The following main findings were observed: 1) CC carriers have 31% increased risk of digestive system cancer compared with the TT/CT combined genotypes (P = 0.023); 2) this association was more pronounced in participants with a lower choline-to-betaine ratio (P-interaction = 0.021); and 3) we proved a mediation effect of choline-to-betaine ratio in PEMT rs7946 and risk of digestive system cancer. The gene discussed is PEMT; the disease is digestive system cancer.