G2Cdb::Gene report

Gene id
G00002175
Gene symbol
GSTO1 (HGNC)
Species
Homo sapiens
Description
glutathione S-transferase omega 1
Orthologue
G00000926 (Mus musculus)

Databases (8)

Curated Gene
OTTHUMG00000019001 (Vega human gene)
Gene
ENSG00000148834 (Ensembl human gene)
9446 (Entrez Gene)
752 (G2Cdb plasticity & disease)
GSTO1 (GeneCards)
Literature
605482 (OMIM)
Marker Symbol
HGNC:13312 (HGNC)
Protein Sequence
P78417 (UniProt)

Synonyms (2)

  • GSTTLp28
  • P28

Literature (52)

Pubmed - other

  • No evidence for glutathione S-transferases GSTA2, GSTM2, GSTO1, GSTO2, and GSTZ1 in breast cancer risk.

    Andonova IE, Justenhoven C, Winter S, Hamann U, Baisch C, Rabstein S, Spickenheuer A, Harth V, Pesch B, Brüning T, Ko YD, Ganev V and Brauch H

    Dr Margarte Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany.

    Breast cancer is a complex disease and in recent years a number of breast cancer susceptibility genes have been identified, but the role of low penetrance susceptibility genes has not been completely resolved. Glutathione S-transferases (GSTs) are phase II xenobiotic metabolizing enzymes involved in the detoxification of chemical carcinogens and environmental pollutants and play an important role in cell defense mechanisms against oxidative stress. They have been in the spot light for the investigation of a potential association with breast cancer risk but so far, sparse or even no data for a potential contribution of GSTA2, GSTM2, GSTO, and GSTZ to breast cancer risk are available. We genotyped GSTA2_448_C > G (rs2180314), GSTA2_742_A > C (rs6577), GSTM2_-832_T > C (rs638820), GSTO1_-1242_G > A (rs2164624), GSTO1_419_A > C (rs4925), GSTO2_-183_A > G (rs2297235), GSTO2_342_A > G (rs156697), GSTZ1_-4378_A > G (rs1046428), and GSTZ1_94_G > A (rs3177427) by MALDI-TOF MS in the German GENICA breast cancer case-control collection of 1021 cases and 1015 controls and performed breast cancer risk association in general and with respect to the stratifications: menopausal status, family history of breast or ovarian cancer, use of oral contraceptives, use of hormone therapy, body mass index, and smoking as well as histopathological tumor characteristics including hormone receptor status, grade, histology, and node status. We did not observe any breast cancer risk associations and conclude that it is unlikely that glutathione S-transferases GSTA2, GSTM2, GSTO1, GSTO2, and GSTZ1 participate in breast cancer susceptibility.

    Breast cancer research and treatment 2010;121;2;497-502

  • Genetic polymorphisms in glutathione S-transferase (GST) superfamily and arsenic metabolism in residents of the Red River Delta, Vietnam.

    Agusa T, Iwata H, Fujihara J, Kunito T, Takeshita H, Minh TB, Trang PT, Viet PH and Tanabe S

    Department of Legal Medicine, Shimane University Faculty of Medicine, Enya 89-1, Izumo 693-8501, Japan; Center for Marine Environmental Studies (CMES), Ehime University, Bunkyo-cho 2-5, Matsuyama 790-8577, Japan.

    To elucidate the role of genetic factors in arsenic metabolism, we investigated associations of genetic polymorphisms in the members of glutathione S-transferase (GST) superfamily with the arsenic concentrations in hair and urine, and urinary arsenic profile in residents in the Red River Delta, Vietnam. Genotyping was conducted for GST omega1 (GSTO1) Ala140Asp, Glu155del, Glu208Lys, Thr217Asn, and Ala236Val, GST omega2 (GSTO2) Asn142Asp, GST pi1 (GSTP1) Ile105Val, GST mu1 (GSTM1) wild/null, and GST theta1 (GSTT1) wild/null. There were no mutation alleles for GSTO1 Glu208Lys, Thr217Asn, and Ala236Val in this population. GSTO1 Glu155del hetero type showed higher urinary concentration of As(V) than the wild homo type. Higher percentage of DMA(V) in urine of GSTM1 wild type was observed compared with that of the null type. Strong correlations between GSTP1 Ile105Val and arsenic exposure level and profile were observed in this study. Especially, heterozygote of GSTP1 Ile105Val had a higher metabolic capacity from inorganic arsenic to monomethyl arsenic, while the opposite trend was observed for ability of metabolism from As(V) to As(III). Furthermore, other factors including sex, age, body mass index, arsenic level in drinking water, and genotypes of As (+3 oxidation state) methyltransferase (AS3MT) were also significantly co-associated with arsenic level and profile in the Vietnamese. To our knowledge, this is the first study indicating the associations of genetic factors of GST superfamily with arsenic metabolism in a Vietnamese population.

    Toxicology and applied pharmacology 2010;242;3;352-62

  • A significantly joint effect between arsenic and occupational exposures and risk genotypes/diplotypes of CYP2E1, GSTO1 and GSTO2 on risk of urothelial carcinoma.

    Wang YH, Yeh SD, Shen KH, Shen CH, Juang GD, Hsu LI, Chiou HY and Chen CJ

    School of Public Health, Taipei Medical University, Taipei 110, Taiwan.

    Cigarette smoking, arsenic and occupational exposures are well-known risk factors for the development of urothelial carcinoma (UC). Therefore, the aim of this study is to investigate whether the effect of cigarette smoking, alcohol consumption, arsenic and occupational exposures on risk of UC could be modified by genetic polymorphisms of cytochrome P450 2E1 and glutathione S-transferase omega. A hospital-based case-control study consisted of 520 histologically confirmed UC cases, and 520 age- and gender-matched cancer-free controls were carried out from September 1998 to December 2007. Genotyping of CYP2E1, GSTO1 and GSTO2 was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Subjects with both of cigarette smoking and alcohol consumption have a significantly increased UC risk (odds ratio [OR]=2.9; 95% confidence interval [CI]=1.9-4.4). Significantly increased UC risks of 1.5 and 1.9 were found for study subjects with high arsenic exposure and those who have been exposed to two or more occupational exposures, respectively. A significantly increased UC risk of 3.9 was observed in study subjects with H2-H2 diplotype of GSTO1 and GSTO2. The significantly highest UC risk of 9.0 was found for those with all environmental risk factors of cigarette smoking, alcohol consumption, arsenic and occupational exposures and two or more risk genotypes/diplotypes of CYP2E1, GSTO1 and GSTO2. Our findings suggest that a significantly joint effect of cigarette smoking, alcohol consumption, arsenic and occupational exposures and risk genotypes/diplotypes of CYP2E1, GSTO1 and GSTO2 on risk of UC was found.

    Toxicology and applied pharmacology 2009;241;1;111-8

  • Synergistic effect of polymorphisms of paraoxonase gene cluster and arsenic exposure on electrocardiogram abnormality.

    Liao YT, Li WF, Chen CJ, Prineas RJ, Chen WJ, Zhang ZM, Sun CW and Wang SL

    Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Taiwan.

    Arsenic has been linked to increased prevalence of cancer and cardiovascular disease (CVD), but the long-term impact of arsenic exposure remains unclear. Human paraoxonase (PON1) is a high-density lipoprotein-associated antioxidant enzyme which hydrolyzes oxidized lipids and is thought to be protective against atherosclerosis, but evidence remains limited to case-control studies. Only recently have genes encoding enzymes responsible for arsenic metabolism, such as AS3MT and GSTO, been cloned and characterized. This study was designed to evaluate the synergistic interaction of genetic factors and arsenic exposure on electrocardiogram abnormality. A total of 216 residents from three tap water implemented villages of previous arseniasis-hyperendemic regions in Taiwan were prospectively followed for an average of 8 years. For each resident, a 12-lead conventional electrocardiogram (ECG) was recorded and coded by Minnesota Code standard criteria. Eight functional polymorphisms of PON1, PON2, AS3MT, GSTO1, and GSTO2 were examined for genetic susceptibility to ECG abnormality. Among 42 incident cases with ECG deterioration identified among 121 baseline-normal subjects, arsenic exposure was significantly correlated with incidence of ECG abnormality. In addition, polymorphisms in two paraoxonase genes were also found associated with the incidence of ECG abnormality. A haplotype R-C-S constituted by polymorphisms of PON1 Q192R, -108C/T and PON2 C311S was linked to the increased risk. Subjects exposed to high levels of As (cumulative As exposure >14.7 ppm-year or drinking artesian well water >21 years) and carrying the R-C-S haplotype had significantly increased risks for ECG abnormality over those with only one risk factor. Results of this study showed a long-term arsenic effect on ECG abnormality and significant gene-gene and gene-environment interactions linked to the incidence of CVD. This finding might have important implications for a novel and potentially useful biomarker of arsenic risk.

    Toxicology and applied pharmacology 2009;239;2;178-83

  • Lack of association of glutathione-S-transferase omega 1(A140D) and omega 2 (N142D) gene polymorphisms with urinary arsenic profile and oxidative stress status in arsenic-exposed population.

    Xu Y, Li X, Zheng Q, Wang H, Wang Y and Sun G

    Department of Occupational and Environmental Health, College of Public Health, China Medical University, Shenyang, Liaoning, PR China.

    Individual variability in arsenic metabolism is suggested to be associated with the effects of chronic arsenic exposure on health. Glutathione-S-transferase omega (GSTO) 1 and 2 are known to have the activity of monomethyl arsenate [MMA(V)] reductase, which is the rate-limiting enzyme for the biotransformation of inorganic arsenic. This study was conducted to investigate the relationship between polymorphisms in the GSTO1 and GSTO2 genes and arsenic metabolism and oxidative stress status in Chinese populations chronically exposed to different levels of arsenic in drinking water. Two polymorphisms (GSTO1*A140D and GSTO2*N142D) with relatively higher mutation frequencies in the Chinese population were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The allele frequencies of 140D and 142D in the entire study population were 0.17 and 0.25, respectively. There were no significant differences in the urinary arsenic profile, the blood reduced glutathione (GSH) levels, the blood superoxide dismutase (SOD) activity, or the urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels between the study subjects with different genotypes of GSTO1*A140D or GSTO2*N142D. Multivariate analysis revealed that there was no association between the urinary profile or oxidative stress status and the polymorphism of GSTO1*A140D or GSTO2*N142D. Collectively, polymorphisms in GSTO1 or GSTO2 do not appear to contribute to the large individual variability in arsenic metabolism or susceptibility to arsenicosis.

    Mutation research 2009;679;1-2;44-9

  • Association of glutathione-S-transferase omega haplotypes with susceptibility to chronic obstructive pulmonary disease.

    Yanbaeva DG, Wouters EF, Dentener MA, Spruit MA and Reynaert NL

    Department of Respiratory Medicine, Nutrition and Toxicology Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, The Netherlands.

