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Sex as an effect modifier in the association between alcohol intake and gastric cancer risk

BACKGROUND The results of previous meta-analyses evaluating the association between the alcohol intake and gastric cancer risk have reported that a statistical significance only for men. AIM To investigate the different association between alcohol intake and gastric cancer risk between men and women. METHODS The selection criteria included a prospective cohort study for evaluating alcohol intake and gastric cancer risk, with relative risks adjusted for potential confounders. Adjusted relative risk (RR) for the potential confounders and its 95% confidence interval (CI) in the highest vs lowest level were extracted from each study and a random-effects meta-analysis was conducted. Subgroup analyses by region, level of adjustment for smoking status, adjusting for body mass index, and year of publication were conducted. RESULTS A meta-analysis of all 27 cohorts showed that alcohol intake increased the risk of gastric cancer (summary RR = 1.13, 95%CI: 1.04-1.23, I2 = 58.2%). Further, 13 men’s cohorts had higher summary RR while maintaining statistical significance, and only seven women’s cohorts had no statistical significance. CONCLUSION The present review suggests that alcohol consumption increases the risk of gastric cancer in men. These findings showed that the sex variable in the association between alcohol intake and gastric cancer risk seemed to be an effect modifier with an interaction term. It is necessary to re-estimate follow-up outcomes after stratifying for sex.


INTRODUCTION
Global cancer statistics 2018 reported that gastric cancer was the fifth most frequently diagnosed cancer and the third leading cause of cancer-related death [1]. As gastric cancer is known to be a multifactorial disease [2], modifiable risk factors such as Helicobacter pylori and Epstein-Barr virus infection, diet, smoking status, and alcohol intake have been identified [3][4][5][6]. Table 1 summarizes the results of three meta-analyses published in 2017, that evaluated the association between alcohol intake and gastric cancer risk [7][8][9]. All summary relative risk (sRR) was over 1, but the results of statistical significance conflicted with each other. Interestingly, all meta-analyses reported that the 95% confidence interval (CI) of sRR in men did not involve 1. This indicates a statistically significant association between alcohol intake and gastric cancer risk in men. However, women did not have statistical significance in any of the meta-analyses. In addition, He et al [8] reported that light alcohol intake was associated with a reduction in gastric cancer in women (sRR = 0.74, 95%CI: 0.57-0.98).
Based on these findings, the author hypothesized that alcohol intake's association with gastric cancer risk may differ between men and women. Thus, the aim was to investigate the suggested hypothesis targeting three meta-analyses in Table 1 and Tramacere et al [10]'s study by performing a meta-epidemiological review [11].

Selection strategies
The selection criterion for this meta-epidemiological study was as follows: A prospective cohort study for evaluating alcohol intake and gastric cancer risk showing RR adjusted for potential confounders.

Statistical analysis
Adjusted RR for potential confounders and its 95%CI in the highest vs lowest level were extracted by sex from each study. As the reference group of Buckland et al[27] was the moderate/high-intake group, the adjusted RR of the study was taken by the reciprocal of the adjusted RR of the no/low-intake group. The level of adjustment for smoking status and the adjustment for body mass index in each cohort study were evaluated. A high level of smoking status was defined as ≥ 3 in the definition suggested by Thomas and Hodges[31]. They defined three levels as adjustments with less than four categories based on smoking status and intensity. The level of heterogeneity among cohorts was evaluated using the I-squared value, and a random-effects model meta-analysis was performed [32]. In addition, subgroup analyses by region, level of adjustment for smoking status, adjusting for body mass index, and year of publication were conducted to evaluate the effects of potential confounders. The level of statistical significance was set at P < 0.05.
The subgroup analysis of the 13 men's cohorts showed that there was statistical significance in Asians, in the group with a high level of adjustment for smoking status, in the group with the adjustment for body mass index, and in more recently published studies (Table 2). These results were not found in the seven women's cohorts.

Summary of the main finding
The results show that alcohol intake increased the risk of gastric cancer, especially in men. However, this association was not seen in women.

Differences between sex groups
Compared to the sRR of 1.21 in men's cohorts of Wang et al[9] in Table 1 1.13 estimated from 13 cohorts was the almost the same level, but the CI was narrower. The sRR of men's cohorts published more recently was the highest and was statistically significant. Cumulative meta-analysis showed that the sRR converged as it moved from the past to the present ( Figure 3). However, the results of the women's cohorts showed that alcohol intake might not increase the risk of gastric cancer. This finding can be supported by the results of He et al [8], who reported that light alcohol intake was associated with a reduction in gastric cancer in women (sRR = 0.74, 95%CI: 0.57-0.98). In addition, incidence rates are two-fold higher in men than in women [1]. Thus, the sex variable in the association between alcohol intake and gastric cancer risk seems not to be a simple confounder but be an effect modifier having an interaction term [38]. In other words, seven cohorts adjusted for sex need to re-estimate outcomes stratified by sex.

Inferences about subgroup analyses
The subgroup analysis of 13 men's cohorts indicated that there was statistical significance in Asians, in the group with the high level of adjustment for smoking status, and in the group adjusted for body mass index. Interestingly, the statistical significance was not shown in the group with a low level of adjustment for smoking status, and in the group not adjusted for body mass index. This is because a RR generally shifts to null as the potential confounder is strengthened. These phenomena strongly support the hypothesis that alcohol intake increases the risk of gastric cancer in men.

Limitations
The main limitation is that the category of alcohol intake varies in each study, such as times per week, amount consumed per day, none/moderate/heavy, or never/ former/current drinker. Therefore, the author extracted the results of the highest and lowest levels from each study and applied a random effect model. Another limitation is that the author could not perform subgroup analysis for cardia and non-cardia because only three cohorts were selected. Thus, the author could not evaluate the argument by sex that "intestinal non-cardia carcinoma was accompanied by heavy alcohol consumption"[3].

CONCLUSION
In conclusion, the present study suggests that alcohol consumption increases the risk of gastric cancer in men. It is necessary to re-estimate the follow-up outcomes by stratification for sex to determine whether there is a sex difference in the association between alcohol intake and gastric cancer risk.

Research background
The previous systematic reviews showed a statistically significant association between alcohol intake and gastric cancer risk in men. However, women did not have statistical significance in any of the meta-analyses.

Research motivation
The author hypothesized that alcohol intake's association with gastric cancer risk may differ between men and women.

Research objectives
The aim was to investigate the suggested hypothesis targeting four previous metaanalyses by performing a meta-epidemiological review.

Research methods
After securing additional cohort studies meeting the selection criteria, updated metaanalysis and subgroup analysis by sex were conducted.