Heavy alcohol drinking is a risk factor of colorectal cancer (CRC), but little is known on the effect of polymorphisms in the alcohol-metabolizing enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) on the alcohol-related risk of CRC in Caucasian populations.
A nested case–control study (1269 cases matched to 2107controls by sex, age, study centre and date of blood collection) was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate the impact of rs1229984 (ADH1B), rs1573496 (ADH7) and rs441 (ALDH2) polymorphisms on CRC risk. Using the wild-type variant of each polymorphism as reference category, CRC risk estimates were calculated using conditional logistic regression, with adjustment for matching factors.
Individuals carrying one copy of the rs1229984(A) (ADH1B) allele (fast metabolizers) showed an average daily alcohol intake of 4.3 g per day lower than subjects with two copies of the rs1229984(G) allele (slow metabolizers) (Pdiff<0.01). None of the polymorphisms was associated with risk of CRC or cancers of the colon or rectum. Heavy alcohol intake was more strongly associated with CRC risk among carriers of the rs1573496(C) allele, with odds ratio equal to 2.13 (95% confidence interval: 1.26–3.59) compared with wild-type subjects with low alcohol consumption (Pinteraction=0.07).
The rs1229984(A) (ADH1B) allele was associated with a reduction in alcohol consumption. The rs1229984 (ADH1B), rs1573496 (ADH7) and rs441 (ALDH2) polymorphisms were not associated with CRC risk overall in Western–European populations. However, the relationship between alcohol and CRC risk might be modulated by the rs1573496 (ADH7) polymorphism.
Alcohol intake has been identified as an important risk factor for the development of various types of cancer,1 including colorectal cancer (CRC). Expert reviews from the International Agency for Research on Cancer2 and the World Cancer Research Fund3 confirm the involvement of alcohol in CRC aetiology. Among other hypotheses, alcohol may affect the intestinal absorption, hepatobiliary metabolism and renal excretion of folate4 and may result in impaired retinol status, thus providing a more tumour-promoting environment,5 or can promote oxidative stress.6 In addition, although evidence from experimental animal models indicate that alcohol by itself is not carcinogenic,2 alcohol intake might have a role in colorectal carcinogenicity through acetaldehyde, an oxidation product of alcohol.7, 8
Acetaldehyde associated with alcoholic beverages has been labelled as carcinogenic to humans (IARC Group 1).9 It is removed from the blood via a second reaction catalysed by aldehyde dehydrogenase (ALDH) enzymes, which oxidize it into acetate.10 The efficiency of each of these reactions depends on multiple alcohol dehydrogenase (ADH) and ALDH enzymes, which are encoded by different genes, and which occur in several variants. Therefore, the risk of CRC incidence in relation to alcohol intake could be modulated by genetic factors, as the efficiency in converting ethanol to acetaldehyde, and its subsequent conversion into acetate is largely determined by the ADH and ALDH gene families.11, 12, 13
Although the few existing studies on CRC in Caucasian populations have been inconclusive,14 studies in Japanese populations showed an increased CRC risk with the ADH1B polymorphism (slow metabolizer)15 and a significant interaction between the ALDH2 and ADH2 polymorphisms, which was more apparent in low folate consumers than in high folate consumers.16
The ADH polymorphisms show sizeable heterogeneity among ethnic groups.10 The allele rs1229984*2 (His) (rs1229984(A) in the present study), which codes for ‘fast’ metabolism of ethanol,17 is a frequent allele in Asian populations, while the allele rs1229984*1 (Arg) (rs1229984(G) in the present study) is a major allele in Caucasians.18
The epidemiological investigations that have so far explored the association between ADH and ALDH polymorphisms and risk of CRC have been of relatively small size and very few data are available from European populations. In light of this, a nested case–control study was conducted within the EPIC, to investigate whether the rs1229984 (ADH1B), rs1573496 (ADH7) and rs441 (ALDH2) polymorphisms are associated with CRC risk in European populations, and whether these genes interact with alcohol intake in the aetiology of CRC. In our study, differences in the associations between single-nucleotide polymorphisms (SNPs) by anatomical sub-sites were also evaluated.
