione S-transferase T1 (GSTT1) null or homozygous variant genotypes of GSTP1. Significant association was observed for monoamine oxidase-B(MAO-B) variant allele G and PD, whereas no difference in genotype and allele frequencies was observed for manganese-superoxide dismutase (MnSOD), dopamine receptor-D2(DRD2), and dopamine transporter (DAT) genes between controls and PD cases. Genotype combinations characterized by the presence of two variant genotypes on their corresponding loci revealed that four combinations of GSTT1 null and MnSOD(-9Val) or GST null and MAOB-G or CYP2E1*5B and MAO-B-AG or CYP2E1*5B and DRD2 (Taq1A-het) genotypes in the patients exhibited severalfold higher and significant association with risk to PD. Our data suggest that polymorphism in the genes involved in detoxification and dopamine regulation may modulate the susceptibility to PD and could be important risk factors in the pathogenesis of PD.     

Effects of glutathione S-transferase T1 and M1 deletions on advanced carotid atherosclerosis, oxidative, lipid and inflammatory parameters

Glutathione S-transferases (GSTs) carry out a wide range of functions in cells, such as detoxification of endogenous compounds, removal of reactive oxygen species, and even catalysis of reactions in metabolic pathways beyond detoxification. Based on previous research, GSTM1 and GSTT1 might modify the risk of atherosclerosis. The aim of our study was to analyze the possible association of GSTM1 and GSTT1 gene polymorphisms with the occurrence of carotid plaque (CP); and biochemical parameters of oxidative stress, lipid profile and inflammation, in 346 consecutive patients with advanced atherosclerosis that underwent endarterectomy. A multiplex polymerase chain reaction (PCR) method was used to detect the deletions in GSTM1 and GSTT1 genes in the genomic DNA in 346 patients and 330 controls. The adjusted OR for CP presence (adjusted for age, gender, smoking, hypertension, BMI, HDLC, TG) was 0.24, 95 %CI 0.08–0.7, p < 0.01 for GSTT1 null and 1.13, 95 %CI 0.62–2.07, p = 0.7 for GSTM1 null genotype. We found significantly lower plasma lipoprotein (a) (Lp(a)) levels in GSTT1 null compared to wild-type genotype carriers in patient group (20.68 ± 26.02 mg/dl vs. 40.66 ± 42.89 mg/dl, mean ± SD, p = 0.04). The serum interleukin-6 (IL-6) values were significantly influenced by both GST polymorphisms in patients with CP. Our results, showing the significant reduction of GSTT1 deletions in patients with CP, suggest involvement of GSTs in carotid atherosclerosis. This study shows additional view of the possible role of GSTs in advanced chronic inflammatory disease of vascular system, but the confirmation in a larger studies in different populations are needed.     

DNA repair gene polymorphisms and risk of early onset colorectal cancer in Lynch syndrome

DNA repair plays a pivotal role in maintaining genomic integrity with over 130 genes involved in various repair pathways that include base excision repair, nucleotide excision repair, double strand break repair and DNA mismatch repair. Polymorphisms within genes that are involved in these processes have been widely reported to be associated with cancer susceptibility in an extensive range of malignancies that include colorectal cancer (CRC). Lynch syndrome is caused by inherited germline mutations in DNA mismatch repair genes, predominantly in MLH1 and MSH2, that predispose to a variety of epithelial malignancies, most notably CRC. Despite being a relatively well understood hereditary cancer syndrome there remain several questions in relation to genetic influences on disease expression. Since Lynch syndrome is associated with a breakdown in DNA mismatch repair variation in other DNA repair genes may influence disease expression. In this report we have genotyped 424 Australian and Polish Lynch syndrome participants for eight common DNA repair gene polymorphisms to assess any association with the age of CRC onset. The DNA repair gene SNPs included in the study were: BRCA2 (rs11571653), MSH3 (rs26279), Lig4 (rs1805386), OGG1 (rs1052133), XRCC1 (rs25487), XRCC2 (rs3218536 and rs1799793) and XRCC3 (rs861539). Cox multi-variant regression modelling failed to provide any convincing evidence of an effect in any of the polymorphisms analysed. The data suggest that polymorphisms in DNA repair genes do not contribute to cancer risk in a population of CRC patients who are at increased risk of disease as a result in a deficiency of DNA mismatch repair.     

