Beware – Gastric Cancer Protection Collapsed By Alcohol Intake
Overview
Dietary folate intake has been suggested as a potentially modifiable factor influencing gastric cancer (GC) risk, though existing evidence remains inconclusive. This study assesses the relationship between dietary folate intake and GC risk, along with the modifying effect of alcohol consumption. Data from 2829 histologically confirmed gastric cancer cases and 8141 controls were pooled from 11 case-control studies within the international Stomach Cancer Pooling Consortium. Dietary folate intake was estimated via food frequency questionnaires. Linear mixed models with random intercepts for each study were employed to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI). Results indicated that higher folate intake correlated with a reduced risk of gastric cancer; however, this association was absent among individuals consuming more than 2.0 alcoholic drinks per day. The OR for the highest quartile of folate intake compared to the lowest was 0.78 (95% CI, 0.67–0.90, P-trend = 0.0002). The OR per quartile increment was 0.92 (95% CI, 0.87–0.96), and per every 100 μg/day of folate intake, it was 0.89 (95% CI, 0.84–0.95). A significant interaction between folate intake and alcohol consumption was observed (P-interaction = 0.02). Notably, the reduced risk of gastric cancer associated with higher folate intake was not evident in participants who consumed over 2.0 drinks per day, with ORQ4v Q1 = 1.15 (95% CI, 0.85–1.56) and OR100 μg/day = 1.02 (95% CI, 0.92–1.15). This study supports a beneficial effect of increased folate intake on reducing GC risk, although this benefit is negated by the consumption of more than 2.0 alcoholic drinks per day.
Introduction
Gastric cancer (GC) ranks as the fourth leading cause of cancer mortality and the fifth most diagnosed cancer globally. Chronic Helicobacter pylori infection is a significant factor in GC etiology, along with other modifiable risk factors such as tobacco smoking, heavy alcohol consumption, and dietary habits. Specifically, diets low in fruits and vegetables, high in red and processed meats, high in salt and salt-preserved foods, insufficient antioxidant minerals and vitamins, and low adherence to the Mediterranean diet have all been linked to increased gastric cancer risk.
Several studies have indicated that higher dietary folate intake is linked to a reduced risk of various cancers, including oropharyngeal, laryngeal, oesophageal, gastric, and colorectal cancers. Regarding gastric cancer, some research has reported inverse relationships between folate intake and cancer risk. A systematic review and meta-analysis of 21 studies demonstrated a significant association between increased folate intake and reduced gastric cancer risk, with a 1.5% risk reduction per every 100 μg/day increase in dietary folate. However, other meta-analyses have reported inconsistent results concerning this association.
Folate is found in many common foods such as vegetables, legumes, and nuts; yet, folate deficiency remains prevalent worldwide. This deficiency is often due to low dietary intake and the poor stability of dietary folates during cooking. Other factors contributing to folate deficiency include increased physiological demands (e.g., pregnancy or malabsorptive conditions), certain medications, and chronic alcohol consumption. Alcohol specifically can interact with dietary folate, limiting its intake and absorption, altering its metabolism, and increasing renal excretion. Several studies have reported significant interactions between dietary folate intake and alcohol consumption for certain cancer types, though some research has found no such interaction.
The Stomach Cancer Pooling (StoP) Project, an international consortium of epidemiological studies on gastric cancer, offers a valuable opportunity to investigate various risk factors with detailed information from a large cohort of individuals. This study aims to evaluate the impact of dietary folate intake on gastric cancer risk within the StoP Consortium and to examine whether alcohol consumption modifies this relationship.
Method
This study is based on data from 11 studies within the StoP Consortium, which includes 34 case-control or nested-within-cohort studies from 15 countries, encompassing 13,121 gastric cancer (GC) cases and 31,420 controls. The StoP Consortium aims to analyze the role of key factors in GC etiology through pooled analyses of individual-level data. The original databases from each study were standardized and harmonized, ensuring consistency and completeness, with all analyses conducted at the University of Milan using a two-stage approach when necessary.
The present analysis focuses on 11 studies with complete dietary folate intake data. These studies originate from Italy, Iran, Portugal, Greece, Japan, the United States, Spain (two studies), and Mexico (three studies). The final analysis included 2,829 histologically confirmed GC cases (ICD-O-3 codes C16.0-C16.9) and 8,141 controls. Among these studies, six were population-based, four were hospital-based, and one was a nested case-control study. In two hospital-based studies, controls were individually matched by age, sex, and residence, while five studies used frequency matching by age, sex, and residence.
Dietary assessment was conducted using country-specific food frequency questionnaires that accounted for standard portion sizes. Daily folate intake (in micrograms per day) was calculated by multiplying reported food frequencies by nutrient content based on country-specific food composition tables. Estimates of daily folate intake were energy-adjusted using the residual method. This study included only natural dietary folate, excluding synthetic, fortified, or supplemental sources. Participants with implausible energy intakes (<500 kcal/day or >4500 kcal/day) were excluded.
