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Gregg Duester – One of the best experts on this subject based on the ideXlab platform.

  • The Xenopus alcohol dehydrogenase gene family : characterization and comparative analysis incorporating amphibian and reptilian genomes
    BMC genomics, 2014
    Co-Authors: Emma Borràs, Gregg Duester, Xavier Parés, Ricard Albalat, Jaume Farrés
    Abstract:

    The alcohol dehydrogenase (ADH) gene family uniquely illustrates the concept of enzymogenesis. In vertebrates, tandem duplications gave rise to a multiplicity of forms that have been classified in eight enzyme classes, according to primary structure and function. Some of these classes appear to be exclusive of particular organisms, such as the frog ADH8, a unique NADP+-dependent ADH enzyme. This work describes the ADH system of Xenopus, as a model organism, and explores the first amphibian and reptilian genomes released in order to contribute towards a better knowledge of the vertebrate ADH gene family. Xenopus cDNA and genomic sequences along with expressed sequence tags (ESTs) were used in phylogenetic analyses and structure-function correlations of amphibian ADHs. Novel ADH sequences identified in the genomes of Anolis carolinensis (anole lizard) and Pelodiscus sinensis (turtle) were also included in these studies. Tissue and stage-specific libraries provided expression data, which has been supported by mRNA detection in Xenopus laevis tissues and regulatory elements in promoter regions. Exon-intron boundaries, position and orientation of ADH genes were deduced from the amphibian and reptilian genome assemblies, thus revealing syntenic regions and gene rearrangements with respect to the human genome. Our results reveal the high complexity of the ADH system in amphibians, with eleven genes, coding for seven enzyme classes in Xenopus tropicalis. Frogs possess the amphibian-specific ADH8 and the novel ADH1-derived forms ADH9 and ADH10. In addition, they exhibit ADH1, ADH2, ADH3 and ADH7, also present in reptiles and birds. Class-specific signatures have been assigned to ADH7, and ancestral ADH2 is predicted to be a mixed-class as the ostrich enzyme, structurally close to mammalian ADH2 but with class-I kinetic properties. Remarkably, many ADH1 and ADH7 forms are observed in the lizard, probably due to lineage-specific duplications. ADH4 is not present in amphibians and reptiles. The study of the ancient forms of ADH2 and ADH7 sheds new light on the evolution of the vertebrate ADH system, whereas the special features showed by the novel forms point to the acquisition of new functions following the ADH gene family expansion which occurred in amphibians.

  • Recommended nomenclature for the vertebrate alcohol dehydrogenase gene family
    Biochemical Pharmacology, 1999
    Co-Authors: Gregg Duester, Jaume Farrés, Michael R. Felder, Roger Holmes, Jan Olov Höög, Xavier Parés, Bryce V. Plapp, Shih-jiun Yin, Hans Jörnvall
    Abstract:

    The alcohol dehydrogenase (ADH) gene family encodes enzymes that metabolize a wide variety of substrates, including ethanol, retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products. Studies on 19 vertebrate animals have identified ADH orthologs across several species, and this has now led to questions of how best to name ADH proteins and genes. Seven distinct classes of vertebrate ADH encoded by non-orthologous genes have been defined based upon sequence homology as well as unique catalytic properties or gene expression patterns. Each class of vertebrate ADH shares ,70% sequence identity with other classes of ADH in the same species. Classes may be further divided into multiple closely related isoenzymes sharing .80% sequence identity such as the case for class I ADH where humans have three class I ADH genes, horses have two, and mice have only one. Presented here is a nomenclature that uses the widely accepted vertebrate ADH class system as its basis. It follows the guidelines of human and mouse gene nomenclature committees, which recommend coordinating names across species boundaries and eliminating Roman numerals and Greek symbols. We recommend that enzyme subunits be referred to by the symbol “ADH” (alcohol dehydrogenase) followed by an Arabic number denoting the class; i.e. ADH1 for class I ADH. For genes we recommend the italicized root symbol “ADH” for human and “Adh” for mouse, followed by the appropriate Arabic number for the class; i.e. ADH1 or Adh1 for class I ADH genes. For organisms where multiple species-specific isoenzymes exist within a class, we recommend adding a capital letter after the Arabic number; i.e. ADH1A, ADH1B, and ADH1C for human a, b, and g class I ADHs, respectively. This nomenclature will accommodate newly discovered members of the vertebrate ADH family, and will facilitate functional and evolutionary studies. BIOCHEM PHARMACOL 58;3:389 -395, 1999. © 1999 Elsevier Science Inc.

