The Mediating Effect of the Choline-to-Betaine Ratio on the Association Between PEMT rs7946 and Digestive System Cancer: A Nested Case-Control Study in a Chinese Population

Background: The enzyme phosphatidylethanolamine N-methyltransferase (PEMT) is responsible for synthesizing phosphatidylcholine by methylating phosphatidylethanolamine. We hypothesized that a polymorphism of the PEMT gene, rs7946, is involved in carcinogenesis. Objectives: We aimed to investigate the relationship between PEMT rs7946 and digestive system cancer and examine possible effect modifiers and mediators. Methods: We conducted a nested, case-control study within the China H-type Hypertension Registry Study, including 751 cases and 1:1 matched controls. To assess the association of PEMT rs7946 and digestive system cancer, we estimated odds ratios with 95% confidence intervals (CIs) using conditional logistic regression. We used the bootstrap test to examine the potential mediating effects of related metabolites. Results: Our results revealed that wild -type homozygous CC genotype carriers of PEMT rs7946 had a significantly increased risk [odds ratio (OR): 1.31; 95% CI: 1.04, 1.66; P = 0.023] compared with the TT/CT combined genotypes. The effect was found to be more pronounced in individuals with a lower choline-to-betaine ratio (<0.412,P -interaction = 0.021). Furthermore, the mediation analysis indicated that the choline-to-betaine ratio played a significant role in mediating 13.55% of the association between PEMT rs7946 and digestive system cancer (P = 0.018). Conclusions: Our study suggested that PEMT rs7946 may affect risk of digestive system cancer through direct and indirect pathways, and the choline-to-betaine ratio may partially mediate the indirect effect. This trial was registered at Chinese Clinical Trial Registry as ChiCTR1800017274.