Additional covariates were harmonized according to a pre-specified format, including age (categorized as <49, 50–59, 60–69, ≥70 years), sex (male, female), social class based on educational level (low: less than high school; intermediate: high school; high: more than high school), smoking status (never, former, current), H. pylori infection status (seronegative, seropositive, missing), anatomical site of GC (cardia, non-cardia, unspecified), histological type of GC (diffuse, intestinal, other types, unspecified), total energy intake (kcal/day), and alcohol consumption (0 drinks/day, 0.1–2.0 drinks/day, >2.0 drinks/day).
Statistical Analysis
Participant characteristics were detailed based on whether they were in the control or case group. For continuous variables, the mean and standard deviation (SD) were provided, while categorical variables were expressed as number (n) and percentages (%).
A one-stage pooled analysis was conducted to investigate the relationship between energy-adjusted dietary folate intake and gastric cancer (GC). Linear mixed effect models with random intercepts for each study were used to calculate the odds ratios (OR) and 95% confidence intervals (CIs) for GC across study-specific quartiles of dietary folate intake. ORs and 95% CIs were also calculated for quartiles as ordinal variables (per quartile increment) and per 100 μg/day of dietary folate intake. Three models were presented: (a) Model 1, adjusted for sex and age; (b) Model 2, which included adjustments for sex, age, social class, smoking, alcohol consumption, and energy intake; (c) Model 3, which included the variables in Model 2 plus H. pylori infection status.
Likelihood ratio tests were used to examine the multiplicative interaction between quartiles of energy-adjusted dietary folate intake and three categories of alcohol consumption. Stratified analyses were also performed based on alcohol consumption categories (0 drinks/day, 0.1–2.0 drinks/day, and >2.0 drinks/day) and sex (male, female), with adjustments for the same variables as in Model 2. Multinomial logistic regression was employed to explore the association between dietary folate intake and the anatomical site of GC (cardia, non-cardia, unspecified) as well as the histological type of GC (diffuse, intestinal, other types, and unspecified).
Result
The study analyzed sociodemographic and lifestyle factors among 8141 controls and 2829 cases of gastric cancer (GC). Cases exhibited a lower social class (54.4%), lower intake of fruits and vegetables (34.7%), and lower prevalence of H. pylori infection (35.1%) compared to controls (45.2%, 28.4%, and 42.5%, respectively). Alcohol consumption >2.0 drinks/day was more prevalent among cases (28.6%) than controls (20.7%), while smoking habits were similar between groups. Mean daily folate intake was slightly lower in cases (291.4 μg/day) than controls (305.1 μg/day). Significant interactions were observed between quartiles of energy-adjusted folate intake and alcohol consumption categories, particularly among those consuming >2.0 drinks/day (OR 1.15, 95% CI 0.85–1.56 for highest vs. lowest folate quartile). Sex-specific analyses showed consistent trends with overall findings, and sub-site analyses indicated significant associations primarily for non-cardia GC and certain histological subtypes like diffuse GC. These findings underscore the complex interplay of dietary folate, alcohol consumption, and gastric cancer risk, suggesting potential preventive strategies tailored to lifestyle factors.
Conclusion
In this pooled analysis from the StoP Consortium encompassing 11 studies, dietary folate intake demonstrated a significant protective association against gastric cancer (GC). The study revealed an inverse dose-response trend across quartiles of folate intake and for every 100 μg/day increase in dietary folate. Specifically, participants in higher quartiles of energy-adjusted folate intake exhibited a 16%, 22%, and 22% lower risk of GC compared to those in the lowest quartile.
Interactions between dietary folate intake and alcohol consumption were also notable. The protective effect of folate intake on GC risk was observed predominantly among individuals consuming ≤2.0 alcoholic drinks/day. Conversely, this protective association was attenuated in individuals consuming >2.0 drinks/day of alcohol.
Folate, a water-soluble vitamin found in plant-based foods and animal products, plays a crucial role in maintaining DNA stability. Folate deficiency has been linked to DNA damage and increased cancer susceptibility, mediated partly through DNA hypomethylation. The study also highlighted the role of alcohol consumption in modifying folate’s protective effects, possibly through mechanisms such as altered folate metabolism and nutrient absorption.
While the findings underscored the consistent protective association of dietary folate intake against GC risk across various subgroups and histological types, the study acknowledged limitations such as potential bias in case-control designs and missing data on relevant variables like H. pylori infection and supplement use. Nonetheless, the results suggest that reducing alcohol consumption to ≤2.0 drinks/day may optimize the protective benefits of folate intake against GC, pending confirmation through prospective cohort studies.
In conclusion, this analysis reinforces the importance of dietary folate intake in mitigating GC risk, contingent on moderate alcohol consumption. Further research is recommended to validate these findings and elucidate underlying mechanisms, advocating for potential public health strategies to promote balanced folate intake and moderate alcohol consumption for GC prevention.
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