  • Genomic Structure and Expression of the ADH7 Gene Encoding Human Class IV Alcohol Dehydrogenase, the Form Most Efficient for Retinol Metabolism in Vitro
    The Journal of biological chemistry, 1995
    Co-Authors: Mirna Zgombic-knight, Mario H. Foglio, Gregg Duester
    Abstract:

    Human alcohol dehydrogenase (ADH) consists of a family of five evolutionarily related classes of enzymes that collectively function in the metabolism of a wide variety of alcohols including ethanol and retinol. Class IV ADH has been found to be the most active as a retinol dehydrogenase, thus it may participate in retinoic acid synthesis. The gene encoding class IV ADH (ADH7) has now been cloned and subjected to molecular examination. Southern blot analysis indicated that class IV ADH is encoded by a single unique gene and has no related pseudogenes. The class IV ADH gene is divided into nine exons, consistent with the highly conserved intron/exon structure of other mammalian ADH genes. The predicted amino acid sequence of the exon coding regions indicates that a protein of 373 amino acids, excluding the amino-terminal methionine, would be translated, sharing greater sequence identity with class I ADH (69%) than with classes II, III or V (59-61%). Expression of class IV ADH mRNA was detected in human stomach but not liver. This correlates with previous protein studies, which have indicated that class IV ADH is the major stomach ADH but unlike other ADHs is absent from liver. Primer extension studies using human stomach RNA were performed to identify the transcription initiation site lying 100 base pairs upstream of the ATG translation start codon. Nucleotide sequence analysis of the promoter region indicated the absence of a TATA box sequence often located about 25 base pairs upstream of the start site as well as the absence of GC boxes, which are quite often seen in promoters lacking a TATA box. The class IV ADH promoter thus differs from the other ADH promoters, which contain either a TATA box (classes I and II) or GC-boxes (class III), suggesting a fundamentally different form of transcriptional regulation.

James Mckay – One of the best experts on this subject based on the ideXlab platform.

  • Effect of alcohol dehydrogenase-1B and -7 polymorphisms on blood ethanol and acetaldehyde concentrations in healthy subjects with a history of moderate alcohol consumption.
    Drug testing and analysis, 2017
    Co-Authors: Roberta Pastorino, Luigi Iuliano, Alessia Vecchioni, Dario Arzani, Mirta Milić, Francesca Annunziata, Chiara Zerbinati, Ettore Capoluongo, Stefano Bonassi, James Mckay
    Abstract:

    Aims To evaluate the effect of ADH1B and ADH7 genotypes on blood acetaldehyde and ethanol levels after alcohol ingestion, and to measure the genotoxic effect of smoking and ethanol on the buccal cells, also controlling for ADH variants. Methods We recruited healthy Italian subjects with at least a moderate history of alcohol consumption. All subjects were given an alcoholic drink of 0.4 g ethanol /kg of body weight. Blood venous samples were collected at baseline, and 30, 60, 90 and 120 minutes after ingestion. Buccal cells were collected before ethanol ingestion. Results Sixty subjects were enrolled in the study. Individuals with the ADH1B GG genotype had median ethanol levels of 5.0 mM (IQR 3.4-7.2), and those with the ADH1B GT/TT genotype had 4.7 mM (IQR 4.2-4.8). Corresponding acetaldehyde levels were 1.5 μM (IQR 0.7-2.6) for ADH1B GG genotype and 1.6 μM (IQR 1.5-1.7) for ADH1B CG/GG genotype. Individuals with the ADH7 CC genotype had median ethanol levels of 5.0 mM (IQR 3.3-7.2), while 5.0 mM (IQR 4.7-5.6) was in those with the ADH7 CG/GG genotype. Corresponding acetaldehyde levels were 1.5 μM (IQR 0.7-2.6) for ADH7 CC genotype and 1.5 μM (IQR 1.4-1.6) for ADH7 CG/GG genotypes. A non significant increase in the frequency of karyolitic and pyknotic cells was found in the group of heavy drinkers and current smokers, when compared to the moderate drinkers and the non-smokers. Conclusions Our study does not support the hypothesis that ADH1B and ADH7 genotypes affect blood ethanol and acetaldehyde concentration.