    Cigarette smoking is the main risk factor for developing the inflammatory lung disease chronic obstructive pulmonary disease (COPD). Differences in susceptibility among smokers have been attributed to a genetic predisposition. A recent publication on the Framingham Heart Study found a strong association of the Asn142Asp SNP in Glutatthione-S-transferase Omega (GSTO) 2 with forced expiratory volume in the first second (FEV(1)) and forced vital capacity (FVC). FEV(1) is the main parameter reflecting the degree of airflow limitation in patients with COPD. Therefore the present study was undertaken to investigate whether the Asn142Asp polymorphism in GSTO2 occurs more frequently in patients with COPD than healthy subjects and to replicate the finding that it strongly correlates with FEV(1). Furthermore, the Ala140Asp substitution in GSTO1 was examined. Genotyping was carried out in 195 healthy controls and 355 patients with COPD. The results demonstrate that the Asn142Asp polymorphism in GSTO2 and the GSTO1140Asp/GSTO2142Asp haplotype were associated with increased risk of COPD. However, single-marker and haplotype-based analyses failed to reveal an association between lung function parameters and investigated non-synonymous coding SNPs in the GSTO genes. In conclusion, GSTO2 is a candidate gene for COPD, but is not associated with FEV(1).

    Free radical research 2009;43;8;738-43

  • An analysis of methylenetetrahydrofolate reductase and glutathione S-transferase omega-1 genes as modifiers of the cerebral response to ischemia.

    Peddareddygari LR, Dutra AV, Levenstien MA, Sen S and Grewal RP

    New Jersey Neuroscience Institute at JFK Medical Center, 65 James Street, Edison, New Jersey, USA. lrpeddareddygari@solarishs.org

    Background: Cerebral ischemia involves a series of reactions which ultimately influence the final volume of a brain infarction. We hypothesize that polymorphisms in genes encoding proteins involved in these reactions could act as modifiers of the cerebral response to ischemia and impact the resultant stroke volume. The final volume of a cerebral infarct is important as it correlates with the morbidity and mortality associated with non-lacunar ischemic strokes.

    Methods: The proteins encoded by the methylenetetrahydrofolate reductase (MTHFR) and glutathione S-transferase omega-1 (GSTO-1) genes are, through oxidative mechanisms, key participants in the cerebral response to ischemia. On the basis of these biological activities, they were selected as candidate genes for further investigation. We analyzed the C677T polymorphism in the MTHFR gene and the C419A polymorphism in the GSTO-1 gene in 128 patients with non-lacunar ischemic strokes.

    Results: We found no significant association of either the MTHFR (p = 0.72) or GSTO-1 (p = 0.58) polymorphisms with cerebral infarct volume.

    Conclusion: Our study shows no major gene effect of either the MTHFR or GSTO-1 genes as a modifier of ischemic stroke volume. However, given the relatively small sample size, a minor gene effect is not excluded by this investigation.

    BMC neurology 2009;9;37

  • Polymorphism of glutathione S-transferase Omega gene: association with risk of childhood acute lymphoblastic leukemia.

    Pongstaporn W, Pakakasama S, Sanguansin S, Hongeng S and Petmitr S

    Faculty of Medical Technology, Rangsit University, Pathum thani, Thailand.

    Purpose: To evaluate the association between glutathione S-transferase Omega (GSTO) genes polymorphism and the susceptibility of acute lymphoblast leukemia (ALL).

    Methods: The polymorphism of GSTO1 and GSTO2 genes were analyzed in 99 ALL patients compared with 100 healthy children by PCR-based restriction fragment length polymorphism (RFLP) analysis.

    Results: GSTO1*A140D polymorphism was significantly associated with susceptibility to ALL (OR = 2.24, 95% CI = 1.16-4.35, P = 0.009) whereas, GSTO2*N142D genotype was significantly interacted with high risk group of childhood ALL (OR = 5.52, 95% CI = 1.72-17.71, P = 0.004).

    Conclusion: This study revealed gene polymorphism in glutathione S-transferase Omega class may be a risk factor to the development of acute childhood lymphoblastic leukemia.

    Journal of cancer research and clinical oncology 2009;135;5;673-8

  • Diversity of glutathione s-transferase omega 1 (a140d) and 2 (n142d) gene polymorphisms in worldwide populations.

    Takeshita H, Fujihara J, Takastuka H, Agusa T, Yasuda T and Kunito T

    Department of Legal Medicine, Shimane University School of Medicine, Izumo, Shimane, Japan. htakeshi@med.shimane-u.ac.jp

    1. Glutathione S-transferase class omega (GSTO) 1 and 2 are members of the glutathione-S-transferase family, which uses glutathione in the process of the biotransformation of drugs, xenobiotics and oxidative stress. Associations with the age-at-onset of Alzheimer's and Parkinson's diseases have been shown in the genetic polymorphism of GSTO1 and GSTO2. 2. In the present study, the frequencies of GSTO1*A140D and GSTO2*N142D in Ovambos (n = 163), Turks (n = 194), Mongolians (n = 243) and Japanese (n = 102) were investigated and compared with findings from other studies. Detection of these single nucleotide polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism analysis. 3. The allele frequencies of these polymorphisms in Ovambos, Turks, Mongolians and Japanese were 0.040, 0.085, 0.128 and 0.108, respectively, for GSTO1*A140D and 0.583, 0.219, 0.173 and 0.216, respectively, for GSTO2*N142D. Ovambos showed the lowest allele frequency of GSTO1*A140D. Conversely, Africans, including Ovambos, showed higher allele frequencies of GSTO2*N142D than Caucasians and Asians. 4. The existence of a certain genetic heterogeneity in the worldwide distribution of these two polymorphisms is revealed in the present study.

    Clinical and experimental pharmacology & physiology 2009;36;3;283-6

  • Nuclear translocation of glutathione transferase omega is a progression marker in Barrett's esophagus.

    Piaggi S, Marchi S, Ciancia E, Debortoli N, Lazzarotti A, Saviozzi M, Raggi C, Fierabracci V, Visvikis A, Bisgaard HC, Casini AF and Paolicchi A

    Dipartimento di Patologia Sperimentale, Sezione Patologia Generale, Pisa, Italy. s.piaggi@med.unipi.it

    Barrett's esophagus (BE) represents a major risk factor for esophageal adenocarcinoma (AC). For this reason, patients with BE are subjected to a systematic endoscopic surveillance to detect initial evolution towards non-invasive neoplasia (NiN) and cancer, that eventually occurs only in a small fraction of BE patients. This study was aimed to investigate the possible role of glutathione-S-transferase-omega 1 (GSTO1), a recently discovered member of the glutathione-S-transferase family, as a progression marker in the Barrett's disease in order to improve the diagnosis of NiN in BE and to understand the mechanisms of the progression from BE to AC. We investigated the expression and subcellular localization of GSTO1 in biopsies from patients with BE and in human cancer cell lines subjected to heath shock treatment. A selective nuclear localisation of GSTO1 was found in 16/16 biopsies with low- or high-grade NiN, while it appeared in only 4/22 BE biopsies without signs of NiN (P<0.0001). Among biopsies of BE without NiN, diffuse (nuclear and cytoplasmic) staining was found in 5/22 cases, while selective cytoplasmic localisation was found in 13/22. The 6 cases with indefinite grade of NiN were equally divided between nuclear, cytoplasmic and diffuse staining (2 each, respectively). Experiments in vitro showed that in human HeLa cancer cells, GSTO1 translocates into the nucleus as a consequence of heath shock. These findings suggested that the nuclear translocation of glutathione-S-transferase-omega 1 could be involved in the stress response of human cells playing a role in the cancer progression of Barrett's esophagus. Its immunohistochemical detection could represent a useful tool in the grading of Barrett's disease.

    Oncology reports 2009;21;2;283-7

  • Association study between the genetic polymorphisms of glutathione-related enzymes and schizophrenia in a Japanese population.

    Matsuzawa D, Hashimoto K, Hashimoto T, Shimizu E, Watanabe H, Fujita Y and Iyo M

    Department of Psychiatry, Chiba University Graduate School of Medicine, Japan.

    Several lines of evidence suggest that oxidative stress plays a role in the pathogenesis of schizophrenia, and that glutathione (GSH) plays a crucial role in antioxidant defense mechanisms. In this study, we performed association studies between GSH-related genes (GSTM1, GSTP1, GSTO1, GSTT1, GSTT2, GPX1, and GCLM) and schizophrenia in a Japanese population. The overall distributions of the genotypes and alleles of each gene were not different between schizophrenic patients and controls. Subjects with residual-type schizophrenia showed different distributions in the analysis of GSTM1 genotype and in the combination analysis of GSTs, GPX1, and GCLM genotypes although the small sample size should be considered as a limitation of this study. In addition, our findings revealed that there were large ethnic differences in the genotype distributions of those GSH-related genes. The present study suggests that GSH-related genes may not play a major role in the pathogenesis of schizophrenia in a Japanese population. However, a dysregulation of GSH metabolism may be one of the vulnerability factors contributing to the development of a certain type of schizophrenia, and it is likely that the ethnic background should be considered in further study for those GSH-related genes.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2009;150B;1;86-94

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

    Starr JM, Shiels PG, Harris SE, Pattie A, Pearce MS, Relton CL and Deary IJ

    MRC Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Royal Victoria Hospital, Edinburgh EH4 2DN, UK. jstarr@staffmail.ed.ac.uk

    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.

    Funded by: Biotechnology and Biological Sciences Research Council: S18386; Chief Scientist Office: CZB/4/505, ETM/55; Medical Research Council; Wellcome Trust

    Mechanisms of ageing and development 2008;129;12;745-51

  • Association study between polymorphisms in glutathione-related genes and methamphetamine use disorder in a Japanese population.

    Hashimoto T, Hashimoto K, Miyatake R, Matsuzawa D, Sekine Y, Inada T, Ozaki N, Iwata N, Harano M, Komiyama T, Yamada M, Sora I, Ujike H and Iyo M

    Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan. hashimoto@faculty.chiba-u.jp

    Accumulating evidence suggests that oxidative stress plays a role in the mechanisms of action of methamphetamine (METH) in the brain. In the present study, we investigated the association between the genetic polymorphisms among glutathione (GSH)-related enzymes; glutathione S-transferases (GSTs) such as GSTT1 (Non-deletion/Null), GSTT2 (Met139Ile), GSTA1 (-69C/T), and GSTO1 (Ala140Asp); glutathione peroxidase 1 (GPX1) (Pro198Leu); and glutamate-cysteine ligase modifier (GCLM) subunit and METH use disorder in a Japanese population. Two hundred eighteen METH abusers and 233 healthy controls were enrolled in the study. There was a significant difference in GSTT1 genotype frequency between patients with METH psychosis and controls (P = 0.039, odds ratio: 1.52, 95% CI 1.03-2.24). Furthermore, the frequency (66.0%) of the GSTT1 null genotype among prolonged-type METH psychotic patients with spontaneous relapse was significantly higher (P = 0.025, odds ratio: 2.43, 95% CI 1.13-5.23) than that (44.4%) of transient-type METH psychotic patients without spontaneous relapse. However, there were no associations between the polymorphisms of other genes and METH abuse. The present study suggests that the polymorphism of the GSTT1 gene might be a genetic risk factor of the development of METH psychosis in a Japanese population.