Materials and methods
EPIC is a multicentre prospective cohort study with more than 520 000 participants enrolled from 23 centres in Denmark, France, Greece, Germany, Italy, The Netherlands, Norway, Spain, Sweden and the United Kingdom. EPIC is designed to investigate the relation between dietary and lifestyle/environmental factors and cancer incidence. The rationale and methods of the EPIC study have been previously reported in detail.19 Between 1992 and 1998, standardized lifestyle questionnaires, anthropometric data and blood samples were collected from most study participants at recruitment, before disease onset or diagnosis. Dietary habits, including alcohol consumption, over the previous 12 months were assessed at recruitment by validated country-specific dietary questionnaires designed to ensure high compliance while accounting for geographical specificity of diet.19, 20
The present study included subjects who, during an average of 7.2 years follow-up, developed cancer of the colon (n=797), specifically in the caecum, appendix, ascending colon and hepatic flexure, transverse colon, splenic flexure (proximal) (C18.0–18.5; International Statistical Classification of Diseases, Injury and Causes of Death, 10th Revision), descending and sigmoid colon (distal) (C18.6–C18.7), tumours that were overlapping or unspecified (C18.8 and C18.9), as well as cancer of the rectum (n=472), with tumours occurring at the rectosigmoid junction (C19) and rectum (C20). CRC is defined as a combination of all the colon and rectal cancer cases. Anal canal tumours were excluded.
For each case (n=1269), upto two controls (n=2107) were randomly selected by incidence density sampling among cohort members alive and free of cancer at the time of case diagnosis, with blood samples available, and matched by sex, age (±2.5 years), centre and date of blood collection (±45 days). Women were further matched by menopausal status (pre-menopausal, post-menopausal, peri-menopausal/unknown), phase of menstrual cycle at blood collection and usage of hormone replacement therapy at the time of blood collection (yes/no). The additional matching criteria for women were of necessity to other EPIC nested case–control studies that were being conducted using the same matched case–control sets.
This study was approved by relevant Ethical Review Boards of IARC and all EPIC centres.
SNP selection/genotyping and folate assessment
The rs1229984 (ADH1B), rs1573496 (ADH7) and rs441 (ALDH2) polymorphisms were chosen because investigations on Central European populations indicate that they are associated with the risk of upper and aero-digestive tract cancer and that the association is potentially modifiable by the level of alcohol consumption.21
Genotyping for rs1229984 (ADH1B), rs1573496 (ADH7) and rs441 (ALDH2) polymorphisms was performed by Taqman methodology in 384-well plates read with the Sequence Detection Software on an ABI-Prism7900 instrument, according to the manufacturer’s instructions (Applied Biosystems / Life Technologies, Saint-Aubin, France). Primers and probes were supplied by Applied Biosystems (Assays-by-Design). Each plate included a negative control (no DNA). Positive controls were duplicated on a separate plate. A random selection of the study subjects (both cases and controls) was re-genotyped for each polymorphism to examine the reliability of the Taqman genotyping assays. Internal duplicate concordance was >99.9% and the genotyping success rate was at least 94%. Some subjects were excluded due to incomplete genotyping data. Thus, the final number of complete case–control sets utilized was: rs1229984 (ADH1B), (number colon=781; number rectal=466), rs1573496 (ADH7) (number colon=761; number rectal=436) and rs441 (ALDH2) (number colon=762; number rectal=451).
