Associations of common polymorphisms in the thymidylate synthase, reduced folate carrier and 5-aminoimidazole-4-carboxamide ribonucleotide transformylase/inosine monophosphate cyclohydrolase genes with folate and homocysteine levels and venous thrombosis risk.
BACKGROUND
Folate is important in purine and thymidylate synthesis and, via homocysteine remethylation, facilitates S-adenosylmethionine-dependent transmethylation. Low folate availability leads to hyperhomocysteinemia, which is a risk factor for arterial vascular disease and venous thrombosis. Genetic variation in folate-metabolizing genes may affect folate availability and hence confer a greater risk of venous thrombosis.


METHODS
We genotyped the thymidylate synthase (TYMS) 28-bp repeat and 6-bp deletion, and the reduced folate carrier (RFC1) 80G>A and AICAR transformylase/inosine monophosphate (IMP) cyclohydrolase (ATIC) 346C>G polymorphisms in population-based controls (n=431), and assessed their effect on plasma total homocysteine (tHcy), and serum and red blood cell (RBC) folate. We investigated the associations between these variants and disease risk in a retrospective case-control study on recurrent venous thrombosis (n=173) as well.


RESULTS
None of the genotypes, alone or in combination, were associated with major changes in tHcy. However, the TYMS 28-bp repeat was associated with serum and RBC folate levels. We found no evidence that the genetic variants studied were associated with recurrent venous thrombosis risk.


CONCLUSIONS
The TYMS 28-bp repeat and 6-bp deletion, and RFC1 80G>A and ATIC 346C>G polymorphisms are not associated with tHcy, but we did observe an association between the TYMS 28-bp repeat and serum and RBC folate in a general population. None of the polymorphisms was associated with recurrent venous thrombosis risk.
Gellekink
Henkjan
H
Laboratory of Pediatrics and Neurology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
Blom
Henk J
HJ
den Heijer
Martin
M
D005492:Folic Acid / Q000097:blood*; D020022:Genetic Predisposition to Disease; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D019877:Hydroxymethyl and Formyl Transferases / Q000235:genetics*; D026901:Membrane Transport Proteins / Q000235:genetics*; D009097:Multienzyme Complexes / Q000235:genetics*; D009709:Nucleotide Deaminases / Q000235:genetics*; D011110:Polymorphism, Genetic; D058978:Reduced Folate Carrier Protein; D013940:Thymidylate Synthase / Q000235:genetics*; D020246:Venous Thrombosis / Q000235:genetics*
D026901:Membrane Transport Proteins; D009097:Multienzyme Complexes; D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; C113120:inosine monophosphate synthase; D006710:Homocysteine; D005492:Folic Acid; D013940:Thymidylate Synthase; D019877:Hydroxymethyl and Formyl Transferases; D009709:Nucleotide Deaminases