    American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 2008;147B;7;1040-6

  • Polymorphisms of glutathione S-transferase A1 and O1 and breast cancer among postmenopausal Danish women.

    Olsen A, Autrup H, Sørensen M, Overvad K and Tjønneland A

    Institute of Cancer Epidemiology, The Danish Cancer Society, Aalborg, Denmark. anja@cancer.dk

    The glutathione S-transferase (GST) family of enzymes is involved in the protection of the cell against foreign compounds and may consequently play a role in the development of cancer. Two of the family members, GSTA1 and GSTO1, have only been considered in a very limited number of studies. The objective of this study was to evaluate the potential relationships between GSTA1 and GSTO1 polymorphisms and breast cancer, taking into account the estrogen receptor statuses of the tumors and potential interactions with smoking, and intake of fruits and vegetables. The basis for the study was a nested case-control study including 396 postmenopausal pairs. Genetic polymorphisms were determined by restriction-fragment length polymorphism-polymerase chain reaction methods, and risks for breast cancer were estimated using conditional logistic regression. No association between GSTA1 polymorphism and breast cancer was found whereas carriers of the GSTO1 *B/*B genotype had higher risks of breast cancer when compared with carriers of the GSTO1 *A/*A genotype (incidence rate ratio 1.62, 95% confidence interval: 1.01-2.61). This association was strongest with regard to estrogen receptor positive breast cancer (incidence rate ratio 2.16, 95% confidence interval: 1.21-3.84). No signs of interaction with smoking or intake of fruits and vegetables were found for either GSTA1 or GSTO1 polymorphism. The study suggests that postmenopausal carriers of the GSTO1 *B/*B genotype may be at increased risk of especially estrogen receptor positive breast cancer. The finding of a higher risk with this genotype is in accordance with the only previous study. Further research is needed to confirm the finding.

    European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation (ECP) 2008;17;3;225-9

  • Polymorphisms of Glutathione S-transferases Omega-1 among ethnic populations in China.

    Fu S, Wu J, Chen F, Sun D and Fu S

    The Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, 150081, China. songbofu@163.com

    Background: Glutathione S-transferases (GSTs) is a genetic factor for many diseases and exhibits great diversities among various populations. We assessed association of the genotypes of Glutathione S-transferases Omega-1 (GSTO1) A140D with ethnicity in China.

    Results: Peripheral blood samples were obtained from 1314 individuals from 14 ethnic groups. Polymorphisms of GSTO1 A140D were measured using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Logistic regression was employed to adjustment for regional factor. The frequency of GSTO1 140A allele was 15.49% in the total 14 ethnic populations. Compared to Han ethnic group, two ethnic populations were more likely to have AA or CA genotype [odds ratio (OR): 1.77, 95% confidence interval (95% CI): 1.05-2.98 for Uygur and OR: 1.78, 95% CI: 1.18-2.69 for Hui]. However, there were no statistically significant differences across 14 ethnic groups when region factor was adjusted. In Han ethnicity, region was significantly associated with AA or CA genotype. Han individuals who resided in North-west of China were more likely to have these genotypes than those in South of China (OR: 1.63, 95% CI: 1.21-2.20).

    Conclusion: The prevalence of the GSTO1 140A varied significantly among different regional populations in China, which showed that geography played a more important role in the population differentiation for this allele than the ethnicity/race.

    BMC genetics 2008;9;29

  • Association study on glutathione S-transferase omega 1 and 2 and familial ALS.

    van de Giessen E, Fogh I, Gopinath S, Smith B, Hu X, Powell J, Andersen P, Nicholson G, Al Chalabi A and Shaw CE

    Department of Neurology, Institute of Psychiatry, King's College London, London, UK. elsmarieke@gmail.com

    Glutathione S-transferase omega 1 and 2 (GSTO1 and 2) protect from oxidative stress, a possible pathogenic mechanism underlying the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. Significant association of age of onset in Alzheimer's patients with GSTO1 and 2 had recently been identified, suggesting a possibly similar association with ALS. In this study 12 Hapmap tagged SNPs in GSTO1 and 2 were genotyped in 251 Caucasian British, Australian and Swedish familial ALS (FALS) cases. No association was found for age of onset and survival of FALS in the British and Australian patients. In the Swedish patients, association for age of onset was found with several SNPs (p = 0.003-0.048). These results suggest a possible effect of the GSTO1 and 2 locus on age of onset of FALS.

    Funded by: Medical Research Council: G0500289

    Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases 2008;9;2;81-4

  • Genetic profiling of genes from the oxidative stress pathway among North and South Indians.

    Tiwari AK, Punia S, Juyal RC and Thelma BK

    Department of Genetics, University of Delhi South Campus, New Delhi 110021, India.

    The case-control association study design has been extensively used for elucidating the genetic basis of complex traits. Considerable variation in frequencies of various gene polymorphisms has been reported across different populations and ethnic groups. Thus before beginning such studies, one must know the gene variants that exist in the population. Such information is not available for the ethnically distinct Indian population, which, on the basis of the languages spoken, can be further subdivided into Indo-Europeans (North Indians) and Dravidians (South Indians). In this study we provide information on allele and genotype frequencies, pairwise linkage disequilibrium, and predominant haplotypes in two populations (North India, n=96; South India, n=96) for several of the commonly investigated polymorphisms in the oxidative stress pathway genes. Of the 33 polymorphisms in 19 genes tested, significant differences in allele and genotype frequencies between the two populations were observed for SOD3 Ala58Thr, UCP1-3826 C/T, NOS3-786 T/C, and TNFA-308 G/A polymorphisms.

    Human biology 2008;80;2;161-79

  • Genetic variants associated with arsenic susceptibility: study of purine nucleoside phosphorylase, arsenic (+3) methyltransferase, and glutathione S-transferase omega genes.

    De Chaudhuri S, Ghosh P, Sarma N, Majumdar P, Sau TJ, Basu S, Roychoudhury S, Ray K and Giri AK

    Molecular and Human Genetics Division, Indian Institute of Chemical Biology, Kolkata, India.

    Background: Individual variability in arsenic metabolism may underlie individual susceptibility toward arsenic-induced skin lesions and skin cancer. Metabolism of arsenic proceeds through sequential reduction and oxidative methylation being mediated by the following genes: purine nucleoside phosphorylase (PNP), arsenic (+3) methyltransferase (As3MT), glutathione S-transferase omega 1 (GSTO1), and omega 2 (GSTO2). PNP functions as arsenate reductase; As3MT methylates inorganic arsenic and its metabolites; and both GSTO1 and GSTO2 reduce the metabolites. Alteration in functions of these gene products may lead to arsenic-specific disease manifestations.

    Objectives: To find any probable association between arsenicism and the exonic single nucleotide polymorphisms (SNPs) of the above-mentioned arsenic-metabolizing genes, we screened all the exons in those genes in an arsenic-exposed population.

    Methods: Using polymerase chain reaction restriction fragment length polymorphism analysis, we screened the exons in 25 cases (individuals with arsenic-induced skin lesions) and 25 controls (individuals without arsenic-induced skin lesions), both groups drinking similar arsenic-contaminated water. The exonic SNPs identified were further genotyped in a total of 428 genetically unrelated individuals (229 cases and 199 controls) for association study.

    Results: Among four candidate genes, PNP, As3MT, GSTO1, and GSTO2, we found that distribution of three exonic polymorphisms, His20His, Gly51Ser, and Pro57Pro of PNP, was associated with arsenicism. Genotypes having the minor alleles were significantly overrepresented in the case group: odds ratio (OR) = 1.69 [95% confidence interval (CI), 1.08-2.66] for His20His; OR = 1.66 [95% CI, 1.04-2.64] for Gly51Ser; and OR = 1.67 [95% CI, 1.05-2.66] for Pro57Pro.

    Conclusions: The results indicate that the three PNP variants render individuals susceptible toward developing arsenic-induced skin lesions.

    Environmental health perspectives 2008;116;4;501-5

  • Genetic variants of glutathione S-transferase as possible risk factors for hepatocellular carcinoma: a HuGE systematic review and meta-analysis.

    White DL, Li D, Nurgalieva Z and El-Serag HB

    The Section of Gastroenterology, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, Houston, TX 77030, USA.

    The authors performed a systematic review and meta-analysis to determine the effect of polymorphisms in genes encoding glutathione S-transferases (GSTs), phase II isoenzymes involved in cellular detoxification, on risk of hepatocellular carcinoma (HCC). Fifteen eligible studies were identified: 14 evaluated GSTM1; 13, GSTT1; three, GSTP1; and one each evaluated GSTM2, GSTM3, GSTA1, GSTA4, GSTO1, and GSTO2, respectively. All were case-control studies performed in populations with high (Asian, African) and medium (European) HCC incidence rates. Random-effects meta-analyses suggested a small excess risk of HCC with GSTT1 null (odds ratio (OR) = 1.19, 95% confidence interval (CI): 0.99, 1.44) and possibly GSTM1 null (OR = 1.16, 95% CI: 0.89, 1.53) genotypes. Cumulative meta-analyses demonstrated that both pooled estimators generally trended toward a small excess risk with publication of more recent studies. Results for GSTP1 A313G suggested no excess risk (OR = 0.75, 95% CI: 0.50, 1.15). A number of potentially interesting gene-gene and gene-environment interactions were reported, but these were too few and inconsistent to allow meta-analysis. The overall results suggest that there may be a small excess risk of HCC in individuals with GSTT1 null and possibly also with GSTM1 null genotypes. However, given the relatively limited total number of subjects examined and observed between-study heterogeneity, chance could not be excluded.

    American journal of epidemiology 2008;167;4;377-89

  • Polymorphism of glutathione transferase Omega 1 in a population exposed to a high environmental arsenic burden.

    Paiva L, Marcos R, Creus A, Coggan M, Oakley AJ and Board PG

    Group of Mutagenesis, Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, Spain.

    The aim of this study was to investigate genetic variation in glutathione transferase omega 1 (GSTO1-1) in Atacameños, an indigenous population from Chile that has been exposed to environmental arsenic for many generations. GSTO1-1 is thought to catalyse the rate-limiting step in the biotransformation of arsenic in humans and may modulate the response of cancer patients to arsenic trioxide therapy. Allele frequencies were determined by PCR-based methods and a polymorphic variant (GSTO1-1 Val236) was expressed in Escherichia coli and functionally characterized. Urinary arsenic profiles were determined by inductive coupled plasma/mass spectrometry.