GST, CYP and PON1 polymorphisms in farmers attributing ill health to organophosphate-containing sheep dip

Previously we reported that in sheep dippers exposed to organophosphates the frequency of paraoxonase (PON1) polymorphisms differed between those with or without self-reported ill health. We have now examined whether polymorphisms in other genes involved in xenobiotic metabolism alter disease risk in this population. There were elevated but non-significant risks associated with the CYP2D6 WT genotype (odds ratio (OR) 1.47, 95% CI 0.83-2.60), or a GSTP1*B or *C allele (OR 1.37, 95% CI 0.88-2.01) or being GSTM1*2/GSTT1*2 homozygous (OR 1.61, 95% CI 0.74-3.48). Similar results were generally obtained after the exclusion of subjects to obtain a more homogenous case-referent population: for double null GSTM1 and GSTT1 homozygotes the OR was 2.06 (95% CI 0.85-2.04). In those also likely to have been exposed to diazinon, risks associated with a GSTP1*B or *C allele (OR 1.82, 95% CI 0.92-3.63) or a GSTM1*2/GSTT1*2 homozygous (OR 2.60, 95% CI 0.72-10.42) were elevated but not to a significant extent. Risk associated with PON1 genotype and phenotype varied with CYP2D6 and GSTP1 genotype but not consistently with a priori hypotheses. Further work is necessary to delineate more clearly pathways of organophosphate activation and non-PON1 pathways of detoxification and to confirm whether CYP and GST polymorphisms alter disease risk in populations exposed to organophosphates.     

Polymorphisms in glutathione S-transferases in French vinyl chloride workers.

The authors have recently demonstrated a significant gene-environment interaction between vinyl chloride exposure and polymorphisms in the DNA repair protein XRCC1 on the occurrence of mutant p53 biomarkers of vinyl chloride-induced genetic damage. The aim of this study was to examine the polymorphisms in the glutathione S-transferases (GSTs) as potential modifiers of this relationship, since these enzymes may be involved in the phase II metabolism of the reactive intermediates of vinyl chloride. A cohort of 211 French vinyl chloride workers was genotyped for common polymorphisms in GSTM1, GSTT1 and GSTP1. Although no independent, statistically significant effect of these polymorphisms on the occurrence of the mutant p53 biomarker was found, the null GSTM1 and null GSTT1 polymorphisms were found to interact with the XRCC 1 polymorphism to increase the occurrence of the biomarker such that, for example, workers with at least one variant XRCC1 allele who were null for both GSTM1 and GSTT1 had a significant odds ratio for the biomarker (OR =8.4, 95% CI = 1.3 54.0) compared with workers who were wild-type for all alleles, controlling for potential confounders including cumulative vinyl chloride exposure.     

Influence of GSTT1, mEH, CYP2E1 and RAD51 polymorphisms on diepoxybutane-induced SCE frequency in cultured human lymphocytes

