Gastric cancer (GC) represents the fifth most common cancer and the third leading cause of cancer deaths in males and females worldwide, with nearly one million new cases and 723,100 deaths from GC every year (1). Given the increasing prevalence of GC and its mortality, new strategies are necessary to minimize the disease burden. Helicobacter pylori infection, high alcohol consumption, obesity, smoking, and dietary factors are the main risk factors of GC (2, 3). Numerous studies have shown the association between nutritional factors and GC (3, 4). In fact, one meta-analysis found that the total dietary fat was positively associated with GC (5).

Cholesterol is a common nutrient in the human diet, with eggs, red meat, dairy products, fish, and poultry representing its major sources (6). It has been indicated that dietary cholesterol can increase serum cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol concentrations (7). Hypercholesterolemia may be involved in cancer development via a rise in the level of inflammatory markers (8).

Some meta-analyses demonstrated that high dietary cholesterol intake increases the risk of ovarian, breast, pancreatic, and esophageal cancers (9–12). However, the association between dietary cholesterol intake and GC risk remains controversial. Some case–control studies have indicated a positive relationship (13, 14), while others showed no association (15, 16). Based on our knowledge, there is no systematic review and meta-analysis to summarize the findings regarding dietary cholesterol intake and GC.

Therefore, considering the conflicting results and increasing incidence of GC worldwide, we carried out a systematic review and meta-analysis to provide a quantitative synthesis of the existing data on the association between dietary cholesterol intake and the risk of GC in adults. Furthermore, we aimed to assess the shape and strength of the dose–response association between dietary cholesterol intake and GC.

The framework of this review was structured according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement [(17); Supplementary Table 1].

After removing 234 duplicate articles from a total of 4,231 papers identified through the initial search, 3,997 papers remained for reviewing the title and abstract. At this stage, 3,964 publications were excluded, and the full texts of 33 remaining articles were checked. Among 19 studies that were eliminated in this step, six used similar datasets, one did not report the CI, 11 were irrelevant, and one reported the population-attributable risk. Finally, 14 case–control studies were eligible for our systematic review and meta-analysis [(13–16, 24–33); Figure 1].

Study-specific characteristics are illustrated in Table 1. Nine population-based case–control (13, 14, 16, 24, 26, 29–31, 33) and five hospital-based case–control studies (15, 25, 27, 28, 32) published from 1990 to 2020 met our criteria. In total, 6,490 GC patients and 17,793 controls aged between 20 and 98 years were included. Studies were conducted in United States (n = 4) (13, 25, 31, 33), Italy (n = 2) (15, 24), China (n = 2) (14, 30), Canada (n = 1) (26), Mexico (n = 1) (29), Poland (n = 1) (16), South Korea (n = 1) (27), Serbia (n = 1) (28), and Iran (n = 1) (32). All studies were conducted on both genders and used food frequency questionnaires (FFQs) for dietary assessment. In 11 case–control studies, matching for age and gender was carried out between the case and control groups (13–16, 24, 26–30, 33). Furthermore, some important covariates, including H. pylori infection (n = 4) (14, 27, 31, 33), total energy intake (n = 13) (13–16, 24–26, 28–33), BMI (n = 8) (13–15, 24–26, 31, 32), alcohol consumption (n = 6) (13, 14, 25, 26, 30, 31), and smoking (n = 12) (13–16, 25, 26, 28–33), were adjusted in the analysis. According to quality assessment findings, nine studies were classified as high-quality (score of ≥7) studies [(13, 15, 16, 24, 26, 29, 30, 32, 33); Supplementary Table 2].

In this systematic review and meta-analysis of 14 case–control studies, we found that higher intakes of dietary cholesterol were associated with a 35% greater risk of GC among adults. In addition, a non-linear dose–response relationship was observed. This study is the first systematic review and meta-analysis to examine the relationship between cholesterol intake and the risk of GC.

Cholesterol plays a vital role in maintaining cellular homeostasis in the body (34). Major dietary sources of cholesterol include red meat, processed meat, egg yolks, dairies, fish, butter, cheese, shrimp, and poultry (35). Considering that a high-cholesterol diet might represent an unhealthy dietary pattern and lead to chronic diseases such as cancer and cardiovascular diseases (36, 37), the relationship between dietary cholesterol and the risk of cancer has received much attention (11, 12). This meta-analysis suggests that high dietary cholesterol intake may elevate the odds of GC. In line with our finding, one hospital-based case–control study in Spain found a positive relationship between cholesterol consumption and GC (38). Jung et al. (39) also expressed that high serum cholesterol was linked to the incidence of GC. Furthermore, some meta-analyses found a significant positive association between dietary cholesterol intake and cancers of the ovaries, breasts, pancreas, esophagus, and lungs (9–12, 34).

