A common insertion/deletion polymorphism of the thymidylate synthase (TYMS) gene is a determinant of red blood cell folate and homocysteine concentrations

Abstract

Substantial evidence suggests that a low folate/high homocysteine phenotype is pathogenic. We analyzed the impact of the thymidylate synthase (TYMS) 3'UTR ins/del polymorphism on folate and homocysteine levels and assessed the relationship between the TYMS 3'UTR ins/del polymorphism and key genetic and lifestyle variables. Among non-smokers only, the TYMS 3'UTR ins/del polymorphism was significantly associated with red blood cell folate (RBC folate; P=0.002) and homocysteine (P=0.03) concentrations. Median RBC folate concentration was much higher for TYMS 3'UTR del/del subjects (434 microg/l) compared with either ins/ins (282 microg/l) or ins/del (298 microg/l) subjects. The median homocysteine concentration for del/del homozygotes was considerably lower compared with either ins/ins homozygotes or ins/del heterozygotes. A possible additive effect for the impact of the TYMS 3'UTR del/del and MTHFR 677CC genotypes on RBC folate concentration was also observed. Our findings suggest that the TYMS 3'UTR del/del genotype is a significant determinant of elevated RBC folate concentration in a non-smoking population of northwestern European adults and that this genotype confers protection against diseases for which a low folate/high homocysteine phenotype appears to be an etiologic component.

Genetic polymorphisms in themethylenetetrahydrofolate reductase andthymidylate synthase genes and risk of hepatocellular carcinoma

“…Individuals possessing the TYMS3ЈUTR1494 homozygous 6-bp deletion polymorphism showed higher circulatory folate and lower homocysteine levels than those with the homozygous 6-bp insertion polymorphism. 21 Epidemiological studies found inconsistent associations between the TYMS3ЈUTR1494del6 polymorphism and risk of various diseases. Several studies reported that individuals possessing the Ϫ6/Ϫ6 genotype are at reduced risk of spina bifida (a folate-deficiency related birth defect), 44 lung cancer, 45 and gastric cancer.…”

“…19,20 The 2 polymorphisms appear to be in linkage disequilibrium, 19 with the 6-bp deletion allele linked with the TYMSER*3R. 20,21 Methylenetetrahydrofolate reductase (MTHFR), a key enzyme in 1-carbon metabolism, catalyzes the irreversible conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the predominant circulatory form of folate. The 5-methyltetrahydrofolate serves as the methyl donor for the remethylation of homocysteine to methionine, the precursor of S-adenosylmethionine (SAMe).…”

Investigation of inter-individual variability of the one-carbon folate pathway: a bioinformatic and genetic review

“…37 Homozygotes for this deletion show lower mRNA expression than homozygotes for the presence of the 6-bp deletion, 38 which is also a determinant of elevated red blood cell folate. 39 DHFR DHFR (EC, 1.5.1.3) reduces dihydrofolate (DHF), formed during dTMP synthesis, back to THF, which subsequently rejoins the pool of folate cofactors. All folate forms in vitamin supplements and fortified food are in the form of folic acid, an unreduced folate, and requires DHFR for reduction.…”

Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy

“…TS 3 0 -UTR 6À/6À genotype was found to be significantly associated with increased folate concentrations in vivo. 38 Folate is a necessary cofactor for 5-fluorouracil TS inhibition and its increased availability may favor 5-fluorouracil activity in TS 3 0 -UTR 6À/6À carriers. The mRNA-binding, decay-promoting protein AUF1 has been found to suppress TS mRNA levels with higher affinity for TS 3 0 -UTR 6À allele mRNA.…”