Blood folate measurements were conducted at the LOCUS for homocysteine and related vitamins, University of Bergen (Norway) using a Lactobacillus casei microbiological assay,22 adapted to a microtiter plate format and carried out by a robotic workstation (Micro-lab AT plus 2; Hamilton Bonaduz AG, Bonaluz, Switzerland).23 Blood collection and storage procedures of the EPIC study have been previously described in detail.24
For each polymorphism, genotype distributions in control subjects were tested for Hardy–Weinberg equilibrium. Means and associated measures of variation (10th and 90th percentiles) of total alcohol intake and intakes of alcoholic beverages were calculated for cases and controls. Differences between cases and controls in (log-transformed) total alcohol intake and intakes of alcoholic beverages at baseline were assessed with linear regression models adjusted by sex and country. Similarly, linear regression models were used to compute adjusted means of total alcohol intake and intakes of alcoholic beverages at baseline (and associated s.e.) for each variants of the rs1229984 (ADH1B), rs1573496 (ADH7) and rs441 (ALDH2) polymorphisms, controlling for sex, country and case–control status. P-values associated with differences of heterozygous and homozygous subjects compared with wild-type individuals were determined with Wald tests, according to a χ2-distribution with 1 d.f. In addition, the frequency of subjects by category of alcohol consumption (low, medium and high) by the three categories of each SNP were calculated.
The association between variants of SNPs and CRC risk was assessed by odds ratio and corresponding 95% confidence interval estimated in conditional logistic regression models, in which the case–control set was used as stratification variable. For each SNP separately, keeping the wild-type category consistently as the reference group, heterozygous and rare homozygous categories were modelled with indicator variables. P-values for statistical significance of odds ratios for heterozygous and rare homozygous compared with wild-type individuals were obtained with Wald test with 2 d.f. Adjustments by blood folate and alcohol intake, both modelled as continuous variables, were performed, but results were not meaningfully altered. Effect modification by sex-specific categories of alcohol intake at baseline (<5, 5–25, >25 g per day in women; <10, 10–50, >50 g per day in men), blood folate (EPIC-wide tertiles), sex and country was assessed using indicator variables (as many as the number of categories minus one), combining the heterozygous and rare homozygous variants, and comparing log-likelihood of models with and without interaction terms to a χ2-distribution with degrees of freedom equal to the number of interaction terms minus one. For the evaluation of potential confounding and assessment of interaction with variants of SNPs, the total number of CRC case–control sets used was 850, due to missing folate measurement data. Potential differences in the associations by colon and rectal cancer were explored in separate models.
All statistical analyses were performed using Stata Software.25 All tests were two-tailed and statistical significance was assessed at the 5% level.
The rs1229984 (ADH1B), rs1573496 (ADH7) and rs441 (ALDH2) polymorphisms were in Hardy–Weinberg equilibrium in controls. Baseline characteristics and description of the study population are shown in Table 1. Total alcohol and beer intakes were significantly higher in cases than controls. For each polymorphism, the frequency of study subjects by combination of genetic categories and groups of alcohol intake are displayed in Supplementary Table 1A. While frequencies of genetic variants are rather constant across category of alcohol consumption for the rs1573496 (ADH7) and rs441 (ALDH2) polymorphisms, the percentage of subjects with low consumption (<5 and 10 g per day in women and men, respectively) showed to be lower among carriers of the ‘slow’ rs1229984(G) (ADH1B) allele (49%) than subjects carrying one copy of the ‘fast’ rs1229984(A) allele (59%). Consistently, opposite trends were observed among individuals with elevated alcohol intake. In Table 2 means of total alcohol intake and intakes of wine, beer and spirits are reported by categories of SNP variants. Heterozygous subjects in the rs1229984 (ADH1B) polymorphisms showed lower intakes of total alcohol and wine intakes. The large mean values of total alcohol and wine intakes displayed in rs1229984(A) (ADH1B) carriers are largely explained by the limited sample size in this group (n=12), thus undermining the precision of these values. Other drinking levels according to variants of the rs1573496 (ADH7) and rs441 (ALDH2) SNPs were not clearly apparent.