  • A Genome-Wide Association Study of Upper Aerodigestive Tract Cancers Conducted within the INHANCE Consortium
    PLoS genetics, 2011
    Co-Authors: James Mckay, David Zaridze, Oxana Shangina, Neonila Szeszenia-dabrowska, Thérèse Truong, Valerie Gaborieau, Amélie Chabrier, Shu Chun Chuang, Graham Byrnes, Jolanta Lissowska
    Abstract:

    Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p≤5×10−7). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10−8) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2×10−8) located in an extended linkage disedisequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5×10−8; rs1229984-ADH1B, p = 7×10−9; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.

  • Sequence variants in the alcohol dehydrogenase (ADH) gene family and the risk of upper aerodigestive tract cancers in Central Europe
    Cancer Research, 2007
    Co-Authors: Mia Hashibe, David Zaridze, James Mckay, Paolo Boffetta, Neonila Szeszenia-dabrowska, D. Mates, Vladimír Janout, Eleonora Fabianova, Vladimir Bencko, Rayjean J. Hung
    Abstract:

    2614 Introduction. Previous studies on alcohol-related cancers have focused on several sequence variants in the ADH gene family such as ADH1B Arg48His and ADH1C Ile350Val. While we have previously reported associations on these polymorphisms and the risk of head and neck cancer, we further investigated whether the other genes in the ADH family may also play a role in cancer susceptibility. Methods. A case-control study was conducted from 2000 to 2002 in 6 centers from 5 Central European countries: Romania, Poland, Russia, Slovakia and the Czech Republic. Patients diagnosed with squamous cell carcinoma of the UADT at designated hospitals were recruited (n=775: 156 oral, 109 pharynx, 315 larynx, 169 esophagus). Controls with a recent diagnosis of diseases unrelated to tobacco and alcohol were included (n=1014). Genomic DNA was extracted from blood samples and genotyping was performed by the Taqman assay for tag SNPs in the ADH4, ADH5, ADH6 and ADH7 genes. Odds ratios (OR) and 95% confidence intervals (CI) were estimated for the risks of UADT cancer overall and for the 4 specific sites (oral, pharynx, larynx, esophagus) for the SNPs. For overall UADT cancer risk, we further stratified by age, smoking status, and alcohol drinking status. Results. A strong association was observed for ADH7 Ala92Gly (rs1573496), with ORs of 0.56 (95%CI=0.41-0.76) for heterozygotes and 0.10 (95%CI=0.03-0.42) for homozygotes (p for trend Conclusion. Our results suggest that sequence variants in ADH4-ADH7 also play an important role in head and neck cancer susceptibility. As a next step, we plan to investigate our positive findings in other large-scale multicenter studies on UADT cancers in Western Europe and South America.

David Zaridze – One of the best experts on this subject based on the ideXlab platform.

  • A Genome-Wide Association Study of Upper Aerodigestive Tract Cancers Conducted within the INHANCE Consortium
    PLoS genetics, 2011
    Co-Authors: James Mckay, David Zaridze, Oxana Shangina, Neonila Szeszenia-dabrowska, Thérèse Truong, Valerie Gaborieau, Amélie Chabrier, Shu Chun Chuang, Graham Byrnes, Jolanta Lissowska
    Abstract:

    Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p≤5×10−7). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10−8) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2×10−8) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5×10−8; rs1229984-ADH1B, p = 7×10−9; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.