1,3-Butadiene (BD) is a common chemical in the human environment. Diepoxybutane (DEB) is the most reactive epoxide metabolite of BD. The aim of the present study was to evaluate the influence of polymorphisms in enzymes operating in DEB-metabolism (epoxide hydrolase mEH, CYP2E1 and GSTT1), as well as in the DNA-repair enzyme RAD51, on the frequency of sister chromatid exchange (SCE) induced by DEB in lymphocyte cultures from 63 healthy donors. Their genotypes were determined using PCR and restriction fragment length polymorphism (RFLP)-PCR techniques. The analysis of xenobiotic-metabolizing genes revealed that GSTT1 and CYP2E1 polymorphisms have an influence on DEB-induced SCE frequency. Individuals with the GSTT1 null genotype and CYP2E1 c2 variant allele heterozygotes were observed to have significantly higher SCE frequency than individuals with more common genotypes. A correlation between sensitivity to DEB and GSTT1 null genotype indicates that this pathway is a major detoxification step in DEB metabolism in whole-blood lymphocyte cultures, which has been shown in many studies. The analysis of combined polymorphisms indicated that, in the presence of GSTT1, a significantly higher DEB-induced SCE frequency is observed in the CYP2E1 c2 variant allele heterozygotes than in individuals with the most common CYP2E1 genotype. In the absence of GSTT1, however, the CYP2E1 polymorphism has no influence on DEB-induced SCEs. A significant difference was also observed between individuals characterized by low and high mEH activity, but only in subjects with the GSTT1 null genotype. Lack of GSTT1 resulted in higher SCE frequency in individuals with mEH high-activity genotypes than in individuals with mEH low-activity genotype. In the present study no statistically significant difference in DEB-induced SCEs was observed for the RAD51 polymorphism. The influence of GSTT1 genotype on SCE-frequency in RAD51 variant allele carriers was not analysed as all individuals in this group (except one person) had the GSTT1 gene present. Our study shows that the combined analysis of polymorphisms in metabolizing enzymes may lead to a better understanding of their contribution to an individual's susceptibility to DEB.     

Genetic polymorphisms of DNA repair and xenobiotic-metabolizing enzymes: effects on levels of sister chromatid exchanges and chromosomal aberrations

Elevated levels of chromosomal aberrations (CAs) in peripheral blood lymphocytes, widely used as a cytogenetic biomarker of genotoxic effects, have been linked to cancer predisposition. However, tobacco smoking, occupational carcinogen exposure, or time since CA analysis do not appear to explain the cancer predictivity of CAs. Alternatively, the observed CA-cancer association could reflect unidentified exposures or individual susceptibility. We assessed the effects of genetic polymorphisms of DNA repair proteins and xenobiotic-metabolizing enzymes (XMEs) on the levels of CAs and sister chromatid exchanges (SCEs) in peripheral lymphocytes of 145 (CAs) and 60 (SCEs) healthy Caucasians. Genotypes of DNA repair genes X-ray repair cross-complementation group 1 (XRCC1 codons 194, 280, 399) and 3 (XRCC3 codon 241 [corrected]), and XME genes glutathione-S-transferase (GST) M1 and T1 and N-acetyl transferase 2 (NAT2) were determined using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP)-based methods. After Poisson regression adjustment for age, sex, smoking, country, and genotypes, a higher frequency of chromosome-type breaks was observed for NAT2 slow acetylators (in nonsmokers) and GSTT1 null subjects (in smokers). Individuals carrying variant alleles for XRCC1 codons 280 and 194 showed a decreased level of chromosome-type breaks. The effect of GSTM1 null and XRCC1 codon 399 genotypes on the frequency of CAs was modified by smoking. In linear regression models adjusting for age, sex, smoking, and genotypes, none of the polymorphisms significantly affected SCE frequency, although GSTT1 null subjects had a slightly elevated SCE level. Our results are in line with earlier findings on the influence of NAT2, GSTT1, and GSTM1 polymorphisms on the level of lymphocyte chromosome damage and suggest that also XRCC1 polymorphism affects CA frequencies, thus apparently influencing DNA repair phenotype. It remains to be examined whether these or other genetic polymorphisms could explain the observed cancer risk predictivity of high CA frequency.     