    Results: A novel allele resulting in an Ala236Val substitution that has not been functionally characterized was detected in Atacameños and Chilean participants at a frequency of 0.033 and 0.009, respectively. The Val236 isoenzyme has diminished specific activity (10-20%) with a range of substrates. This loss of activity appears to result from a decrease in the kcat. The Val236 variant is also unstable and rapidly loses activity during purification or when heated at 45 degrees C. The percent of inorganic arsenic in the urine of 205 Chilean participants showed a bimodal distribution that was not associated with the Ala140Asp, Glu155del or Ala236Val polymorphisms in GSTO1-1.

    Conclusion: It is likely that heterozygotes inheriting the Val236 variant subunit would have a partial deficiency of GSTO1-1 activity. Despite their effects on enzyme function the known variants of GSTO1-1 do not appear to explain the observed variability in the excretion of inorganic arsenic.

    Pharmacogenetics and genomics 2008;18;1;1-10

  • Polymorphisms of homocysteine metabolism are associated with intracranial aneurysms.

    Semmler A, Linnebank M, Krex D, Götz A, Moskau S, Ziegler A and Simon M

    Department of Neurology, University of Bonn, Bonn, Germany.

    Background: Impaired homocysteine metabolism is associated with a number of vasculopathies including extracranial aneurysms. We analyzed the possible association of nine genetic variants of homocysteine metabolism with the occurrence of intracranial aneurysms.

    Methods: Caucasian patients (n = 255) treated at two German hospitals for intracranial aneurysms and local controls (n = 348) were genotyped for the following polymorphisms: methionine synthase (MTR) c.2756A-->G, methylenetetrahydrofolate reductase (MTHFR) c.677C-->T, MTHFR c.1298A-->C, cystathionine beta-synthase (CBS) c.844_855ins68, CBS c.833T-->C, dihydrofolate reductase (DHFR) c.594 + 59del19bp, glutathione S-transferase Omega-1 (GSTO1) c.428C-->A, reduced folate carrier 1 (RFC1) c.80G-->A and transcobalamin 2 (Tc2) c.776C-->G.

    Results: The G-allele of the missense polymorphism Tc2 c.777C-->G was found to be underrepresented in patients, suggesting that this variant may protect from the formation of cerebral aneurysms [odds ratio per two risk alleles (OR) 0.48; 95% confidence interval (CI) 0.30-0.77; p = 0.002]. We obtained borderline results for the G-allele of RFC1 c.80G-->A (OR 1.64; 95% CI 1.01-2.65; p = 0.051) and the insertion allele of DHFR c.594 + 59del19bp (OR 1.61; 95% CI 1.00-2.60; p = 0.059), which were found to be overrepresented in patients.

    Conclusion: Polymorphisms of homocysteine metabolism are possible risk factors for the formation of intracranial aneurysms.

    Cerebrovascular diseases (Basel, Switzerland) 2008;26;4;425-9

  • Deletion of Glu155 causes a deficiency of glutathione transferase Omega 1-1 but does not alter sensitivity to arsenic trioxide and other cytotoxic drugs.

    Schmuck E, Cappello J, Coggan M, Brew J, Cavanaugh JA, Blackburn AC, Baker RT, Eyre HJ, Sutherland GR and Board PG

    John Curtin School of Medical Research, Australian National University, Canberra, Australia.

    The Omega class glutathione transferase GSTO1-1 can catalyze the reduction of pentavalent methylated arsenic species and is responsible for the biotransfomation of potentially toxic alpha-haloketones. We investigated the cause of GSTO1-1 deficiency in the T-47D breast cancer cell line and found that the cell line is hemizygous for a polymorphic allele that encodes the deletion of Glu155. Northern and Western blots show that T-47D cells contain GSTO1 mRNA but no GSTO1-1 protein suggesting that the deletion of Glu155 causes GSTO1-1 deficiency in vivo. In further support of this contention we found that lymphoblastoid cell lines from subjects who are heterozygous for the deletion of Glu155 have only 60% of normal activity with the GSTO1-1 specific substrate 4-nitrophenacyl glutathione. Pulse-chase studies showed that the deletion of Glu155 causes increased turnover of GSTO1-1 in T47-D cells. These data establish the fact that the polymorphic deletion of Glu155 can cause GSTO1-1 deficiency in vivo. GSTO1-1 expression is elevated in some cell lines that are resistant to the cytotoxic cancer drugs adriamycin, etoposide and cisplatinum but its specific contribution to multi drug resistance has not been evaluated. In this study GSTO1-1 deficient T47-D cells were used to determine if GSTO1-1 contributes directly to arsenic and drug resistance. We established stable expression of normal GSTO1-1 in T-47D cells and found that this did not alter sensitivity to arsenic trioxide, cisplatinum daunorubicin or etoposide.

    The international journal of biochemistry & cell biology 2008;40;11;2553-9

  • Association of the glutathione S-transferase omega-1 Ala140Asp polymorphism with cerebrovascular atherosclerosis and plaque-associated interleukin-1 alpha expression.

    Kölsch H, Larionov S, Dedeck O, Orantes M, Birkenmeier G, Griffin WS and Thal DR

    Glutathione S-transferase omega-1 is a multifunctional enzyme. The Asp/Asp genotype of the Ala140Asp polymorphism of the GSTO1 gene has been alleged to increase the risk of vascular dementia. The objective of this study is to address the question of whether common vessel disorders known to cause vascular dementia are modified in their severity by this polymorphism.

    Methods: The severity and expansion of atherosclerosis in the circle of Willis vessels, cerebral small vessel disease, and cerebral amyloid angiopathy were studied in a sample of 79 autopsy cases. Genotyping of the GSTO1 Ala140Asp polymorphism as well as immunohistochemistry for glutathione S-transferase omega-1 was performed.

    Results: Carriers of the GSTO1 Asp/Asp genotype presented with more severe and widespread atherosclerosis than noncarriers. However, there was no effect on small vessel disease expansion and cerebral amyloid angiopathy severity. Immunohistochemically, we detected interleukin-1 alpha expressing macrophages in the lipid core of atherosclerosis plaques exhibiting glutathione S-transferase omega-1-positive material. GSTO1 Asp/Asp carriers showed larger areas of atherosclerosis plaques containing interleukin-1 alpha-positive material than carriers of the GSTO1 Ala-allele.

    Conclusions: The GSTO1 Asp/Asp genotype presumably modulates the severity and expansion of atherosclerosis in the circle of Willis. The cellular colocalization of glutathione S-transferase omega-1 and interleukin-1 alpha suggests a functional interaction between both proteins which in part might explain the function of glutathione S-transferase omega-1 in the pathogenesis of cerebral atherosclerosis.

    Funded by: NIA NIH HHS: AG12411

    Stroke 2007;38;10;2847-50

  • Glutathione S-transferase omega in the lung and sputum supernatants of COPD patients.

    Harju TH, Peltoniemi MJ, Rytilä PH, Soini Y, Salmenkivi KM, Board PG, Ruddock LW and Kinnula VL

    Department of Medicine, Division of Pulmonary Diseases, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. terttu.harju@oulu.fi

    Background: The major contribution to oxidant related lung damage in COPD is from the oxidant/antioxidant imbalance and possibly impaired antioxidant defence. Glutathione (GSH) is one of the most important antioxidants in human lung and lung secretions, but the mechanisms participating in its homeostasis are partly unclear. Glutathione-S-transferase omega (GSTO) is a recently characterized cysteine containing enzyme with the capability to bind and release GSH in vitro. GSTO has not been investigated in human lung or lung diseases.

    Methods: GSTO1-1 was investigated by immunohistochemistry and Western blot analysis in 72 lung tissue specimens and 40 sputum specimens from non-smokers, smokers and COPD, in bronchoalveolar lavage fluid and in plasma from healthy non-smokers and smokers. It was also examined in human monocytes and bronchial epithelial cells and their culture mediums in vitro.

    Results: GSTO1-1 was mainly expressed in alveolar macrophages, but it was also found in airway and alveolar epithelium and in extracellular fluids including sputum supernatants, bronchoalveolar lavage fluid, plasma and cell culture mediums. The levels of GSTO1-1 were significantly lower in the sputum supernatants (p = 0.023) and lung homogenates (p = 0.003) of COPD patients than in non-smokers.

    Conclusion: GSTO1-1 is abundant in the alveolar macrophages, but it is also present in extracellular fluids and in airway secretions, the levels being decreased in COPD. The clinical significance of GSTO1-1 and its role in regulating GSH homeostasis in airway secretions, however, needs further investigations.

    Respiratory research 2007;8;48

  • A genetic association analysis of cognitive ability and cognitive ageing using 325 markers for 109 genes associated with oxidative stress or cognition.

    Harris SE, Fox H, Wright AF, Hayward C, Starr JM, Whalley LJ and Deary IJ

    Department of Psychology, University of Edinburgh, Edinburgh, UK. Sarah.Harris@hgu.mrc.ac.uk <Sarah.Harris@hgu.mrc.ac.uk&gt;

    Background: Non-pathological cognitive ageing is a distressing condition affecting an increasing number of people in our 'ageing society'. Oxidative stress is hypothesised to have a major role in cellular ageing, including brain ageing.

    Results: Associations between cognitive ageing and 325 single nucleotide polymorphisms (SNPs), located in 109 genes implicated in oxidative stress and/or cognition, were examined in a unique cohort of relatively healthy older people, on whom we have cognitive ability scores at ages 11 and 79 years (LBC1921). SNPs showing a significant positive association were then genotyped in a second cohort for whom we have cognitive ability scores at the ages of 11 and 64 years (ABC1936). An intronic SNP in the APP gene (rs2830102) was significantly associated with cognitive ageing in both LBC1921 and a combined LBC1921/ABC1936 analysis (p < 0.01), but not in ABC1936 alone.

    Conclusion: This study suggests a possible role for APP in normal cognitive ageing, in addition to its role in Alzheimer's disease.

    Funded by: Medical Research Council: MRC_MC_U127561128

    BMC genetics 2007;8;43

  • Metabolism of low-dose inorganic arsenic in a central European population: influence of sex and genetic polymorphisms.

    Lindberg AL, Kumar R, Goessler W, Thirumaran R, Gurzau E, Koppova K, Rudnai P, Leonardi G, Fletcher T and Vahter M

    Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.

    Background: There is a wide variation in susceptibility to health effects of arsenic, which, in part, may be due to differences in arsenic metabolism. Arsenic is metabolized by reduction and methylation reactions, catalyzed by reductases and methyltransferases.

    Our goal in this study was to elucidate the influence of various demographic and genetic factors on the metabolism of arsenic.

    Methods: We studied 415 individuals from Hungary, Romania, and Slovakia by measuring arsenic metabolites in urine using liquid chromatography with hydride generation and inductively coupled plasma mass spectrometry (HPLC-HG-ICPMS). We performed genotyping of arsenic (+III) methyltransferase (AS3MT), glutathione S-transferase omega 1 (GSTO1), and methylene-tetrahydrofolate reductase (MTHFR).