  • Multiple ADH genes are associated with upper aerodigestive cancers
    Nature Genetics, 2008
    Co-Authors: Mia Hashibe, James D Mckay, Maria Paula Curado, José Carlos De Oliveira, Sergio Koifman, Rosalina Koifman, David Zaridze, Oxana Shangina, Victor Wünsch-filho, J. Eluf-neto
    Abstract:

    Alcohol is an important risk factor for upper aerodigestive cancers and is principally metabolized by alcohol dehydrogenase (ADH) enzymes. We have investigated six ADH genetic variants in over 3,800 aerodigestive cancer cases and 5,200 controls from three individual studies. Gene variants rs1229984 ( ADH1B ) and rs1573496 ( ADH7 ) were significantly protective against aerodigestive cancer in each individual study and overall ( P = 10^−10 and 10^−9, respectively). These effects became more apparent with increasing alcohol consumption ( P for trend = 0.0002 and 0.065, respectively). Both gene effects were independent of each other, implying that multiple ADH genes may be involved in upper aerodigestive cancer etiology.

  • Sequence variants in the alcohol dehydrogenase (ADH) gene family and the risk of upper aerodigestive tract cancers in Central Europe
    Cancer Research, 2007
    Co-Authors: Mia Hashibe, David Zaridze, James Mckay, Paolo Boffetta, Neonila Szeszenia-dabrowska, D. Mates, Vladimír Janout, Eleonora Fabianova, Vladimir Bencko, Rayjean J. Hung
    Abstract:

    2614 Introduction. Previous studies on alcohol-related cancers have focused on several sequence variants in the ADH gene family such as ADH1B Arg48His and ADH1C Ile350Val. While we have previously reported associations on these polymorphisms and the risk of head and neck cancer, we further investigated whether the other genes in the ADH family may also play a role in cancer susceptibility. Methods. A case-control study was conducted from 2000 to 2002 in 6 centers from 5 Central European countries: Romania, Poland, Russia, Slovakia and the Czech Republic. Patients diagnosed with squamous cell carcinoma of the UADT at designated hospitals were recruited (n=775: 156 oral, 109 pharynx, 315 larynx, 169 esophagus). Controls with a recent diagnosis of diseases unrelated to tobacco and alcohol were included (n=1014). Genomic DNA was extracted from blood samples and genotyping was performed by the Taqman assay for tag SNPs in the ADH4, ADH5, ADH6 and ADH7 genes. Odds ratios (OR) and 95% confidence intervals (CI) were estimated for the risks of UADT cancer overall and for the 4 specific sites (oral, pharynx, larynx, esophagus) for the SNPs. For overall UADT cancer risk, we further stratified by age, smoking status, and alcohol drinking status. Results. A strong association was observed for ADH7 Ala92Gly (rs1573496), with ORs of 0.56 (95%CI=0.41-0.76) for heterozygotes and 0.10 (95%CI=0.03-0.42) for homozygotes (p for trend Conclusion. Our results suggest that sequence variants in ADH4-ADH7 also play an important role in head and neck cancer susceptibility. As a next step, we plan to investigate our positive findings in other large-scale multicenter studies on UADT cancers in Western Europe and South America.

Howard J. Edenberg – One of the best experts on this subject based on the ideXlab platform.

  • An enhancer-blocking element regulates the cell-specific expression of alcohol dehydrogenase 7
    Gene, 2014
    Co-Authors: Sowmya Jairam, Howard J. Edenberg
    Abstract:

    The class IV alcohol dehydrogenase gene ADH7 encodes an enzyme that is involved in ethanol and retinol metabolism. ADH7 is expressed mainly in the upper gastrointestinal tract and not in the liver, the major site of expression of the other closely related ADHs. We identified an intergenic sequence (iA1C), located between ADH7 and ADH1C, that has enhancer-blocking activity in liver-derived HepG2 cells that do not express their endogenous ADH7. This enhancer blocking function was cell- and position-dependent, with no activity seen in CP-A esophageal cells that express ADH7 endogenously. iA1C function was not specific to the ADH enhancers; it had a similar cell-specific effect on the SV40 enhancer. The CCCTC-binding factor (CTCF), an insulator binding protprotein, bound iA1C in HepG2 cells but not in CP-A cells. Our results suggest that in liver-derived cells, iA1C blocks the effects of ADH enhancers and thereby contributes to the cell specificity of ADH7 expression.

