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Chunk #1 — 1. Introduction

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Identification of a FOXA-dependent enhancer of human alcohol dehydrogenase 4 (ADH4).
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Alcoholism is a complex disease affecting millions, and the third leading cause of the preventable death in the United States (Mokdad et al., 2004). Chronic alcohol abuse is associated with numerous health risks like liver cirrhosis, cancer, and cardiovascular diseases (Cargiulo, 2007). Several studies have reported association of variations in the ADH region with the risk for alcoholism (Birley et al., 2009; Edenberg and Foroud, 2006; Edenberg et al., 2006; Reich et al., 1998; Williams et al., 1999). The activity of alcohol metabolizing enzymes could determine the rate of alcohol metabolism, which in turn affects the susceptibility to alcohol dependence. A single nucleotide polymorphism (SNP) in the coding sequence of ADH1B that changes Arg48 to His48 increases the activity of that enzyme by 90-fold (Hurley et al., 2003). ADH1B-His48 (ADH1B*2) is frequent in East Asian populations, in which it reduces the risk for alcohol dependence between 5 and 8-fold (Edenberg, 2007). Variations in cis-regulatory elements that affect the levels of ADH enzymes have also been associated with alcoholism. A SNP at position −136 (relative to the +1 translational start site)