    Results: The results show that the M287T (T-->C) polymorphism in the AS3MT gene, the A222V (C-->T) polymorphism in the MTHFR gene, body mass index, and sex are major factors that influence arsenic metabolism in this population, with a median of 8.0 microg/L arsenic in urine. Females < 60 years of age had, in general, higher methylation efficiency than males, indicating an influence of sex steroids. That might also explain the observed better methylation in overweight or obese women, compared with normal weight men. The influence of the M287T (T-->C) polymorphism in the AS3MT gene on the methylation capacity was much more pronounced in men than in women.

    Conclusions: The factors investigated explained almost 20% of the variation seen in the metabolism of arsenic among men and only around 4% of the variation among women. The rest of the variation is probably explained by other methyltransferases backing up the methylation of arsenic.

    Environmental health perspectives 2007;115;7;1081-6

  • Arsenic metabolism, genetic susceptibility, and risk of premalignant skin lesions in Bangladesh.

    Ahsan H, Chen Y, Kibriya MG, Slavkovich V, Parvez F, Jasmine F, Gamble MV and Graziano JH

    Departments of Epidemiology, Columbia University, USA. habib@uchicago.edu

    We conducted a case-control study to investigate interindividual variability in susceptibility to health effects of inorganic arsenic due to arsenic metabolism efficiency, genetic factors, and their interaction. A total of 594 cases of arsenic-induced skin lesions and 1,041 controls was selected from baseline participants in a large prospective cohort study in Bangladesh. Adjusted odds ratios (OR) for skin lesions were estimated in relation to the polymorphisms in the glutathione S-transferase omega1 and methylenetetrahydrofolate reductase genes, the percentage of monomethylarsonous acid (%MMA) and dimethylarsinic acid (%DMA) in urine, and the ratios of MMA to inorganic arsenic and DMA to MMA. Water arsenic concentration was positively associated with %MMA and inversely associated with %DMA. The dose-response relationship of risk of skin lesion with %MMA was more apparent than those with other methylation indices; the ORs for skin lesions in relation to increasing %MMA quartiles were 1.00 (reference), 1.33 [95% confidence interval (95% CI), 0.92-1.93], 1.68 (95% CI, 1.17-2.42), and 1.57 (95% CI, 1.10-2.26; P for trend = 0.01). The ORs for skin lesions in relation to the methylenetetrahydrofolate reductase 677TT/1298AA and 677CT/1298AA diplotypes (compared with 677CC/1298CC diplotype) were 1.66 (95% CI, 1.00-2.77) and 1.77 (95% CI, 0.61-5.14), respectively. The OR for skin lesions in relation to the glutathione S-transferase omega1 diplotype containing all at-risk alleles was 3.91 (95% CI, 1.03-14.79). Analysis of joint effects of genotypes/diplotypes with water arsenic concentration and urinary %MMA suggests additivity of these factors. The findings suggest that arsenic metabolism, particularly the conversion of MMA to DMA, may be saturable and that differences in urinary arsenic metabolites, genetic factors related to arsenic metabolism, and their joint distributions modulate arsenic toxicity.

    Funded by: NCI NIH HHS: CA016087, R01CA102484, R01CA107431; NIEHS NIH HHS: ES000260, P30ES09089, P42 ES010349, P42ES10349

    Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 2007;16;6;1270-8

  • Genetic polymorphisms influencing arsenic metabolism: evidence from Argentina.

    Schläwicke Engström K, Broberg K, Concha G, Nermell B, Warholm M and Vahter M

    Division of Occupational and Environmental Medicine, Department of Laboratory Medicine, Lund University, 22185 Lund, Sweden. karin.engstrom@med.lu.se

    The susceptibility to arsenic-induced diseases differs greatly between individuals, possibly due to interindividual variations in As metabolism that affect retention and distribution of toxic metabolites. To elucidate the role of genetic factors in As metabolism, we studied how polymorphisms in six genes affected the urinary metabolite pattern in a group of indigenous women (n = 147) in northern Argentina who were exposed to approximately 200 microg/L As in drinking water. These women had low urinary percentages of monomethylated As (MMA) and high percentages of dimethylated As (DMA). MMA has been associated with adverse health effects, and DMA has the lowest body retention of the metabolites. The genes studied were arsenic(+III)methyltransferase (AS3MT), glutathione S-transferase omega 1 (GSTO1), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), methylenetetrahydrofolate reductase (MTHFR), and glutathione S-transferases mu 1 (GSTM1) and theta 1 (GSTT1). We found three intronic polymorphisms in AS3MT (G12390C, C14215T, and G35991A) associated with a lower percentage of MMA (%MMA) and a higher percentage of DMA (%DMA) in urine. The variant homozygotes showed approximately half the %MMA compared with wild-type homozygotes. These polymorphisms were in strong linkage, with high allelic frequencies (72-76%) compared with other populations. We also saw minor effects of other polymorphisms in the multivariate regression analysis with effect modification for the deletion genotypes for GSTM1 (affecting %MMA) and GSTT1 (affecting %MMA and %DMA). For pregnant women, effect modification was seen for the folate-metabolizing genes MTR and MTHFR. In conclusion, these findings indicate that polymorphisms in AS3MT-and possibly GSTM1, GSTT1, MTR, and MTHFR-are responsible for a large part of the interindividual variation in As metabolism and susceptibility.

    Environmental health perspectives 2007;115;4;599-605

  • Glutathione S-transferase mu, omega, pi, and theta class variants and smoking in Parkinson's disease.

    Wahner AD, Glatt CE, Bronstein JM and Ritz B

    Department of Epidemiology, UCLA School of Public Health, Los Angeles, CA 90095-1772, USA. awahner@ucla.edu

    GSTs are a family of inducible phase II enzymes that may play a neuroprotective role in Parkinson's disease (PD). GSTs may also modify PD risk by metabolizing compounds in cigarettes, as cigarette smoking is generally found to be associated with a decrease in PD risk. Using a population-based case-control study design, we examined polymorphisms of the mu, omega, pi, and theta classes of GST to elucidate the main effects and smoking-GST interactions on PD risk. From three rural California counties, we recruited 289 incident idiopathic PD cases, clinically confirmed by our study neurologist, and 270 population controls, marginally matched by age, gender, and race. We assessed main gene polymorphism associations and evaluated interactions between smoking and GST polymorphisms as departures from a multiplicative scale adjusting for age, gender, and race. We also restricted analyses to Caucasian subjects to address the potential for population stratification (n=235 cases, 220 controls). Among Caucasians, we observed a risk reduction in subjects carrying at least one variant allele for GSTO1 (OR=0.68, 95% CI: 0.47-0.98) and also GSTO2 (OR=0.64, 95% CI: 0.44-0.93); both genes were in strong linkage disequilibrium. No main gene effects were observed for the remaining polymorphisms. We noted a multiplicative interaction between ever having smoked regularly and GSTO1 (OR(interaction)=0.55, 95% CI: 0.33-0.92) and GSTO2 (OR(interaction)=0.54, 95% CI: 0.32-0.90). Results were similar when combining all races. These findings and the paucity of similar studies suggest a need for further inquiry into the association between GSTs, smoking, and PD risk.

    Funded by: NIEHS NIH HHS: 5P30 ES07048, ES012078, R01 ES010544, U54 ES012078

    Neuroscience letters 2007;413;3;274-8

  • Frequency of two human glutathione-S-transferase omega-1 polymorphisms (E155 deletion and E208K) in Ovambo and Japanese populations using the PCR-based genotyping method.

    Fujihara J, Kunito T and Takeshita H

    Department of Legal Medicine, Shimane University School of Medicine, Izumo, Shimane, Japan.

    Background: Human glutathione S-transferase omega-1 (hGSTO1) has monomethylarsonate (MMA(v)) reductase activity. Recent study suggests that two polymorphisms (E155 deletion and E208K) in hGSTO1 can be related to inter-individual variations in inorganic arsenic metabolism. As useful PCR-based genotyping methods for these hGSTO1 polymorphisms are not available and data on hGSTO1 polymorphism in African and Asian populations are insufficient, the aim of the present study was to develop a PCR-based genotyping method for E155del and E208K, and to investigate the allele frequencies of these two polymorphisms in Ovambo and Japanese populations.

    Methods: The E155del and E208K polymorphisms were detected using confronting two-pair primers analysis and PCR-restriction fragment length polymorphism, respectively.

    Results: Allele frequencies for the hGSTO1 polymorphisms were investigated in Ovambo (n=144) and Japanese (n=144) populations. For E155del, the mutation frequency in Ovambo and Japanese subjects was 0.000 and 0.017, respectively, similar to those for other populations. As for E208K polymorphism, no mutation allele was found in Ovambo or Japanese subjects.

    Conclusions: The present study developed a PCR-based hGSTO1 genotyping method that could be applied to a large number of individuals at most locations.

    Clinical chemistry and laboratory medicine 2007;45;5;621-4

  • Smoking and susceptibility to thyroid cancer: an inverse association with CYP1A1 allelic variants.

    Bufalo NE, Leite JL, Guilhen AC, Morari EC, Granja F, Assumpcao LV and Ward LS

    Laboratory of Cancer Molecular Genetics, Medical Sciences School, State University of Campinas - UNICAMP, Sao Paulo, Brazil.

    In contrast to most human malignancies, epidemiologic studies have frequently reported a reduced risk of differentiated thyroid cancer in tobacco consumers. Cytochrome P4501A1 (CYP1A1) gene variants may be related to an increased capacity to activate polycyclic aromatic hydrocarbons, producing highly reactive electrophilic intermediates that might damage DNA. Hence, the germline inheritance of a wild-type CYP1A1 gene may decrease the susceptibility for thyroid cancer. The present study was designed to investigate CYP1A1 (m1 and m2) role in thyroid tumorigenesis and its connection with GSTM1, GSTT1, GSTP1, GSTO1, and codon 72 of p53 genotypes. A total of 248 patients with thyroid nodules, including 67 benign goiters, 13 follicular adenomas, 136 papillary carcinomas, and 32 follicular carcinomas, and 277 controls with similar ethnic backgrounds were interviewed on their lifetime dietary and occupational histories, smoking habit, previous diseases, and other anamnestic data. DNA was extracted from a blood sample and submitted to PCR-restriction fragment length polymorphism assays. The wild-type CYP1A1m1 genotype was more frequent among papillary carcinoma patients (74.26%) than in the control population (62.45%; P=0.0147), reducing the risk for this type of cancer (odds ratio=0.564; 95% confidence interval=0.357-0.894). A multiple logistic regression analysis showed an inverse correlation between cigarette smoking (P=0.0385) and CYP1A1 germline inheritance (P=0.0237) with the susceptibility to papillary carcinomas. We were not able to find any correlation between smoking, clinical features, parameters of aggressiveness at diagnosis or during follow-up, and any of the GST or CYP genotypes considered separately or in different combinations. We suggest that CYP1A1 genotype might be associated with the reported reduced risk to papillary carcinomas among smokers.