Variants of rs1229984 (ADH1B), rs1573496 (ADH7) and rs441 (ALDH2) polymorphisms were overall not associated with colorectal, colon and rectal cancer risk (Table 3). Similarly to previous findings in the EPIC cohort,26 in this study total alcohol intake was associated with a significant increase in the risk of colorectal, colon and rectal cancer (results not shown). As reported in Table 4, alcohol intake showed a more pronounced association with CRC risk among subject carriers of the rare rs1573496(C) (ADH7) allele (Pinteraction=0.07), with odds ratio=1.80 (95% confidence interval: 1.02–3.17; P=0.04) comparing high vs low alcohol intake among heterozygous and wild-type homozygous subjects (estimates obtained using a linear combination of model parameters).
No evidence of heterogeneity by blood folate (Pinteraction=0.76, 0.69, 0.73 for rs1229984 (ADH1B), rs1573496 (ADH7), rs441 (ALDH2), respectively), sex (Pinteraction=0.90, 0.37, 0.90 for rs1229984 (ADH1B), rs1573496 (ADH7), rs441 (ALDH2), respectively) or country (Pinteraction=0.79, 0.89, 0.26 for rs1229984 (ADH1B), rs1573496 (ADH7), rs441 (ALDH2), respectively) were apparent in the associations between each polymorphism and CRC risk (data not shown).
The results from this study nested within a European cohort suggest that heterozygous subjects with the ‘fast’ rs1229984(A) (ADH1B) allele have an average of 4.3 g per day lower alcohol intake compared with homozygous participants, carrying two copies of the ‘slow’ rs1229984(G) (ADH1B). The reduction is mainly attributable to lower wine intake, whereas the consumption of beer and spirits are virtually unchanged in the two groups. No clear differences in drinking levels were observed across variants of the rs1573496 (ADH7) and rs441 (ALDH2) polymorphisms. Subjects carrying copies of the fast alcohol metabolizer show a tendency towards lower alcohol consumption, in line with previous observations among Caucasian populations.27, 28, 29, 30
The present study also shows that polymorphisms in the rs1229984 (ADH1B), rs1573496 (ADH7) and rs441 (ALDH2) genes are not associated with risk of CRC or of colon or of rectal cancers in Caucasian populations. However, further analyses in the rs1573496 (ADH7) polymorphism showed that alcohol intake was associated with CRC risk among heterozygous and homozygous carriers of the rare rs1573496(C) (ADH7) allele, while among homozygous wild-type participants the alcohol CRC association was weak. With respect to SNPs in the ALDH family, similar genes alcohol interactions have been previously observed for upper aero-digestive tract cancer,21 for head and neck cancer,31 and for CRC.15
The alleles encoding the different ADH variants are heterogeneously distributed among ethnic groups.10 The allele rs1229984(A) (ADH1B) codes for fast metabolism of ethanol,17 and is a major allele in Asian populations. In contrast, the allele rs1229984(G) (ADH1B), which codes for slow metabolizer, is a major allele in Caucasians.18 The frequency of subjects with two copies of the rs1229984(G) (ADH1B) allele (‘slow’ metabolizer), of the heterozygous subjects, and of the homozygous carrying two rs1229984(A) (ADH1B) (‘fast’ metabolizer) was 90%, 9% and <1% in our study, respectively, while it was around 5%, 35% and 60% in studies conducted in Japan.16, 19 This major difference in frequency, that is, degree of genetic exposure, may explain the inconsistency in risk estimates with respect to genetic factors as the statistical power to detect an association will be greater in the Japanese studies than ours.
The slow alcohol metabolizer of the rs1229984(G) (ADH1B) polymorphism has been shown to be associated with various alcohol-related conditions, such as an increased risk of alcoholic liver disease,32 or cerebral infarction.33 For alcohol-related cancers, an increased risk of upper aero-digestive tract cancers has been observed consistently in studies conducted in Europe21, 34 and in Japan.35
For CRC, no clear explanation for the increased risk associated with the slow alcohol metabolizer rs1229984(G) (ADH1B) allele observed in Asian populations15, 16 has been provided. High intracolonic acetaldehyde concentrations may result from oxidation of ethanol by some strains of colonic bacteria, which possesses ADH activity.8 This has been observed in vitro36 and in vivo where acetaldehyde production was inhibited by antibiotic treatment.37, 38 Low activity of ALDH in colonic aerobic bacteria and in mucosa may lead to acetaldehyde accumulation in the colon.8, 39 This so called bacterio-colonic pathway of ethanol oxidation could be a mechanism responsible for increased CRC risk associated with elevated alcohol intake, in conjunction with a lack of link with variants of the ADH genes, at least in Caucasian populations, where limited genetic variability in the ADH family is observed. However, testing this hypothesis is beyond the scope of the present work.
