The results of this population-based case-control study in NL, Canada, demonstrated that the association between alcohol intake and risk of CRC differed by obesity status. The increased risk of alcohol drinking on CRC was observed in people with obesity, and this association remained persistent regardless of how the exposure was defined.
Previous studies have suggested that alcohol consumption may increase the risk of developing CRC [4, 8, 28, 29]. However, our study observed a higher risk of CRC for drinking alcohol in people with obesity. While we are not able to offer a conclusive statement regarding discrepancy, there are several plausible explanations. First, obesity status is a CRC risk factor usually considered as a potential confounder in most studies investigating the alcohol -CRC association. This study examined how obesity modified the effects of alcohol on CRC rather than treated it as a confounder. Thus, our findings may help, in part, reconcile some discrepancies in the literature in terms of the risk for CRC related to alcohol drinking and provide some evidence for assessing possible interactions between alcohol and obesity in future epidemiological studies. Another possible reason for this may be that NL is a founder population geographically isolated . A higher proportion of CRC incidence in NL may be mainly attributed to genetic cause that may shade the roles of other environmental factors in the CRC carcinogenesis such as alcohol consumption [19, 30].
The elevated risk of CRC related to alcohol consumption only observed in obese participants in this study suggests a synergistic effect between alcohol and obesity. Although the biological mechanism for the synergy is not fully understood, a similar pattern has been detected in patients with liver, esophageal, and stomach cancer [31, 32]. Possible explanations for this include that alcohol is principally metabolized to acetaldehyde, an established carcinogen causing mucosal damage and cell proliferation to humans [14, 33]; while obesity is characterized by a low-grade chronic inflammatory state correlated with an increase in oxidative stress . In the presence of acetaldehyde (the primary metabolite of alcohol), pro-oxidative conditions, in general, produce acetaldehyde-modified protein, which has been suggested as one of the major events initiating cellular damages and causing diseases . Additionally, consistent with the elevated oxidative stress, the amount of GSTA4, an important enzyme that is responsible for the proper breakdown of acetaldehyde, has been found to decrease approximately 3-4-fold in obesity , resulting in an increased local toxicity of acetaldehyde. The biological mechanism, however, requires further investigation, and this observation needs to be validated in other populations.
A main strength of this study is that both cases and controls were selected from population-based samples identified through Newfoundland Cancer Registry and Telephone Roll provided by Aliant Company, respectively, resulting in a relatively large sample size (702 cases and 717 controls). All participants completed three self-administered questionnaires (i.e., a PHQ, a FHQ, and a FFQ), gathering detailed information on personal history, lifestyle and dietary habits for each participant. This allowed for the comprehensive assessment of other factors that could act as possible confounders that may distort the results .
This study is subject to several limitations. First, research in which people may participate has greatly proliferated in the past decades, resulting in an increased reject rate in all studies . Despite our best efforts, the participation rates of both cases and controls were relatively low. Case patients were more likely to respond because of a pre-existing awareness of the disease. Given the strength of the reported associations, the magnitude of the possible bias was unable to accurately estimate. It is possible that participating controls tended to have a higher socioeconomic status than the general population, which may lead to over-estimating the risk of alcohol drinking in this study. However, an analysis of the differences in demographic characteristics (only age, sex and residence in controls) between the eligible cases and controls, between participating cases and controls, between participating and non-participating cases, and between participating and non-participating controls in this study did not show evidence that non-participation greatly affected the results of the study (data not shown). Thus, possible participation bias was unlikely to fully explained observed association in this study.
Secondly, this study may be influenced by recall bias that could lead to exposure misclassification. Because the questionnaire did not distinguish respondents who never drank alcohol from those who drank less than one drink per day, the referent category (i.e., "non-drinkers") included occasional drinkers with non-drinkers. Lifetime measures might be inaccurate due to the concern about the adequacy of long-term recall after 18 years . When questioned on exposure status, participants were more likely to underestimate the amount of alcohol they drank , which would generally bias the association towards to the null [37–39]. The validity of self-reported alcohol consumption may differ between cases and controls since the cases and controls by definition are people who differ with respect to their disease experience, and this difference may affect recall . The bias caused by differential misclassification is variable . However, the main protection against bias in this study was the standardization of methods. The questions were identical and presented in an identical fashion to both cases and controls. Furthermore, analyses conducted to assess the validity of self-reporting lifetime alcohol consumption in this study (data not shown) did not provide any evidence that inaccurate or differential reporting of alcohol consumption for cases and controls may have biased the association.