title: Thymidylate synthase polymorphisms, folate and B-vitamin intake, and risk of colorectal adenoma.
abstract: The effects of polymorphisms in genes coding for key folate metabolism enzymes such as thymidylate synthetase (TS) on colorectal neoplasia risk are likely to be influenced by gene-gene and gene-nutrient interactions. We investigated the combined effects of three polymorphisms in the TS gene region, TSER, TS 3R G>C, and TS 1494del6, dietary intakes of folate and other B vitamins, and genotype for other folate metabolism variants, in a colorectal adenoma (CRA) case-control study. Individuals homozygous for TS 1494del6 del/del were at significantly reduced CRA risk compared to those with either ins/del or ins/ins genotypes (odds ratio 0.52; 95% confidence interval: 0.31-0.85, P=0.009). We also observed evidence of interactions between TS 1494del6 genotype and intake of folate, and vitamins B6 and B12, and MTHFR C677T genotype, with the reduction in risk in del/del homozygotes being largely confined to individuals with high nutrient intakes and MTHFR 677CC genotype (P interaction=0.01, 0.006, 0.03, and 0.07, respectively). TSER genotype, when considered either alone or in combination with TS 3R G>C genotype, did not significantly influence CRA risk. These findings support a role for TS in colorectal carcinogenesis, and provide further evidence that functional polymorphisms in folate metabolism genes act as low-risk alleles for colorectal neoplasia and participate in complex gene-gene and gene-nutrient interactions.
authors.affiliation: Section of Cancer Genetics, Institute of Cancer Research, 15 Cotswold Road, Sutton SM2 5NG, UK. Richard.Hubner@icr.ac.uk
authors.forename: R A
authors.initials: RA
authors.lastname: Hubner
authors.forename: J-F
authors.initials: JF
authors.lastname: Liu
authors.forename: G S
authors.initials: GS
authors.lastname: Sellick
authors.forename: R F A
authors.initials: RF
authors.lastname: Logan
authors.forename: R S
authors.initials: RS
authors.lastname: Houlston
authors.forename: K R
authors.initials: KR
authors.lastname: Muir
mesh_terms: D000236:Adenoma / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D004032:Diet; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage* / Q000378:metabolism; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012307:Risk Factors; D011795:Surveys and Questionnaires; D013940:Thymidylate Synthase / Q000235:genetics* / Q000378:metabolism; D014803:Vitamin B Complex / Q000008:administration & dosage*
chemical_list: D014803:Vitamin B Complex; D005492:Folic Acid; D013940:Thymidylate Synthase