Polymorphisms in Alcohol Metabolism Genes ADH1B and ALDH2, Alcohol Consumption and Colorectal Cancer

Marta Crous-Bou,Levy Kopelovich,Gad Rennert,David Cordero,Daniel Cuadras,Steven Monroe Lipkin,Flavio Lejbkowicz,Stephen Bernard Gruber,Hedy Saltz Rennert,Victor Moreno,Ramon Salazar

doi:10.1371/journal.pone.0080158

Abstract

BackgroundColorectal cancer (CRC) is a leading cause of cancer death worldwide. Epidemiological risk factors for CRC included alcohol intake, which is mainly metabolized to acetaldehyde by alcohol dehydrogenase and further oxidized to acetate by aldehyde dehydrogenase; consequently, the role of genes in the alcohol metabolism pathways is of particular interest. The aim of this study is to analyze the association between SNPs in ADH1B and ALDH2 genes and CRC risk, and also the main effect of alcohol consumption on CRC risk in the study population.Methodology/Principal FindingsSNPs from ADH1B and ALDH2 genes, included in alcohol metabolism pathway, were genotyped in 1694 CRC cases and 1851 matched controls from the Molecular Epidemiology of Colorectal Cancer study. Information on clinicopathological characteristics, lifestyle and dietary habits were also obtained. Logistic regression and association analysis were conducted. A positive association between alcohol consumption and CRC risk was observed in male participants from the Molecular Epidemiology of Colorectal Cancer study (MECC) study (OR = 1.47; 95%CI = 1.18-1.81). Moreover, the SNPs rs1229984 in ADH1B gene was found to be associated with CRC risk: under the recessive model, the OR was 1.75 for A/A genotype (95%CI = 1.21-2.52; p-value = 0.0025). A path analysis based on structural equation modeling showed a direct effect of ADH1B gene polymorphisms on colorectal carcinogenesis and also an indirect effect mediated through alcohol consumption.Conclusions/SignificanceGenetic polymorphisms in the alcohol metabolism pathways have a potential role in colorectal carcinogenesis, probably due to the differences in the ethanol metabolism and acetaldehyde oxidation of these enzyme variants.

Highlights

Colorectal cancer (CRC) is a leading cause of death worldwide, with over one million new cases and half a million deaths around the world every year [1,2]
The aim of the present study is to assess the association between Single nucleotide polymorphisms (SNPs) in alcohol metabolism genes, in particular in alcohol dehydrogenase-1B (ADH1B) and aldehyde dehydrogenase-2 (ALDH2) genes, and CRC, and the main effect of alcohol consumption on CRC risk in the study population
Polymorphism rs1229984 in ADH1B has been found to be directly associated with CRC risk and it shows an indirect effect, mediated through alcohol consumption, even when energy intake, physical activity and religion are included in the model as potential confounders

Summary

Introduction

Colorectal cancer (CRC) is a leading cause of death worldwide, with over one million new cases and half a million deaths around the world every year [1,2]. Alcohol consumption has been reported to be associated with modest increased risks of CRC in some studies [17], but cancer risk may differ by tumor molecular subtype and anatomical site. The mechanism by which alcohol influences CRC risk remains not well understood [18], different hypothesis have been suggested: a carcinogenic effect of chemicals other than ethanol present in alcoholic beverages such as nitrosamines, a solvent action than facilitates absorption of other carcinogens, an inhibition of methylation caused by ethanol, or a carcinogenic and genotoxic role for acetaldehyde, the major metabolite of ethanol [19,20]. There is increasing evidence that acetaldehyde, a cytotoxic, mutagenic, and carcinogenic metabolite of ethanol, is responsible for tumor enhancing effects leading to aberrant cell proliferation. The aim of this study is to analyze the association between SNPs in ADH1B and ALDH2 genes and CRC risk, and the main effect of alcohol consumption on CRC risk in the study population

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