Polymorphisms in glutathione S-transferases in French vinyl chloride workers

The authors have recently demonstrated a significant gene–environment interaction between vinyl chloride exposure and polymorphisms in the DNA repair protein XRCC1 on the occurrence of mutant p53 biomarkers of vinyl chloride-induced genetic damage. The aim of this study was to examine the polymorphisms in the glutathione S-transferases (GSTs) as potential modifiers of this relationship, since these enzymes may be involved in the phase II metabolism of the reactive intermediates of vinyl chloride. A cohort of 211 French vinyl chloride workers was genotyped for common polymorphisms in GSTM1, GSTT1 and GSTP1. Although no independent, statistically significant effect of these polymorphisms on the occurrence of the mutant p53 biomarker was found, the null GSTM1 and null GSTT1 polymorphisms were found to interact with the XRCC1 polymorphism to increase the occurrence of the biomarker such that, for example, workers with at least one variant XRCC1 allele who were null for both GSTM1 and GSTT1 had a significant odds ratio for the biomarker (OR=8.4, 95% CI=1.3–54.0) compared with workers who were wild-type for all alleles, controlling for potential confounders including cumulative vinyl chloride exposure.     

Glutathione S-transferase gene polymorphisms in Turkish patients with diabetes mellitus

Glutathione S-transferases (GSTs) are enzymes involved in the metabolism of many disease-causing electrophilic substrates and protect the cells against oxidative stress. In the present study, we investigated the GSTM1, GSTT1 and GSTP1 gene polymorphisms in diabetic patients and healthy individuals and searched whether polymorphisms in GST genes are associated with diabetes mellitus (DM) in the Turkish population. The study population consisted of 98 unrelated healthy individuals and 98 patients with DM. Genotyping of GSTM1, GSTT1 and GSTP1 genes was performed using real time polymerase chain reaction with a Light Cycler instrument. Patients had a higher frequency of the GSTM1 null genotype than the control group (Odds ratios, OR = 3.7; 95% confidence intervals, CI = 2.05-6.70). However, there was no significant difference in the frequencies of the GSTT1 and GSTP1 gene polymorphisms between the patients and control group. The combined analysis of these three GST genotypes showed a further DM risk increase (OR = 5.7, 95% CI = 1.51-31.07). This is the first study to determine the association of diabetes with GST gene polymorphism in the Turkish population. These results show that GSTM1 null genotype may play a significant role in the aetiopathogeneses of DM and the GSTM1 gene may be a useful marker in the prediction of DM susceptibility of the Turkish population.     

Polymorphisms of DNA base‐excision repair genes APE/Ref‐1 and XRCC1 are not associated with the risk for Graves' disease

Oxidative stress has been implicated in etiopathogenesis of Graves' disease (GD). Increased lipid peroxidation and oxidative DNA damage have been found in GD patients. Oxidative DNA damage is mainly repaired by the base‐excision repair (BER) pathway. Polymorphisms in DNA‐repair genes have been associated with the increased risk of various diseases and could also be related to the etiology of GD. Therefore, we conducted a study including 197 patients with GD and age‐ and sex‐matched 303 healthy subjects to examine the role of single‐nucleotide polymorphisms of BER genes, APE/Ref‐1 (codon 148) and XRCC1 (codons 194 and 399) as a risk factor for GD. These polymorphisms were determined by quantitative real‐time PCR and melting curve analysis using LightCycler. No significant association was observed between the variant alleles of APE/Ref‐1 codon 148 [odds ratio (OR) = 0.89, 95% confidence interval (CI) = 0.69–1.17], XRCC1 codon 194 (OR = 1.24, 95% CI = 0.79–1.94), and XRCC1 codon 399 (OR = 1.12, 95% CI = 0.86–1.46) and GD. These preliminary results suggest that APE/Ref‐1 (codon 148) and XRCC1 (codons 194 and 399) polymorphisms are not significant risk factors for developing GD. Copyright © 2009 John Wiley & Sons, Ltd.     