    Endocrine-related cancer 2006;13;4;1185-93

  • Polymorphism of glutathione S-transferase omega gene and risk of cancer.

    Marahatta SB, Punyarit P, Bhudisawasdi V, Paupairoj A, Wongkham S and Petmitr S

    Department of Tropical Nutrition and Food Science, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand.

    Polymorphic glutathione S-transferase (GST) genes causing variations in enzyme activity may influence individual susceptibility to cancer. Though polymorphisms have been reported in GSTO1 and GSTO2, their predisposition to cancer risk has not yet been explored. In this case control study, 28 cases of hepatocellular carcinoma, 30 cases of cholangiocarcinoma, 31 cases of colorectal cancer, 30 cases of breast cancer and 98 controls were compared for frequencies of GSTO1 and GSTO2 genotypes. The statistical analysis provided the support for the difference in genotypic distribution for GSTO1*A140D between hepatocellular carcinoma (OR 23.83, CI 95%: 5.07-127), cholangiocarcinoma (OR 8.5, CI 95%: 2.07-37.85), breast cancer (OR 3.71, CI 95%: 1.09-13.02) and control. With regards to GSTO2*N140D polymorphism, there was no difference in genotypic distribution between all the types of cancer and control. The study suggests that GSTO1*A140D polymorphism could play an important role as a risk factor for the development of hepatocellular carcinoma, cholangiocarcinoma and breast cancer.

    Cancer letters 2006;236;2;276-81

  • A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease.

    Grupe A, Li Y, Rowland C, Nowotny P, Hinrichs AL, Smemo S, Kauwe JS, Maxwell TJ, Cherny S, Doil L, Tacey K, van Luchene R, Myers A, Wavrant-De Vrièze F, Kaleem M, Hollingworth P, Jehu L, Foy C, Archer N, Hamilton G, Holmans P, Morris CM, Catanese J, Sninsky J, White TJ, Powell J, Hardy J, O'Donovan M, Lovestone S, Jones L, Morris JC, Thal L, Owen M, Williams J and Goate A

    Celera Diagnostics, Alameda, CA, USA.

    Strong evidence of linkage to late-onset Alzheimer disease (LOAD) has been observed on chromosome 10, which implicates a wide region and at least one disease-susceptibility locus. Although significant associations with several biological candidate genes on chromosome 10 have been reported, these findings have not been consistently replicated, and they remain controversial. We performed a chromosome 10-specific association study with 1,412 gene-based single-nucleotide polymorphisms (SNPs), to identify susceptibility genes for developing LOAD. The scan included SNPs in 677 of 1,270 known or predicted genes; each gene contained one or more markers, about half (48%) of which represented putative functional mutations. In general, the initial testing was performed in a white case-control sample from the St. Louis area, with 419 LOAD cases and 377 age-matched controls. Markers that showed significant association in the exploratory analysis were followed up in several other white case-control sample sets to confirm the initial association. Of the 1,397 markers tested in the exploratory sample, 69 reached significance (P < .05). Five of these markers replicated at P < .05 in the validation sample sets. One marker, rs498055, located in a gene homologous to RPS3A (LOC439999), was significantly associated with Alzheimer disease in four of six case-control series, with an allelic P value of .0001 for a meta-analysis of all six samples. One of the case-control samples with significant association to rs498055 was derived from the linkage sample (P = .0165). These results indicate that variants in the RPS3A homologue are associated with LOAD and implicate this gene, adjacent genes, or other functional variants (e.g., noncoding RNAs) in the pathogenesis of this disorder.

    Funded by: Intramural NIH HHS; Medical Research Council: MRC_G0300429, MRC_G0701075, MRC_G9810900; NHGRI NIH HHS: T32 HG000045; NIA NIH HHS: AG 05146, AG05128, P01 AG003991, P01 AG03991, P50 AG005128, P50 AG005131, P50 AG005146, P50 AG005681, P50 AG008671, P50 AG016570, P50 AG05131, P50 AG05681, P50 AG16570, P50-AG08671, R01 AG016208, R01 AG16208, U24 AG021886; NIGMS NIH HHS: GM065509, P50 GM065509; NIMH NIH HHS: MH60451, P50 MH060451, U01 MH046281, U01 MH046290, U01 MH046373; NINDS NIH HHS: NS39764, P50 NS039764

    American journal of human genetics 2006;78;1;78-88

  • A human protein-protein interaction network: a resource for annotating the proteome.

    Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S, Timm J, Mintzlaff S, Abraham C, Bock N, Kietzmann S, Goedde A, Toksöz E, Droege A, Krobitsch S, Korn B, Birchmeier W, Lehrach H and Wanker EE

    Max Delbrueck Center for Molecular Medicine, 13092 Berlin-Buch, Germany.

    Protein-protein interaction maps provide a valuable framework for a better understanding of the functional organization of the proteome. To detect interacting pairs of human proteins systematically, a protein matrix of 4456 baits and 5632 preys was screened by automated yeast two-hybrid (Y2H) interaction mating. We identified 3186 mostly novel interactions among 1705 proteins, resulting in a large, highly connected network. Independent pull-down and co-immunoprecipitation assays validated the overall quality of the Y2H interactions. Using topological and GO criteria, a scoring system was developed to define 911 high-confidence interactions among 401 proteins. Furthermore, the network was searched for interactions linking uncharacterized gene products and human disease proteins to regulatory cellular pathways. Two novel Axin-1 interactions were validated experimentally, characterizing ANP32A and CRMP1 as modulators of Wnt signaling. Systematic human protein interaction screens can lead to a more comprehensive understanding of protein function and cellular processes.

    Cell 2005;122;6;957-68

  • Three SNPs in the GSTO1, GSTO2 and PRSS11 genes on chromosome 10 are not associated with age-at-onset of Alzheimer's disease.

    Ozturk A, Desai PP, Minster RL, Dekosky ST and Kamboh MI

    Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, PA 15261, USA.

    Linkage studies suggest the presence of putative risk and/or age-at-onset genes for Alzheimer's disease on Chromosome 10. Recently, a genomic converging approach using a combination of linkage, expression and association studies has reported significant associations of the glutathione S-transferase omega 1 and 2 (GSTO1 and GSTO2) genes and possibly the protease serine 11 (PRSS11) gene on chromosome 10 with age-at-onset, but not risk, for Alzheimer's disease (AD) and Parkinson disease. We investigated the association of the reported three polymorphisms in 990 sporadic late-onset AD cases (26% autopsy confirmed) and 735 controls. In our sample, we found no association either with age-at-onset in AD cases or with disease risk in the case-control cohort. However, haplotype analysis revealed a modest association of one haplotype with AD risk (p = 0.04). Additional markers in these genes need to be screened to explore their role in the etiology of AD.

    Funded by: NIA NIH HHS: AG05133, AG13672

    Neurobiology of aging 2005;26;8;1161-5

  • GSTO polymorphism analysis in thyroid nodules suggest that GSTO1 variants do not influence the risk for malignancy.

    Granja F, Morari EC, Assumpção LV and Ward LS

    Laboratory of Cancer Molecular Genetics, Department of Medicine, State University of Campinas, Tessalia Vieira de Camargo 126, 13084-970 Campinas, São Paulo, Brazil.

    A new class of glutathione S-transferase enzymes named omega (GSTO) has been recently identified and shown to be expressed in a wide range of human tissues. A genetic polymorphism of the GSTO1 gene causing an alanine-to-aspartate (A140D) substitution in amino acid 140 produces a variant with lowered enzyme activities in the biotransformation of inorganic arsenic, a common contaminant of drinking water in many regions of the world and a well-known carcinogen. In order to investigate the role of GSTO1 inheritance pattern on thyroid cancer risk we used a polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP)-sequencing approach to compare the genotypes of 173 (87 women, 86 men; 18-81 years old; 47+/-18 years old) healthy control individuals with those of 145 patients with thyroid nodules (84 women, 61 men; 17-81 years old; 49+/-14 years old) including 17 follicular carcinomas, 76 papillary carcinomas, 21 follicular adenomas and 31 multinodular goiters. The incidence of GSTO1 variants was similar in the control population and population with the benign and malignant nodules. There was no association between genotype and the patients' clinical features, tumour parameters of aggressiveness at diagnosis or behaviour during follow-up. We conclude that GSTO1 variants do not influence the risk for thyroid nodules or their pathologic and clinical characteristics.

    European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation (ECP) 2005;14;3;277-80

  • Polymorphisms in glutathione S-transferase omega-1 and AD, vascular dementia, and stroke.

    Kölsch H, Linnebank M, Lütjohann D, Jessen F, Wüllner U, Harbrecht U, Thelen KM, Kreis M, Hentschel F, Schulz A, von Bergmann K, Maier W and Heun R

    Department of Psychiatry, University of Bonn, Germany. heike.koelsch@ukb.uni-bonn.de

    Background: Glutathione S-transferase omega-1 (GSTO1) protects from oxidative stress, a risk factor for Alzheimer disease (AD), vascular dementia (VaD), and stroke. Polymorphisms in GSTO1 might influence the function of the protein and thus the risk of AD, VaD, and stroke.

    Methods: The GSTO1 gene was screened for variations. The effect of the detected polymorphisms on the risk of AD, VaD, and stroke was evaluated. CSF levels of cholesterol and plasma homocysteine levels were compared according to the GSTO1 genotype.

    Results: Two missense polymorphisms in exon 4 of GSTO1 (Ala140Asp and Glu155DeltaGlu) were detected and tested for their association with AD, VaD, and stroke. The Asp/Asp and Ala/Asp genotypes increased the risk of stroke (p = 0.003, OR = 2.1), and the Asp/Asp genotype increased the risk of VaD (p = 0.02, OR = 2.2). GSTO1 polymorphisms did not influence the risk of AD, but the Asp allele influenced the age at onset (p = 0.05). In nondemented probands CSF levels of cholesterol were increased in carriers of the Asp/Asp genotype (p = 0.004); however, in patients with manifest dementia the authors found decreased CSF levels of cholesterol in carriers of the Asp/Asp genotype (p = 0.028). Serum homocysteine levels in stroke patients were higher in carriers of at least one Asp allele (p = 0.011).

    Conclusion: The GSTO1 Asp allele may be a genetic risk factor for cerebrovascular diseases, and might influence the course of Alzheimer disease, even though effects vary in different studies.

