Fruits and certain vegetables have a protective effect on gastric cancer (GC) and folate is one of the nutrients in fruits and vegetables. We hypothesized that the polymorphisms of thymidylate synthase ( TYMS ) gene involved in folate metabolism are associated with GC risk. In a population-based case–control study of 337 GC cases and 326 controls, frequency-matched by age, sex and residential areas in a southern Chinese population, we genotyped the 28 bp tandem repeat in the TYMS 5′-untranslated enhanced region ( TSER ) and the 6 bp deletion/insertion at bp 1494 in the TYMS 3′-untranslated region ( TS3 ′ UTR ).We found that although the TSER polymorphism had no main effect on GC risk, the TS3′UTR 6 bp/6 bp genotype was associated with a significantly increased risk of GC [adjusted odds ratio (OR) = 1.96, 95% confidence interval (CI) = 1.18–3.25], especially the non-cardiac gastric cancer (2.16, 1.22–3.82), compared with the 0 bp/0 bp genotype. However, when we evaluated these two polymorphisms together and used the combined genotype with zero variant allele ( TSER 2R and TS3 ′ UTR 6 bp variant alleles) as the reference, we found that the combined genotype with three or four variant alleles was associated with a significantly increased risk of GC (2.06, 1.12–3.79), especially the non-cardiac gastric cancer (2.33, 1.19–4.59), and this significant association was more pronounced among older women (>60 years old), non-smokers, and never tea drinkers. In conclusion, the TYMS polymorphisms, especially the TS3′UTR polymorphism, are associated with GC risk, especially the non-cardiac gastric cancer, and the TSER 2R and TS3′UTR 6 bp alleles may jointly play a role in the etiology of GC in the southern Chinese population. Larger studies are warranted to verify these findings.

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