GSTM1 and mEPHX polymorphisms in Parkinson's disease and age of onset

Both environmental and genetic factors are involved in the development of PD and biotransformation of exogenous and endogenous compounds and may play a role in inter-individual susceptibility. Therefore, we investigated the presence of null genotypes of GSTM1, GSTT1, and two polymorphisms of mEPHX in subjects with Parkinson's disease and in a reference population. The study included 35 male PD patients and a male control group including 283 subjects. Homozygosity of the histidine (H) 113 isoform of mEPHX was significantly increased in PD patients (odds ratio = 3.8 CI 95% 1. 2-11.8) and analysis of allele frequencies displayed an increased frequency of the H-allele among PD patients (odds ratio = 1.9 CI 95% 1.1-3.3). However, a significantly elevated median age for the onset of PD was found among GSTM1 gene carriers (median age = 68 years) compared to PD patients being GSTM1 null genotypes (median age = 57 years). Our observations suggest that (H) 113 isoform of mEPHX, which has been suggested as a low activity isoform, is overrepresented in PD patients and that inherited carriers of the GSTM1 gene postpone the onset of PD. These detoxification pathways may represent important protective mechanisms against reactive intermediates modifying the susceptibility and onset of PD.     

Influence of glutathione S-transferase polymorphisms (GSTT1, GSTM1, GSTP1) on type-2 diabetes mellitus (T2D) risk in an endogamous population from north India

Glutathione S-transferases (GSTs) belong to a group of multigene and multifunctional detoxification enzymes, which defend cells against a wide variety of toxic insults and oxidative stress. Oxidative stress leads to cellular dysfunction which contributes to the pathophysiology of diseases such as cancer, atherosclerosis, and diabetes mellitus. It is important to assess whether the glutathione S-Transferase (GSTT1, GSTM1 and GSTP1) genotypes are associated with type 2 diabetes mellitus as deletion polymorphisms have an impaired capability to counteract the oxidative stress which is a feature of diabetes. GSTT1, GSTM1 and GSTP1 gene polymorphisms were analysed in 321 patients and 309 healthy controls from an endogamous population from north India. An association analysis was carried out at two levels (a) individual genes and (b) their double and triple combinations. The proportion of GSTT1 and GSTM1 null genotypes was higher in diabetics compared to controls (GSTT1 30.8 vs. 21.0 %; GSTM1 49.5 vs. 27.2 %). The frequency of the null genotype at both loci was higher in diabetics (19.6 vs. 7.8 %) leading to an odds ratio of 2.90 (CI 1.76–4.78, P < 0.0001). At GSTP1locus, patients had a higher frequency of the V/V genotype (15.6 vs. 7.5 %) and significant susceptible odds ratio (2.56, CI 1.47–4.48, P < 0.001). A combination of null genotypes at GSTT1 and GSTM1 loci and V/V genotype of GSTP1 locus showed highest odds ratio (9.64, CI 1.53–60.63, P < 0.01). Overall this study highlights that GST genes may play an important role in the pathogenesis of type 2 diabetes. The risk is higher in individuals carrying more than one susceptible genotype at these loci. The potential role of GST polymorphisms as markers of susceptibility to type 2 diabetes needs further investigations in a larger number of patients and populations.     

Association of variations in monoamine oxidases A and B with Parkinson's disease subgroups

Idiopathic Parkinson's disease (PD) is an age dependent, neurodegenerative disorder and is predominantly a sporadic disease. A minority of patients has a positive family history for PD and the majority of those families exhibit a complex mode of inheritance. The monoamine oxidases A and B (MAO-A and -B) genes, which are involved in serotonin and dopamine metabolism, are possible candidate genes for susceptibility to PD. Previous association studies of MAO-A and -B in PD have been inconclusive. To determine the role of MAO-A and -B in the development of PD, we screened a sample of 96 patients with familial PD, 164 with sporadic PD, and 180 matched normal controls with dinucleotide repeat markers in these genes. MAO-A and -B gene polymorphisms were strongly associated with total PD (p < 0.00001), familial PD (p < 0.00001), and sporadic PD (p < 0.00001). There were no significant differences between familial or sporadic PD with age of onset younger than 50 years compared to those with age of onset older than 51 years for both MAO-A and -B genes. There was no linkage disequilibrium between these genes in male PD and control groups. The frequency of common haplotypes from MAO-A and -B was different in PD and control group (p = 0.02). Our data indicate that MAO-A and -B may play a role in susceptibility to PD in our sample.     

