The long term goals of this research are to understand the mechanisms that regulate humanalcohol dehydrogenase (ADH) gene expression, and the physiological and pathological consequences of alterations in ADH expression. Wehypothesize that differences in the expression of the ADH genes affect the metabolism of alcohol, the risk for alcoholism, and thephysiological and pathological consequences of alcohol consumption. To begin testing this hypothesis we will identify the regions that control ADH expression, identify poly-morphisms in these regions, and then analyze whether these polymorphisms affect gene expression. We will identify cw-acting elements important in the regulation of the human ADH genes, with primary focus on the class I genes and ADH7. These have different patterns of expression, and produce enzymes that influence important metabolic processes including metabolism of ethanol and retinol. Cw-acting elements will be identified by a combination of functional studies (transfections) and protein-binding analyses (DNasel footprintingand gel retardation). We will identify transcription factors that bind to these sequences. The ADH genes are clustered on chromosome 4, and we hypothesize that distant flanking sequences are important in regulating this group of genes. We will test this hypothesis by studying more distant sequences, extending at least 10 kb from the coding regions. We will also analyze the regulation of large chromosomal segments (BACs) carrying groups of ADH genes to detect potential interactions in a chromosomal context. We hypothesize that inter-individual differences in regulatory sequences cause differences in ADH gene expression. We will identify and characterize polymorphisms in the regulatory regions and test their effects on gene expression in vitro. These two aims will be closely coupled, with the localization of cw-acting elements directing our search for polymorphisms, and our detection of functional polymorphisms helping to prioritize further study of the cw-acting elements. These studies will contribute to our understanding of the genetic factors underlyingdifferences among individuals in the metabolic, pharmacological and pathological effects of alcohol consumption. They will also increase our basic understanding of gene regulation.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Murray, Gary
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Indiana University-Purdue University at Indianapolis
Schools of Medicine
United States
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Criado, José R; Gizer, Ian R; Edenberg, Howard J et al. (2014) CHRNA5 and CHRNA3 variants and level of neuroticism in young adult Mexican American men and women. Twin Res Hum Genet 17:80-8
Jairam, Sowmya; Edenberg, Howard J (2014) Single-nucleotide polymorphisms interact to affect ADH7 transcription. Alcohol Clin Exp Res 38:921-9
Edenberg, Howard J; Foroud, Tatiana (2014) Genetics of alcoholism. Handb Clin Neurol 125:561-71
Jairam, Sowmya; Edenberg, Howard J (2014) An enhancer-blocking element regulates the cell-specific expression of alcohol dehydrogenase 7. Gene 547:239-44
Edenberg, Howard J; Foroud, Tatiana (2013) Genetics and alcoholism. Nat Rev Gastroenterol Hepatol 10:487-94
Pochareddy, Sirisha; Edenberg, Howard J (2012) Chronic alcohol exposure alters gene expression in HepG2 cells. Alcohol Clin Exp Res 36:1021-33
Edenberg, Howard J (2012) Genes contributing to the development of alcoholism: an overview. Alcohol Res 34:336-8
Hurley, Thomas D; Edenberg, Howard J (2012) Genes encoding enzymes involved in ethanol metabolism. Alcohol Res 34:339-44
Pochareddy, Sirisha; Edenberg, Howard J (2011) Variation in the ADH1B proximal promoter affects expression. Chem Biol Interact 191:38-41
Gizer, Ian R; Edenberg, Howard J; Gilder, David A et al. (2011) Association of alcohol dehydrogenase genes with alcohol-related phenotypes in a Native American community sample. Alcohol Clin Exp Res 35:2008-18

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