The association between alcohol and CRC risk has been consistently observed in several epidemiological investigations,40, 41, 42 and in a pooled analysis of eight cohort studies.43 Similarly, in a full cohort analysis of the EPIC study lifetime alcohol intake and alcohol intake at recruitment were positively associated with the risk of CRC, the association being stronger for rectum than for colon cancer.26 Similarly, in the present study alcohol appeared to be positively associated with the risk of CRC (data not shown).
Given drinking avoidance behaviour of 4.3 g per day associated with rs1229984 (ADH1B) heterozygous subjects compared with rs1229984(A) homozygous individuals in the present study, relatively weak associations between alcohol-related SNPs and risk of CRC are likely to be captured in this context. High alcohol consumption may result in inadequate folate status by decreasing intestinal absorption and increasing renal excretion.4 It is hypothesized that low folate status increases the risk of CRC by altering DNA methylation and DNA synthesis.44, 45 It is known that acetaldehyde, rather than alcohol itself, can cleave folate chemically. A high intracolonic concentration of acetaldehyde from bacterial production and metabolism of alcohol could thus lead to decreased folate levels in the colonic mucosa. However, the present study lacks the statistical power required to properly evaluate how intake of dietary folate or blood folate levels may modulate the CRC risk association between alcohol consumption and ADH/ALDH genes.
To the best of our knowledge, this study is the largest study to date conducted regarding the role of rs1229984 (ADH1B), rs1573496 (ADH7) and rs441 (ALDH2) genes on CRC risk in Caucasian populations. Our study confirmed that the fast alcohol metabolizer allele in the ADH1B polymorphism is associated with a reduction of alcohol intake, mainly ascribable to wine consumption, and that the rs1229984 (ADH1B) and rs441 (ALDH2) polymorphisms showed no association with CRC risk. The relationship between alcohol intake and risk of CRC seemed to be modulated by the rs1573496(C) (ADH7) polymorphism.
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The EPIC study was funded by the ‘Europe Against Cancer’ Programme of the European Commission (SANCO); the Ligue contre le Cancer (France); the Société 3 M (France); the Mutuelle Générale de l’Education Nationale; the Institut National de la Santé et de la Recherche Médicale (INSERM); the German Cancer Aid; the German Cancer Research Center; the German Federal Ministry of Education and Research; the Danish Cancer Society; the Health Research Fund (FIS) of the Spanish Ministry of Health (RETIC-RD06/0020); the participating regional governments and institutions of Spain; The ISCIII Red de Centro RCESP (C03/09); the Cancer Research, UK; the Medical Research Council, UK; the Stroke Association, UK; the British Heart Foundation; the Department of Health, UK; the Food Standards Agency, UK; the Wellcome Trust, UK; the Greek Ministry of Health and Social Solidarity; the Hellenic Health Foundation and Stavros Niarchos Foundation; the Italian Association for Research on Cancer; the Italian National Research Council; the Compagnia di San Paolo; the Dutch Ministry of Public Health, Welfare and Sports; the Dutch Ministry of Health; the Dutch Prevention Funds; the LK Research Funds; the Dutch ZON (Zorg Onderzoek Nederland); the World Cancer Research Fund; the Swedish Cancer Society; the Swedish Scientific Council; the Regional Government of Skane, Sweden and the Norwegian Cancer Society.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on European Journal of Clinical Nutrition website
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