The present study aimed to determine the association between dietary ORAC intake and GC risk according to the GSTP1 genetic variant. A high dietary ORAC intake was considerably associated with a decreased risk of GC in a Korean population. Regarding genetic variants in the GSTP1 gene, dietary ORAC intake showed significant inverse associations of GC risk according to GSTP1 rs1871042 genotypes.
Gastric adenocarcinoma occurs when normal mucosa cells are continuously exposed to a variety of carcinogens that lead to uncontrolled cell proliferation in the gastric mucosa membrane (38). There are two major mechanisms linked to the development of GC with H. pylori infection: 1) epigenetic alterations in gastric epithelial cells by H. pylori infection and 2) H. pylori-induced inflammation of gastric mucosa (39). Many studies have shown that persistent inflammation, through cytokines, chemokines, growth factors, and oxygen-derived free radicals, is responsible for GC risk associated with H. pylori infection (39, 40). The role of oxidative stress from inflammation in GC has been determined, suggesting the importance of the balance between radical production and the antioxidant defense system (41). Numerous studies have reported that the intake of fruits and vegetables is inversely associated with GC risk, while some studies found no association (42–46). Specifically, high intake of fruits by H. pylori-negative subjects decreased the risk of GC compared to low intake of fruits by H. pylori-positive subjects, indicating that the intake of fruits and vegetables may play a role in preventing H. pylori-induced gastric carcinogenesis (45–47). In contrast, the data on the effects of vitamin A, vitamin C, vitamin E, and carotenoids on GC risk were inconsistent or conflicting with the different doses used (48–50). In this study, we examined the antioxidant capacity of food and determined the antioxidant effects of ORAC on gastric carcinogenesis. A recent meta-analysis reported inverse associations between cancer risk and dietary TAC by using multiple methods, including ORAC (51). Other previous studies found inverse associations between ORAC intake and other cancers but not GC risk (52–55). We observed similar findings between GC risk and three indices of dietary ORAC, namely, H-ORAC, L-ORAC, and TPs, after adjusting for H. pylori infection and other potential confounding factors. Furthermore, in the comparisons of the food items that highly contribute to the ORAC level, the food items with the highest ORAC were brewed green tea and fruits for H-ORAC, spicy red or black pepper for L-ORAC, and canned tomato juice for TPs (Supplementary Tables S4-S6).
The major function of GSTP1 is to detoxify exogenous or endogenous factors involved in carcinogenesis by regulating cell death and DNA damage (21, 56). Additionally, GSTP1 plays a role as a modifier gene in regulating the molecular expression and activation of enzymes from other GST subfamilies and their effects on cancer, and GSTP1 expression regulates cellular redox homeostasis in carcinogenesis (20, 57, 58). Although many studies have shown the associations between GSTP1 polymorphisms and various types of cancer, the results of a few studies on the associations between GC risk and GSTP1 genetic variants are inconsistent across geographic areas and diverse populations. In a Chinese population, the Val allele of GSTP1, namely, the Val/Val genotype, was significantly associated with an increased risk of GC (37, 59, 60). However, the GSTP1 Ile105Val (rs1695) and GSTP1 Val114Ala (rs1138272) polymorphisms were not associated with the risk of GC in either a South European or an Indian population (61, 62). In a Korean population, we observed that five GSTP1 polymorphisms (rs1695, rs749174, rs1871042, rs4891, and rs947895) located in the same block with a strong correlation of high LD had a tendency to increase GC risk, although the risk increase with the rs1695 polymorphism was not statistically significant. These conflicting results suggest that ethnic differences in GSTP1 genetic susceptibility may affect the development of GC with epigenetic interactions of environmental factors and that the relevance of GSTP1 genetic variants regarding GC risk needs to be confirmed in the future. Among the five GSTP1 polymorphisms in this study, four (rs749174, rs1871042, rs4891, and rs947895) have been investigated by only a few studies in the context of lung cancer and asthma, and their associations with GC risk have yet to be determined (63–65).
In this study, we observed an association between high intake of dietary ORAC and reduced GC risk according to the GSTP1 rs1871042 polymorphism. Our findings can be explained by the interconnections between dietary TAC and the role of the GSTP1 gene in regulating oxidative stress and detoxification of the immune response against gastric carcinogenesis-induced chronic inflammation by H. pylori infection. Imbalanced oxidative stress plays an obligatory role in gastric carcinogenesis by increasing the level of ROS induced by H. pylori infection, leading to DNA damage and tumor progression (4, 66). High intake of dietary ORAC is responsible for scavenging substances produced by H. pylori-infected gastric cells and, thus, may protect against the promotion of gastric carcinogenesis. More than half of H. pylori strains produce various cytotoxins, such as Cag-A, which can damage gastric mucosal cell membranes and trigger local immune responses (67). Previous evidence has shown that vitamin C protects against H. pylori infection-related GC by neutralizing free radicals and directly modifying the anticancer immune response against malignant progression (68, 69). within addition to the role of the GSTP1 gene, the specific allele of GSTP1 is able to regulate oxidative stress and detoxification against carcinogenesis (21, 58). Moreover, the impact of H. pylori infection on GSTP1 genetic polymorphisms regarding GC risk varies, suggesting that H. pylori infection may have different oncogenic effects, including controlling the activation of the detoxification system, resulting in gastric carcinogenesis, that depend on the GSTP1 genetic polymorphism (36, 70). High intake of dietary ORAC may synergistically interact with the GSTP1 rs1871042 polymorphism by detoxifying and eradicating excessive ROS, eventually leading to protection against the development of GC.
Nevertheless, some limitations should be noted as follows. First, selection and recall bias might be considered; controls recruited among those who visited the clinic for a health check-up may have been more health conscious than patients with GC. Second, the number of food items in our food database was insufficient to cover all of the United States Department of Agriculture (USDA) ORAC database. Additionally, the antioxidant capacity from ORAC is based on in vitro antioxidant assays limited to measure the absorption rate in the body. Third, the sample size is relatively small in each tertile of the case group. Further prospective studies are needed to confirm and extend our findings with a number of sample size.