Interaction between a single nucleotide polymorphism in the alcohol dehydrogenase 3 gene, alcohol consumption and oral cancer risk

Abstract

We investigated effects on oral cancer (OC) risk of an interaction between a single nucleotide polymorphism (SNP) in the alcohol dehydrogenase 3 (ADH 3 ) gene and alcohol consumption levels using a hospital-based study of 93 cases and 99 controls conducted in Athens, Greece. This SNP affects ethanol metabolism in vitro and appeared to interact with alcohol consumption in a previous OC study. We also evaluated a SNP in CYP2E1, another gene involved in ethanol metabolism, reported to be associated with OC risk in a European population. Data on genotypes and risk factors obtained from interviews were analyzed using multivariate logistic regression, accounting for potential confounders. No overall (marginal) association was found between OC risk and ADH 3 genotypes. An interaction between ADH 3 genotypes and alcohol consumption levels, however, was suggested. In non-drinkers, the ADH 3 1-1 genotype has higher risk than ADH 3 1-2 or ADH 3 2-2 genotypes, but for subjects consuming alcohol, lower risk was observed for ADH 3 Many epidemiological studies conducted around the world have documented the strong association between increased risk of oral cancer (OC) and heavy alcohol consumption. [1][2][3][4][5] The mechanism by which alcohol causes OC, however, remains unclear. Questions exist about the importance of consumption patterns, alcohol concentration and other components of different beverages and possible carcinogenic metabolites vs. tissue permeability effects in the mode of action. 6,7 Recent reports strongly implicate the metabolite of ethanol, acetaldehyde, as the main carcinogen in OC. Acetaldehyde has been found to cause mutations, form DNA adducts and inhibit DNA repair. 8 -11 Acetaldehyde levels are regulated primarily by 2 enzymatic systems: alcohol dehydrogenase (ADH) that oxidizes ethanol to acetaldehyde and acetaldehyde dehydrogenase that converts acetaldehyde to acetate. Oxidation of ethanol occurs primarily in the liver, but also in the gastrointestinal tract and oral cavity. [12][13][14][15][16] Seven human genes coding for ADH have been identified to date and 3 of these (ADH1, ADH2 and ADH3) are located in a cluster on chromosome 4. 17,18 Single nucleotide polymorphisms (SNPs) that exhibit different enzymatic properties have been reported for some of these ADH genes. 17,19 -22 For example, it has been shown that cells with the ADH 3 1-1 genotype exhibit a V max for ethanol oxidation that is 2.5-fold higher than that that of the ADH 3 2-2 genotype. 19 Ethanol is also metabolized, to a lesser extent, by CYP2E1 19 and genetic polymorphisms have also been identified for this gene. 23 Because alcohol consumption is a major risk factor for OC, this SNP in ADH 3 is a prime candidate for mediating differences among individuals in OC susceptibility. Evidence of this SNPs interaction with alcohol consumption in OC risk was reported in a case control study conducted in Puerto Rico. 6 By contrast, in a study recently reported using a French population, 24 no association was found with the ADH 3 SNP but an a...

Alcohol Dehydrogenase 3 and Risk of Squamous Cell Carcinomas of the Head and Neck

“…However, our data did not show the risk of HNSCC to be significantly associated with the genotypes of ADH3 after adjusting for age, race, tobacco, and alcohol usage. This lack of association with ADH3 genotypes was also noted by other investigators (6,7,14,15). Our results were in contrast with two other reports which showed that participants with the ADH3 1-1 genotype had a much higher risk of head and neck cancer (5,13), and another study showing that participants with ADH3 1-1 had borderline higher risk for oral cancer only (17).…”

“…Second, sample size is an important issue in genetic studies. Interestingly, the sample sizes for the two studies showing that ADH3 1-1 had significantly increased risk of head and neck cancer were much smaller than the ones that did not find the association (5)(6)(7)(13)(14)(15). In addition, the controls of these two studies were either alcoholics or heavy drinker (z57drinks per week).…”

“…This conclusion was opposite to that of Harty and Coutelle and was also contrary to the hypothesis that the fast allele of ADH3*1 was of higher risk than ADH3*2. Three other studies (6,7,14) had larger sample sizes, together with one with a smaller sample size (15) and hospital recruited controls, all showed no significant difference in head and neck cancer risk from different ADH3 genotypes. When the original data from the seven studies on ADH3 were combined (17), no significant increased cancer risk was observed among all head and neck cancer sites, but a slightly increased risk for oral cavity cancer cases was noted among individuals with ADH3 1-1 .…”

“…Harty et al (5) also reported that the ADH3 1-1 genotype increased the risk of oropharyngeal cancers among Puerto Rican heavy alcohol drinkers. However, Bouchardy, Olshan, Sturgis, and Zavras and their coworkers found no evidence to support the main effect of ADH3 genotypes, and no joint effects or interactions were detected between ADH3 genotypes and the amount or duration of alcohol consumption (6,7,14,15). Schwartz et al (16) found that individuals with ADH3 2-2 had increased risk of head and neck squamous cell carcinomas (HNSCC) compared with those with ADH3 1-2 and ADH3 genotype.…”

Current topics in the epidemiology of oral cavity and oropharyngeal cancers

“…58 Elevated odds (OR 5.3, 95% CI, 1.0-28.8) of oral cancer in association with the ADH1C*1-1 genotype were observed only among heavy alcohol users (57 drinks per week) in Puerto Rico 59 and among alcoholics in Germany 60 and France. 55,61 However, contradictory conclusions were reported in studies conducted in the U.S. 62,63 and Greece, 64 in which the ''slow metabolizing'' ADH1C*2-2 genotype was associated with increased risk for HNSCC among heavy drinkers. Other studies reported no associations between ADH genotype and risk of HNSCC.…”