The human mucin (MUC) family consists of MUC1 to MUC21, which are classified into secretory (e.g. MUC2, MUC5AC, MUC5B, and MUC6) and transmembrane members (e.g., MUC1, MUC4, and MUC20) (21). MUC1, MUC4, MUC13, and MUC16 are single pass type I transmembrane proteins and act as a protective mucus gel through their O-glycosylated repetitive ectodomines. The MUC1 N-terminal subunit (MUC1-N) contains highly conserved 20 amino acid tandem repeats that are extensively modified by O-glycans. Alterations in glycosyl-transferase expression in malignant cells leads to glycosylation of MUC1-N tandem repeats (22). According to evidence, homozygous AA genotype (small size VNTR) is associated with an increased risk of H. pylori infection and gastric cancer (23–28).
In this study, allelic comparison (G vs. A) and genotype comparison (GA vs. AA; GG vs. AA) were done and dominant model (AG + AA vs. GG), recessive model (AA vs. AG + GG), and over-dominant model (AA + GG vs. AG) were tested (29). We tested samples from case group with gastric cancer and hospital-based control group without gastric cancer to evaluate the association between rs4072037 polymorphism and H. pylori with susceptibility to gastric cancer. In our previous study in 91 patients with gastric cancer and 96 population-based control group, a significant relationship was observed between rs4072037G > A polymorphism and susceptibility to gastric cancer (30). The present study, unlike our former report, did not show a significant association between rs4072037G > A and risk of gastric cancer. Fifty individuals with gastritis were investigated as controls in this study and this may contradict the result if rs4072037G > A play a role in susceptibility to gastric cancer. similarly, a meta-analysis by Xinyang Liu et al. included a hospital-based control group with gastritis and a healthy population-based control group. In that analysis, hospital-based control group limited the role of rs4072037 polymorphism of MUC1 gene in carcinogenesis (31).
Silva et al. reported that Colombian and Portuguese patients with chronic gastritis were genetically different in VNTR locus. They showed that smaller VNTR genotypes of the MUC1 gene increase susceptibility to intestinal metaplasia in Colombian patients with gastritis. They also observed that MUC1 gene polymorphism is involved in development of chronic atrophic gastritis and intestinal metaplasia, which is a precursor to gastric carcinoma (32). Moreover, immunohistochemical analysis of 95 patients with gastritis in Northern Europe showed that the length of functional allele of MUC1 gene is involved in susceptibility to gastritis (33).
H. pylori causes a wide range of gastrointestinal injuries from gastric ulcers to gastric adenocarcinoma (34). MUC1 membrane mucosa is abnormally expressed in different cancers and in the stomach, it is a ligand for H. pylori and plays a key role in gastric carcinogenesis (18). MUC1 is involved in negative regulation of NLRP3 inflammation by regulating NF-κB nuclear factor pathway. Regulation of NLRP3 inflammatory activity by MUC1 is critical for prevention of severe gastritis (22). Variable number of 20 amino-acid tandem repeat units (VNTR) lead to polymorphisms in the extracellular domain MUC1. People infected with H. pylori with shorter TRs are more susceptible to gastritis and increased risk of stomach cancer (33).
Functional polymorphism rs4072037 in MUC1 gene involved in inflammatory response in patients with H. pylori is significantly associated with a predisposition to gastric cancer (26). An immunohistochemical analysis based on TR antibody showed that H. pylori may react with TR domain of MUC1 on the surface of gastric epithelium and stimulate shedding and internalization. Also, an association was found between functional allele length differences in response to H. pylori (33). The association between small sizes of VNTR and increased risk of H. pylori infection is confirmed (35) and homozygote Short-Short (SS) VNTR of the MUC1 gene is reported to be associated with H. pylori compared to the Long-Long (LL) genotype (36, 37). Other studies also found an association between SS genotype versus LL MUC6 VNTR and the risk of H. pylori (36). Plummer et al. found that 89% of patients with non-cardiac gastric cancer were infected with H. pylori (38), however, other studies did not report a significant association between rs4072037 polymorphism of MUC1 gene and H. pylori with gastric cancer (39, 40).
In this study, using different genotypic models (AA genotype of negative H. pylori group vs GA/GG negative genotype of H. pylori and AA and GA/GG genotypes of H. pylori positive vs GA/GG genotype of negative H. pylori), we investigated the association between H. pylori and rs4072037G > A polymorphism and risk of gastric cancer. In our study, GA/GG genotype and H. pylori were significantly associated with an increased risk of gastric cancer (OR = 0.251, 95% CI: 0.128–0.493, p = 0.000).