  • single nucleotide polymorphisms interact to affect ADH7 transcription
    Alcoholism: Clinical and Experimental Research, 2014
    Co-Authors: Sowmya Jairam, Howard J. Edenberg
    Abstract:

    Background The class IV alcohol dehydrogenase (ADH7, µ-ADH, σ-ADH) is important in the metabolism of ethanol and retinol. ADH7 is the only ADH not expressed in liver, instead being expressed mainly in the upper gastro-intestinal tract. Genome wide studies have identified significant associations between single nucleotide polymorphisms (SNPs) in ADH7 and alcoholism and cancer, but the causative variants have not been identified.

  • Single‐Nucleotide Polymorphisms Interact to Affect ADH7 Transcription
    Alcoholism clinical and experimental research, 2014
    Co-Authors: Sowmya Jairam, Howard J. Edenberg
    Abstract:

    Background The class IV alcohol dehydrogenase (ADH7, µ-ADH, σ-ADH) is important in the metabolism of ethanol and retinol. ADH7 is the only ADH not expressed in liver, instead being expressed mainly in the upper gastro-intestinal tract. Genome wide studies have identified significant associations between single nucleotide polymorphisms (SNPs) in ADH7 and alcoholism and cancer, but the causative variants have not been identified.

Mia Hashibe – One of the best experts on this subject based on the ideXlab platform.

  • Multiple ADH genes are associated with upper aerodigestive cancers
    Nature Genetics, 2008
    Co-Authors: Mia Hashibe, James D Mckay, Maria Paula Curado, José Carlos De Oliveira, Sergio Koifman, Rosalina Koifman, David Zaridze, Oxana Shangina, Victor Wünsch-filho, J. Eluf-neto
    Abstract:

    Alcohol is an important risk factor for upper aerodigestive cancers and is principally metabolized by alcohol dehydrogenase (ADH) enzymes. We have investigated six ADH genetic variants in over 3,800 aerodigestive cancer cases and 5,200 controls from three individual studies. Gene variants rs1229984 ( ADH1B ) and rs1573496 ( ADH7 ) were significantly protective against aerodigestive cancer in each individual study and overall ( P = 10^−10 and 10^−9, respectively). These effects became more apparent with increasing alcohol consumption ( P for trend = 0.0002 and 0.065, respectively). Both gene effects were independent of each other, implying that multiple ADH genes may be involved in upper aerodigestive cancer etiology.

  • Sequence variants in the alcohol dehydrogenase (ADH) gene family and the risk of upper aerodigestive tract cancers in Central Europe
    Cancer Research, 2007
    Co-Authors: Mia Hashibe, David Zaridze, James Mckay, Paolo Boffetta, Neonila Szeszenia-dabrowska, D. Mates, Vladimír Janout, Eleonora Fabianova, Vladimir Bencko, Rayjean J. Hung
    Abstract:

    2614 Introduction. Previous studies on alcohol-related cancers have focused on several sequence variants in the ADH gene family such as ADH1B Arg48His and ADH1C Ile350Val. While we have previously reported associations on these polymorphisms and the risk of head and neck cancer, we further investigated whether the other genes in the ADH family may also play a role in cancer susceptibility. Methods. A case-control study was conducted from 2000 to 2002 in 6 centers from 5 Central European countries: Romania, Poland, Russia, Slovakia and the Czech Republic. Patients diagnosed with squamous cell carcinoma of the UADT at designated hospitals were recruited (n=775: 156 oral, 109 pharynx, 315 larynx, 169 esophagus). Controls with a recent diagnosis of diseases unrelated to tobacco and alcohol were included (n=1014). Genomic DNA was extracted from blood samples and genotyping was performed by the Taqman assay for tag SNPs in the ADH4, ADH5, ADH6 and ADH7 genes. Odds ratios (OR) and 95% confidence intervals (CI) were estimated for the risks of UADT cancer overall and for the 4 specific sites (oral, pharynx, larynx, esophagus) for the SNPs. For overall UADT cancer risk, we further stratified by age, smoking status, and alcohol drinking status. Results. A strong association was observed for ADH7 Ala92Gly (rs1573496), with ORs of 0.56 (95%CI=0.41-0.76) for heterozygotes and 0.10 (95%CI=0.03-0.42) for homozygotes (p for trend Conclusion. Our results suggest that sequence variants in ADH4-ADH7 also play an important role in head and neck cancer susceptibility. As a next step, we plan to investigate our positive findings in other large-scale multicenter studies on UADT cancers in Western Europe and South America.