    Neurology 2004;63;12;2255-60

  • The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

    Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Morrin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J and MGC Project Team

    The National Institutes of Health's Mammalian Gene Collection (MGC) project was designed to generate and sequence a publicly accessible cDNA resource containing a complete open reading frame (ORF) for every human and mouse gene. The project initially used a random strategy to select clones from a large number of cDNA libraries from diverse tissues. Candidate clones were chosen based on 5'-EST sequences, and then fully sequenced to high accuracy and analyzed by algorithms developed for this project. Currently, more than 11,000 human and 10,000 mouse genes are represented in MGC by at least one clone with a full ORF. The random selection approach is now reaching a saturation point, and a transition to protocols targeted at the missing transcripts is now required to complete the mouse and human collections. Comparison of the sequence of the MGC clones to reference genome sequences reveals that most cDNA clones are of very high sequence quality, although it is likely that some cDNAs may carry missense variants as a consequence of experimental artifact, such as PCR, cloning, or reverse transcriptase errors. Recently, a rat cDNA component was added to the project, and ongoing frog (Xenopus) and zebrafish (Danio) cDNA projects were expanded to take advantage of the high-throughput MGC pipeline.

    Funded by: PHS HHS: N01-C0-12400

    Genome research 2004;14;10B;2121-7

  • The DNA sequence and comparative analysis of human chromosome 10.

    Deloukas P, Earthrowl ME, Grafham DV, Rubenfield M, French L, Steward CA, Sims SK, Jones MC, Searle S, Scott C, Howe K, Hunt SE, Andrews TD, Gilbert JG, Swarbreck D, Ashurst JL, Taylor A, Battles J, Bird CP, Ainscough R, Almeida JP, Ashwell RI, Ambrose KD, Babbage AK, Bagguley CL, Bailey J, Banerjee R, Bates K, Beasley H, Bray-Allen S, Brown AJ, Brown JY, Burford DC, Burrill W, Burton J, Cahill P, Camire D, Carter NP, Chapman JC, Clark SY, Clarke G, Clee CM, Clegg S, Corby N, Coulson A, Dhami P, Dutta I, Dunn M, Faulkner L, Frankish A, Frankland JA, Garner P, Garnett J, Gribble S, Griffiths C, Grocock R, Gustafson E, Hammond S, Harley JL, Hart E, Heath PD, Ho TP, Hopkins B, Horne J, Howden PJ, Huckle E, Hynds C, Johnson C, Johnson D, Kana A, Kay M, Kimberley AM, Kershaw JK, Kokkinaki M, Laird GK, Lawlor S, Lee HM, Leongamornlert DA, Laird G, Lloyd C, Lloyd DM, Loveland J, Lovell J, McLaren S, McLay KE, McMurray A, Mashreghi-Mohammadi M, Matthews L, Milne S, Nickerson T, Nguyen M, Overton-Larty E, Palmer SA, Pearce AV, Peck AI, Pelan S, Phillimore B, Porter K, Rice CM, Rogosin A, Ross MT, Sarafidou T, Sehra HK, Shownkeen R, Skuce CD, Smith M, Standring L, Sycamore N, Tester J, Thorpe A, Torcasso W, Tracey A, Tromans A, Tsolas J, Wall M, Walsh J, Wang H, Weinstock K, West AP, Willey DL, Whitehead SL, Wilming L, Wray PW, Young L, Chen Y, Lovering RC, Moschonas NK, Siebert R, Fechtel K, Bentley D, Durbin R, Hubbard T, Doucette-Stamm L, Beck S, Smith DR and Rogers J

    The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK. panos@sanger.ac.uk

    The finished sequence of human chromosome 10 comprises a total of 131,666,441 base pairs. It represents 99.4% of the euchromatic DNA and includes one megabase of heterochromatic sequence within the pericentromeric region of the short and long arm of the chromosome. Sequence annotation revealed 1,357 genes, of which 816 are protein coding, and 430 are pseudogenes. We observed widespread occurrence of overlapping coding genes (either strand) and identified 67 antisense transcripts. Our analysis suggests that both inter- and intrachromosomal segmental duplications have impacted on the gene count on chromosome 10. Multispecies comparative analysis indicated that we can readily annotate the protein-coding genes with current resources. We estimate that over 95% of all coding exons were identified in this study. Assessment of single base changes between the human chromosome 10 and chimpanzee sequence revealed nonsense mutations in only 21 coding genes with respect to the human sequence.

    Nature 2004;429;6990;375-81

  • Glutathione transferase Omega class polymorphisms in Parkinson disease.

    Whitbread AK, Mellick GD, Silburn PA, Le Couteur DG and Board PG

    John Curtin School of Medical Research, Australian National University, Canberra Act.

    Neurology 2004;62;10;1910-1

  • Glutathione S-Transferase Omega 1 variation does not influence age at onset of Huntington's disease.

    Arning L, Jagiello P, Wieczorek S, Saft C, Andrich J and Epplen JT

    Department of Human Genetics, Ruhr-University, 44780 Bochum, Germany. larissa.arning@rub.de

    Background: Huntington's disease (HD) is a fully penetrant, autosomal dominantly inherited disorder associated with abnormal expansions of a stretch of perfect CAG repeats in the 5' part of the IT15 gene. The number of repeat units is highly predictive for the age at onset (AO) of the disorder. But AO is only modestly correlated with repeat length when intermediate HD expansions are considered. Circumstantial evidence suggests that additional features of the HD course are based on genetic traits. Therefore, it may be possible to investigate the genetic background of HD, i.e. to map the loci underlying the development and progression of the disease. Recently an association of Glutathione S-Transferase Omega 1 (GSTO1) and possibly of GSTO2 with AO was demonstrated for, both, Alzheimer's (AD) and Parkinson's disease (PD).

    Methods: We have genotyped the polymorphisms rs4925 GSTO1 and rs2297235 GSTO2 in 232 patients with HD and 228 controls.

    Results: After genotyping GSTO1 and GSTO2 polymorphisms, firstly there was no statistically significant difference in AO for HD patients, as well as secondly for HD patients vs. controls concerning, both, genotype and allele frequencies, respectively.

    Conclusion: The GSTO1 and GSTO2 genes flanked by the investigated polymorphisms are not comprised in a primary candidate region influencing AO in HD.

    BMC medical genetics 2004;5;7

  • Glutathione S-transferase omega-1 modifies age-at-onset of Alzheimer disease and Parkinson disease.

    Li YJ, Oliveira SA, Xu P, Martin ER, Stenger JE, Scherzer CR, Hauser MA, Scott WK, Small GW, Nance MA, Watts RL, Hubble JP, Koller WC, Pahwa R, Stern MB, Hiner BC, Jankovic J, Goetz CG, Mastaglia F, Middleton LT, Roses AD, Saunders AM, Schmechel DE, Gullans SR, Haines JL, Gilbert JR, Vance JM, Pericak-Vance MA, Hulette C and Welsh-Bohmer KA

    Department of Medicine, Center for Human Genetics, Institute for Genome Science and Policy, Duke University Medical Center, Box 3445, Durham, NC 27710, USA. yiju.li@duke.edu

    We previously reported genetic linkage of loci controlling age-at-onset in Alzheimer disease (AD) and Parkinson's disease (PD) to a 15 cM region on chromosome 10q. Given the large number of genes in this initial starting region, we applied the process of 'genomic convergence' to prioritize and reduce the number of candidate genes for further analysis. As our second convergence factor we performed gene expression studies on hippocampus obtained from AD patients and controls. Analysis revealed that four of the genes [stearoyl-CoA desaturase; NADH-ubiquinone oxidoreductase 1 beta subcomplex 8; protease, serine 11; and glutathione S-transferase, omega-1 (GSTO1)] were significantly different in their expression between AD and controls and mapped to the 10q age-at-onset linkage region, the first convergence factor. Using 2814 samples from our AD dataset (1773 AD patients) and 1362 samples from our PD dataset (635 PD patients), allelic association studies for age-at-onset effects in AD and PD revealed no association for three of the candidates, but a significant association was found for GSTO1 (P=0.007) and a second transcribed member of the GST omega class, GSTO2 (P=0.005), located next to GSTO1. The functions of GSTO1 and GSTO2 are not well understood, but recent data suggest that GSTO1 maybe involved in the post-translational modification of the inflammatory cytokine interleukin-1beta. This is provocative given reports of the possible role of inflammation in these two neurodegenerative disorders.

    Funded by: NCRR NIH HHS: RR00865; NIA NIH HHS: AG05128, AG10123, AG11268, AG13308, AG19085, U24 AG021886; NIMH NIH HHS: MH52453, MH59528; NINDS NIH HHS: NS031153, NS26630, NS31153, NS39764

    Human molecular genetics 2003;12;24;3259-67

  • Genetic variation in genes associated with arsenic metabolism: glutathione S-transferase omega 1-1 and purine nucleoside phosphorylase polymorphisms in European and indigenous Americans.

    Yu L, Kalla K, Guthrie E, Vidrine A and Klimecki WT

    Arizona Respiratory Center, Tucson, Arizona, USA.

    Individual variability in human arsenic metabolism has been reported frequently in the literature. This variability could be an underlying determinant of individual susceptibility to arsenic-induced disease in humans. Recent analysis revealing familial aggregation of arsenic metabolic profiles suggests that genetic factors could underlie interindividual variation in arsenic metabolism. We screened two genes responsible for arsenic metabolism, human purine nucleoside phosphorylase (hNP), which functions as an arsenate reductase converting arsenate to arsenite, and human glutathione S-transferase omega 1-1 (hGSTO1-1), which functions as a monomethylarsonic acid (MMA) reductase, converting MMA(V) to MMA(III), to develop a comprehensive catalog of commonly occurring genetic polymorphisms in these genes. This catalog was generated by DNA sequencing of 22 individuals of European ancestry (EA) and 24 individuals of indigenous American (IA) ancestry. In (Italic)hNP(/Italic), 48 polymorphic sites were observed, including 6 that occurred in exons, of which 1 was nonsynonymous (G51S). One intronic polymorphism occurred in a known enhancer region. In hGSTO1-1, 33 polymorphisms were observed. Six polymorphisms occurred in exons, of which 4 were nonsynonymous. In contrast to hNP, in which the IA group was more polymorphic than the EA group, in hGSTO1-1 the EA group was more polymorphic than the IA group, which had only 1 polymorphism with a frequency > 10%. Populations representing genetic admixture between the EA and IA groups, such as Mexican Hispanics, could vary in the extent of polymorphism in these genes based upon the extent of admixture. These data provide a framework in which to conduct genetic association studies of these two genes in relevant populations, thereby allowing hNP and hGSTO1-1 to be evaluated as potential susceptibility genes in human arsenicism.

    Funded by: NHLBI NIH HHS: HL66801, HL66806, HL67672; NIEHS NIH HHS: ES06694

    Environmental health perspectives 2003;111;11;1421-7

  • Characterization of the human Omega class glutathione transferase genes and associated polymorphisms.

    Whitbread AK, Tetlow N, Eyre HJ, Sutherland GR and Board PG

    Molecular Genetics Group, John Curtin School of Medical Research, Australian National University, Canberra, Australia.

