GLUTATHIONE<i>S</i>-TRANSFERASE OMEGA 1 AND OMEGA 2 PHARMACOGENOMICS

Mukherjee, Baidehi; Salavaggione, Oreste E.; Pelleymounter, Linda L.; Moon, Irene; Eckloff, Bruce W.; Schaid, Daniel J.; Wieben, Eric D.; Weinshilboum, Richard M.

doi:10.1124/dmd.106.009613

Cited by 80 publications

(61 citation statements)

References 47 publications

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“…A study reported that the enzyme activity of GSTO1 Ala/Asp genotype was 75% of that of GSTO1 Ala/Ala genotype indicating this genetic variation may lead to defective protection against oxidative stresses [15]. However, several studies reported that the GSTO1 Ala140Asp polymorphism would not influence the thioltransferase activity and further modify the risk of malignancy [20][21][22][23]. The discrepancies between our findings and previous studies may be due to ethnic variation.…”

Section: Discussioncontrasting

confidence: 57%

Association between human glutathione S-transferase omega rs4925 polymorphism and bladder cancer

Hu¹,

Su²,

Huang³

et al. 2013

ABB

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Glutathione S-transferases (GSTs) play an important role in the detoxification of polycyclic aromatic hydrocarbons and aromatic amines, the toxic substances contained in cigarettes. GST Omega 1 (GSTO1) not only utilizes glutathione in conjugation reaction but also contributes to the biotransformation of several xenobiotics. A single nucleotide polymorphism (Ala140Asp) of GSTO1 gene causing variations in enzyme activity may influence individual susceptibility to bladder cancer (BC). It is hypothesized that genetic polymorphism of GSTO1 gene has an effect on BC risk in particular by interacting with cigarette smoking. A total of histopathologically confirmed 300 BC patients and 300 cancer-free controls were recruited from February 2002 to February 2009. Genotyping of the GSTO1 Ala140Asp polymorphism was determined using a polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP) method. The odds ratio (OR) and 95% confidence interval (CI) were calculated as a measure of the combined effect of cigarette smoking and the GSTO1 Ala140Asp polymorphism on BC risk. We found that study subjects with the GSTO1 Ala/Ala genotype have a significantly increased BC risk (OR = 1.5; 95% CI = 1.1 -2.7). A statistically significant increased BC risk was also found in ever smokers with the GSTO1 Ala/Ala genotype (OR = 4.9; 95% CI = 2.8 -9.7). In conclusion, this study provides an epidemiologic evidence of a significantly increased BC risk among ever smokers with the GSTO1 Ala/Ala genotype.

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Section: Discussioncontrasting

confidence: 57%

Association between human glutathione S-transferase omega rs4925 polymorphism and bladder cancer

Hu¹,

Su²,

Huang³

et al. 2013

ABB

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“…With 60 DNA samples (120 alleles) for each of the 4 ethnic groups studied, we had 90% power to detect a variant allele with a true population frequency of ≥ 2% [16]. All polymorphisms detected during resequencing were tested for Hardy-Weinberg equilibrium.…”

Section: Discussionmentioning

confidence: 99%

Human betaine-homocysteine methyltransferase (BHMT) and BHMT2: Common gene sequence variation and functional characterization

Feng

Lee

et al. 2008

Molecular Genetics and Metabolism

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Betaine-homocysteine methyltransferase (BHMT) catalyzes the remethylation of homocysteine. BHMT2 encodes a protein 73% identical in amino acid sequence to BHMT, but the function of BHMT2 remains unclear. We set out to identify and functionally characterize common genetic variation in BHMT and BHMT2. Specifically, we sequenced exons, exon-intron splice junctions and the 5′-flanking regions (5′-FRs) of BHMT and BHMT2 using 240 DNA samples from four ethnic groups. Twenty-five single nucleotide polymorphisms (SNPs), including 4 nonsynonymous SNPs, and 39 SNPs, including 4 nonsynonymous, were observed in BHMT and BHMT2, respectively. BHMT wild type (WT) and variant allozymes were expressed in COS-1 cells. Variant allozymes showed no significant differences from WT in levels of enzyme activity or immunoreactive protein, but there were statistically significant differences in apparent K m values. Luciferase reporter gene constructs were created for the three most common BHMT 5′-FR haplotypes, and significant variation was observed in the ability of these constructs to drive transcription. Although BHMT2 mRNA has been observed in human liver and kidney, expression of the protein has not been reported. We were unable to express BHMT2 in mammalian cells, and the protein aggregated after bacterial expression. Furthermore, BHMT2 was rapidly degraded in a rabbit reticulocyte lysate, but it could be stabilized by cotransfection of COS-1 cells with BHMT and, after cotransfection, it coprecipitated with BHMT. These studies have defined common genetic variation in BHMT and BHMT2 and functionally characterized BHMT SNPs. They may also help to explain why BHMT2 has not previously been defined functionally.

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“…All of these DNA samples had been anonymized by the National Institute of General Medical Sciences prior to deposit, and all subjects had provided written consent for the use of their DNA for experimental purposes. These DNA samples have been widely used for human gene resequencing studies [17][18][19][20]. The present study was reviewed and approved by Mayo Clinic Institutional Review Board.…”

Section: Dna Samplesmentioning

confidence: 99%

Human 3β-hydroxysteroid dehydrogenase types 1 and 2: Gene sequence variation and functional genomics

Wang

Salavaggione

Pelleymounter

et al. 2007

The Journal of Steroid Biochemistry and Molecular Biology

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The 3β-hydroxysteroid dehydrogenase/Δ 5 -Δ 4 isomerase isoenzymes 1 and 2 (HSD3B1 and HSD3B2) are membrane-bound enzymes that play essential roles in the biosynthesis of steroid hormones. Therefore, variation in the HSD3B1 and HSD3B2 genes might play a role in the pathophysiology of steroid hormone-related disease. We set out to systematically identify common polymorphisms and haplotypes in human HSD3B1 and HSD3B2. We identified 17 single nucleotide polymorphisms (SNPs) in HSD3B1 and 9 in HSD3B2 -the majority of which were not present in public databases -by resequencing human HSD3B1 and HSD3B2 using 240 DNA samples from four different ethnic groups (60 samples per group). Functional genomic studies of the 5 nonsynonymous cSNPs in HSD3B1 and the one observed in HSD3B2 showed that two of these polymorphisms resulted in significant decreases in the quantity of enzyme protein expressed. However, none of the 3 nonsynonymous SNPs located in areas encoding putative membrane-binding domains altered subcellular localization of the enzyme as determined by immunofluorescence microscopy. Finally, common variant haplotypes in the 5′-flanking regions of these genes showed significant cell linedependent variation in their ability to drive transcription. In aggregate, these results provide a basis for study of the possible role in human disease of common genetic variation in HSD3B1 and HSD3B2.

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GLUTATHIONES-TRANSFERASE OMEGA 1 AND OMEGA 2 PHARMACOGENOMICS

Cited by 80 publications

References 47 publications

Association between human glutathione S-transferase omega rs4925 polymorphism and bladder cancer

Association between human glutathione S-transferase omega rs4925 polymorphism and bladder cancer

Human betaine-homocysteine methyltransferase (BHMT) and BHMT2: Common gene sequence variation and functional characterization

Human 3β-hydroxysteroid dehydrogenase types 1 and 2: Gene sequence variation and functional genomics

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