Polymorphisms of drug-metabolizing enzymes in healthy nonagenarians and centenarians: difference at GSTT1 locus

Drug metabolizing enzymes are involved in the detoxification of several drugs, environmental substances, and carcinogenic compounds, and their polymorphisms have been associated with risk for a variety of cancer. In this paper, we compared the frequency of polymorphisms in cytochrome P450-1A1 gene (CYP1A1), a phase 1 gene (oxidation, activation), and of two polymorphisms of glutathione S-transferase enzymes (GSTM1, GSTT1), two phase 2 genes (conjugation, detoxification). Two groups were studied and compared, i.e., 94 nonagenarians and centenarians and 418 control subjects of younger age. A significant difference in the proportion of nonagenarians and centenarians homozygotes for a GSTT1 deletion (28%) was observed in comparison to control subjects (19%, P = 0.03). The distribution of the other gene polymorphisms did not differ in the two groups. These findings on phase 2 drug-metabolizing enzyme gene polymorphisms may help in disentangling gene-environmental interactions which can have a role in successful aging and longevity, as well as in cancer incidence in the oldest old.     

GST,CYP and PON1 polymorphisms in farmers attributing ill health to organophosphate-containing sheep dip

Previously we reported that in sheep dippers exposed to organophosphates the frequency of paraoxonase (PON1) polymorphisms differed between those with or without self-reported ill health. We have now examined whether polymorphisms in other genes involved in xenobiotic metabolism alter disease risk in this population. There were elevated but non-significant risks associated with the CYP2D6 WT genotype (odds ratio (OR) 1.47, 95% CI 0.83–2.60), or a GSTP1*B or *C allele (OR 1.37, 95% CI 0.88–2.01) or being GSTM1*2/GSTT1*2 homozygous (OR 1.61, 95% CI 0.74–3.48). Similar results were generally obtained after the exclusion of subjects to obtain a more homogenous case-referent population: for double null GSTM1 and GSTT1 homozygotes the OR was 2.06 (95% CI 0.85–2.04). In those also likely to have been exposed to diazinon, risks associated with a GSTP1*B or *C allele (OR 1.82, 95% CI 0.92–3.63) or a GSTM1*2/GSTT1*2 homozygous (OR 2.60, 95% CI 0.72–10.42) were elevated but not to a significant extent. Risk associated with PON1 genotype and phenotype varied with CYP2D6 and GSTP1 genotype but not consistently with a priori hypotheses. Further work is necessary to delineate more clearly pathways of organophosphate activation and non-PON1 pathways of detoxification and to confirm whether CYP and GST polymorphisms alter disease risk in populations exposed to organophosphates.     

Absence of association between GSTM1 and GSTT1 polymorphisms and melanoma susceptibility: a meta-analysis

Glutathione S-transferases (GSTs) are a family of multifunctional enzymes that are involved in the metabolism of many xenobiotics, including a wide range of environmental carcinogens. The null genotypes GSTM1 and GSTT1 have been implicated in the development of carcinogenesis. We conducted a meta-analysis to examine the association of GSTM1 and GSTT1 homozygous deletion polymorphisms with melanoma risk. In total, 8 relevant studies were identified in searches of the PubMed and Embase databases: 8 investigated GSTM1 (1349 cases and 1560 controls) and 5 GSTT1 (977 cases and 1060 controls). Fixed- and random-effects models were used to assess the summary odds ratios (ORs). No significant association of the GSTM1 and GSTT1 polymorphisms or the GSTM1-GSTT1 interaction on the risk of melanoma was observed (for GSTM1: OR=1.09; 95% confidence interval, 0.94-1.27; and for GSTT1: OR=0.95; 95% confidence interval, 0.76-1.19). Similarly, no significant association was found in a subgroup analysis of hair color. These results indicate that the GSTM1 and GSTT1 polymorphisms may not be a risk factor for developing melanoma.