    The Omega class glutathione transferases (GSTs) have been identified in many organisms, including human, mou 1f40 se, rat, pig, Caenorhabditis eglands and Drosophila melanogaster. These GSTs have poor activity with common GST substrates, but exhibit novel glutathione-dependent thioltransferase, dehydroascorbate reductase and monomethylarsonate reductase activities, and modulate Ca release by ryanodine receptors. An investigation of the genomic organization of human GSTO1 identified a second actively transcribed member of the Omega class (GSTO1). Both GSTO1 and GSTO2 are composed of six exons and are separated by 7.5 kb on chromosome 10q24.3. A third sequence that appears to be a reverse-transcribed pseudogene (GSTO3p) has been identified on chromosome 3. GSTO2 has 64% amino acid identity with GSTO1 and conserves the cysteine residue at position 32, which is thought to be important in the active site of GSTO1. Expression of GSTO2 mRNA was seen in a range of tissues, including the liver, kidney, skeletal muscle and prostate. The strongest GSTO2 expression was in the testis, which also expresses a larger transcript than other tissues. Characterization of recombinant GSTO2 has been limited by its poor solubility. Two functional polymorphisms of GSTO1 have been identified. One alters a splice junction and causes the deletion of E155 and another results in an A140D substitution. Characterization of these variants revealed that the A140D substitution affects neither heat stability, nor activity towards 1-chloro-2,4-dinitrobenzene or hydroxyethyl disulphide. In contrast, deletion of residue E155 appears to contribute towards both a loss of heat stability and increased enzymatic activity.

    Pharmacogenetics 2003;13;3;131-44

  • Functional characterization of two variant human GSTO 1-1s (Ala140Asp and Thr217Asn).

    Tanaka-Kagawa T, Jinno H, Hasegawa T, Makino Y, Seko Y, Hanioka N and Ando M

    Division of Environmental Chemistry, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan.

    Glutathione-S-transferase class Omega (GSTO 1-1) belongs to a new subfamily of GSTs, which is identical with human monomethylarsonic acid (MMA(V)) reductase, the rate limiting enzyme for biotransformation of inorganic arsenic, environmental carcinogen. Recombinant GSTO 1-1 variants (Ala140Asp and Thr217Asn) were functionally characterized using representative substrates. No significant difference was observed in GST activity towards 1-chloro-2,4-dinitrobenzene, whereas thioltransferase activity was decreased to 75% (Ala140Asp) and 40% (Thr217Asn) of the wild-type GSTO 1-1. For MMA(V) reductase activity, the Ala140Asp variant exhibited similar kinetics to wild type, while the Thr217Asn variant had lower V(max) (56%) and K(m) (64%) values than the wild-type enzyme. The different activities of the enzyme variants may influence both the intracellular thiol status and arsenic biotransformation. This can help explain the variation between individuals in their susceptibility to oxidative stress and inorganic arsenic.

    Biochemical and biophysical research communications 2003;301;2;516-20

  • Immunohistochemistry of omega class glutathione S-transferase in human tissues.

    Yin ZL, Dahlstrom JE, Le Couteur DG and Board PG

    Canberra Clinical School of the Sydney University, The Canberra Hospital, Australia.

    Omega class glutathione transferase (GSTO) has been recently described in a number of mammalian species. We used immunohistochemistry to determine the cellular and tissue distribution of GSTO1-1 in humans. Expression of GSTO1-1 was abundant in a wide range of normal tissues, particularly liver, macrophages, glial cells, and endocrine cells. We also found nuclear staining in several types of cells, including glial cells, myoepithelial cells of the breast, neuroendocrine cells of colon, fetal myocytes, hepatocytes, biliary epithelium, ductal epithelium of the pancreas, Hoffbauer cells of the placenta, and follicular and C-cells of the thyroid. These observations and the known activity of GSTO1-1 suggest biological functions that are not shared with other GSTs.

    The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 2001;49;8;983-7

  • Human ERp29: isolation, primary structural characterisation and two-dimensional gel mapping.

    Hubbard MJ and McHugh NJ

    Department of Biochemistry, University of Otago, Dunedin, New Zealand. mike.hubbard@stonebow.otago.ac.nz

    Recently we characterised a novel 29 kDa endoplasmic reticulum protein that is widely expressed in rat tissues, and named it ERp29. Several ERp29-like gene products have been reported in human tissues but uncertainty surrounds their relationships with each other and rat ERp29. To clarify these issues, ERp29 was isolated from human liver and characterised by primary structural analysis and two-dimensional gel mapping. Comparisons with rat ERp29 revealed striking homologies both in sequence and physical properties. Characterisation of the isoelectric heterogeneity and anomalous mass on two-dimensional gels enabled two reported homologues (UL35 and ERp31) to be identified as ERp29. Resolution of a sequence discrepancy led to unequivocal correlation of human ERp29 with the cognate cDNA previously named ERp31 and ERp28. Consequent links established to human genome and proteome projects showed that ERp29 is encoded by a gene on chromosome 12 that is expressed universally in human tissues. Together, these findings unified various ERp29 homologues as products of a single gene orthologous to rat ERp29 and established ERp29 as the only known member of a new protein class. Investigations of ERp29 function in human health and disease should benefit from the integrated links between genome, proteome and murine model organisms established here.

    Electrophoresis 2000;21;17;3785-96

  • Identification, characterization, and crystal structure of the Omega class glutathione transferases.

    Board PG, Coggan M, Chelvanayagam G, Easteal S, Jermiin LS, Schulte GK, Danley DE, Hoth LR, Griffor MC, Kamath AV, Rosner MH, Chrunyk BA, Perregaux DE, Gabel CA, Geoghegan KF and Pandit J

    Molecular Genetics Group and Human Genetics Group, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory 2601, Australia.

    A new class of glutathione transferases has been discovered by analysis of the expressed sequence tag data base and sequence alignment. Glutathione S-transferases (GSTs) of the new class, named Omega, exist in several mammalian species and Caenorhabditis elegans. In humans, GSTO 1-1 is expressed in most tissues and exhibits glutathione-dependent thiol transferase and dehydroascorbate reductase activities characteristic of the glutaredoxins. The structure of GSTO 1-1 has been determined at 2.0-A resolution and has a characteristic GST fold (Protein Data Bank entry code ). The Omega class GSTs exhibit an unusual N-terminal extension that abuts the C terminus to form a novel structural unit. Unlike other mammalian GSTs, GSTO 1-1 appears to have an active site cysteine that can form a disulfide bond with glutathione.

    The Journal of biological chemistry 2000;275;32;24798-806

  • The cloning and characterization of a new stress response protein. A mammalian member of a family of theta class glutathione s-transferase-like proteins.

    Kodym R, Calkins P and Story M

    Department of Experimental Radiation Oncology, University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

    Using differential display, a cDNA fragment was identified as being overexpressed in a mouse lymphoma cell line that had gained resistance to cell death after exposure to a variety of agents used in cancer therapy. The full-length cDNA of 1.1 kb that was cloned contained an open reading frame coding for a previously unidentified 28-kDa mammalian protein, p28. p28 showed significant homologies to a large family of stress response proteins that contain a glutathione S-transferase (GST) domain. In correspondence with the sequence homology, p28 was found to bind glutathione; however, GST or glutathione peroxidase activity could not be demonstrated. Northern analysis of the mRNA of this protein showed abundant expression in mouse heart and liver tissues, whereas anti-p28 antibody binding identified p28 expression in mouse 3T3 cells and early passage mouse embryo fibroblasts. Subcellular protein fractionation revealed p28 localization in the cytoplasm, but with thermal stress p28 relocated to the nuclear fraction of cellular proteins. Based on sequence homology and protein activity we conclude that p28 acts as a small stress response protein, likely involved in cellular redox homeostasis, and belongs to a family of GST-like proteins related to class theta GSTs.

    Funded by: NCI NIH HHS: CA62209, CA77050

    The Journal of biological chemistry 1999;274;8;5131-7

  • Molecular cloning and functional expression of rat liver glutathione-dependent dehydroascorbate reductase.

    Ishikawa T, Casini AF and Nishikimi M

    Department of Biochemistry, Wakayama Medical College, Wakayama 641-0012, Japan.

    We have isolated a cDNA clone for a novel glutathione-dependent dehydroascorbate reductase from a rat liver cDNA library in lambdagt11 by immunoscreening. The authenticity of the clone was confirmed as follows: first, the antibody that had been purified through affinity for the protein expressed by the cloned lambdagt11 phage recognized only the enzyme in a crude extract from rat liver; and second, two internal amino acid sequences of purified enzyme were identified in the protein sequence predicted from the cDNA. The predicted protein consists of 213 amino acids with a molecular weight of 24,929, which is smaller by approximately 3,000 than the value obtained by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. This discrepancy of the molecular weight was explained by post-translational modification because the recombinant protein expressed by a mammalian system (Chinese hamster ovary cells) was of the same size as rat liver enzyme but larger than the protein expressed by a bacterial system (Escherichia coli). Chinese hamster ovary cells, originally devoid of glutathione-dependent dehydroascorbate reductase activity, was made to elicit the enzyme activity (1.5 nmol/min/mg of cytosolic protein) by expression of the recombinant protein. Additionally, the cells expressing the enzyme were found to accumulate 1.7 times as much ascorbate as the parental cells after incubation with dehydroascorbate. This result points to the importance of the dehydroascorbic acid reductase in maintaining a high concentration of ascorbate in the cell.

    The Journal of biological chemistry 1998;273;44;28708-12

  • The addition of 5'-coding information to a 3'-directed cDNA library improves analysis of gene expression.

    Matoba R, Okubo K, Hori N, Fukushima A and Matsubara K

    Institute for Molecular and Cellular Biology, Osaka University, Japan.

    Large-scale sequencing of a 3'-cDNA library permits one to analyse gene expression profiles in various tissues. However, many such sequences lack enough information about the encoded proteins. To overcome this problem, we tested a new library, consisting of a 3'-directed cDNA sequence fused to a to a 5' sequence of about 300 bp. Such 'joint molecules' of about 600 bp were amplified by PCR and directly sequenced. About 40% of these joint molecules included the 5' and 3' terminal portions of the mRNA, and most of the remaining clones contained the middle portion and 3' end of the mRNA. The upstream sequences contained sufficient information with which to search for similarity, ORFs, motifs and hydropathy, thus allowing the mRNAs to be categorized and their functions predicted. The rapid categorization of the cDNAs will help to sort those clones that merit further analysis.

    Gene 1994;146;2;199-207

Gene lists (3)

Gene List Source Species Name Description Gene count
L00000009 G2C Homo sapiens Human PSD Human orthologues of mouse PSD adapted from Collins et al (2006) 1080
L00000016 G2C Homo sapiens Human PSP Human orthologues of mouse PSP adapted from Collins et al (2006) 1121
L00000069 G2C Homo sapiens BAYES-COLLINS-HUMAN-PSD-FULL Human cortex biopsy PSD full list 1461
© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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