In contrast, in two meta-analyses, intake of red meat and eggs (rich sources of cholesterol) was not associated with the risk of GC (40, 41). Given that cholesterol is consumed in combination with other compounds such as salt, nitrates, multivitamins, minerals, and high-quality protein, the interaction between different nutrients prevents us from understanding the individual effect of cholesterol. We know that cholesterol is found in animal foods and high-cholesterol diets are poor sources of plant foods, including fruits and vegetables. Evidence indicates that people who consume high amounts of vegetables and fruits have a lower risk of GC (42, 43). This effect might be due to the presence of many antioxidants (particularly vitamin C, vitamin E, and carotenoids) in fruits and vegetables, which possess anticarcinogenic properties (44). In addition, an inverse association was seen between serum cholesterol concentrations and the occurrence of GC in some cohort studies (45, 46). The amount of cholesterol in cancer cells is higher than the normal cells, and cholesterol helps in cancer promotion (47). It is still ambiguous whether low serum cholesterol is a cause or effect in relation to GC, and this issue needs to be examined. Therefore, it is likely that dietary cholesterol increases the risk of cancer without augmenting blood cholesterol levels.

The inconsistencies among studies may be explained by variations in study design, geographic regions, adjustments, reporting of dietary data, quality of studies, and/or the number of cases. It has been shown that H. pylori infection, smoking, alcohol consumption, obesity, salt-rich diet, nitrites, and hot meals are the determinants of GC (48, 49). High dietary cholesterol intake may take part in GC initiation or progression by supporting H. pylori infection. H. pylori infection leads to gastric atrophy and hypochlorhydria, which promote the colonization of acid-intolerant bacteria (50) and elevate the occurrence of GC (51). Our findings indicated no association between dietary cholesterol intake and GC after adjusting our results for H. pylori infection. Furthermore, most of the included studies were adjusted for smoking and energy intake, which are the critical risk factors of GC. Besides, we found a significant positive association between cholesterol intake and GC in studies adjusted for BMI.

There are some potential mechanisms regarding the relationship between cholesterol and GC. Dietary cholesterol might play a role in cancer development via changes in lipid metabolism, which are related to cellular inflammation (52). An increase in total cholesterol and LDL as well as a decrease in HDL could induce the production of inflammatory biomarkers such as interleukin-6 and tumor necrosis factor-α (53).

This study possessed some strengths. First, linear and non-linear dose–response analyses help us to reveal the shape and strength of probable association. Second, most of included studies applied an interview-administered questionnaire. Self-reported questionnaires for cholesterol intake assessment might inevitably lead to some misclassification of participants in terms of exposure. Third, most studies took into account a wide range of important confounding factors, including energy intake, smoking, alcohol consumption, and BMI. Finally, publication bias was not detected. Nonetheless, our study had some limitations. First, based on our knowledge, there was no cohort study to examine the association between dietary cholesterol and GC. Because case–control studies have diverse kinds of bias, including selection bias, recall bias, and measurement bias, the case–control nature of included studies prevented us from reaching a decisive conclusion. Second, some fundamental residual confounders such as H. pylori infection, dietary factors (salt, nitrates, etc.), and lipid-lowering medications (especially statin use) were ignored in the adjustments of most studies. Third, although we tried to detect the sources of heterogeneity among studies, we could not find them through subgroup analysis and meta-regression. Due to a limited number of studies, we could not perform subgroup analysis for other potential relevant factors. Finally, measurement errors are unavoidable in estimates of dietary cholesterol intake.

In conclusion, this review illustrated an association between high dietary cholesterol intake and GC development in case–control studies. This study suggests the importance of dietary cholesterol modification in the prevention of GC. Considering that all of the included studies had case–control designs prone to biases, these results warrant cohort investigations. Large, long-duration, prospective cohort studies that consider the important dietary and non-dietary covariates are obligatory to achieve a comprehensive understanding of this matter.

PM and LG designed the work, extracted the data, analyzed the data, and critically reviewed the manuscript. LG wrote the first draft of the manuscript. Both authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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