title: Polymorphisms in the one-carbon metabolic pathway, plasma folate levels and colorectal cancer in a prospective study.
abstract: One-carbon (e.g., folate) metabolism plays a pivotal role in the etiology of colorectal cancer (CRC). Cytosolic serine hydroxymethyltransferase (cSHMT), methylenetetrahydrofolate dehydrogenase (MTHFD1) and glutamate carboxypeptidase II (GCPII) are key genes involved in this pathway. Several new polymorphisms have been identified and there is evidence implicating their functionality. We examined whether polymorphisms in these genes, i.e., cSHMT L474F, MTHFD1 R653Q and GCPII H475Y, modify the risk of CRC in the prospective Physicians' Health Study. Among the 270 incident CRC cases and 453 controls, none of the one-carbon polymorphisms were associated with risk of CRC. Compared to the wild-type genotype, the multivariate-adjusted relative risks and 95% confidence intervals were 1.14 [0.68, 1.93] for cSHMT 474FF, 1.04 [0.67, 1.62] for MTHFD1 653QQ and 1.00 [0.55, 1.82] for GCPII 474HY. Furthermore, we examined the associations between one-carbon polymorphisms and folate status in terms of plasma folate and homocysteine levels in this population. No independent gene effect was observed. Although compound homozygous variants at cSHMT and MTHFD1 loci had the lowest plasma folate levels compared to other compound genotypes, no significant gene-gene interactions were observed. Findings from our prospective investigation indicate that these newly identified polymorphisms in one-carbon metabolizing genes have limited functionality in modifying folate status and related CRC risk.
authors.affiliation: Departments of Community and Preventive Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA. jia.chen@mssm.edu
authors.forename: Jia
authors.initials: J
authors.lastname: Chen
authors.forename: Charles
authors.initials: C
authors.lastname: Kyte
authors.forename: Martin
authors.initials: M
authors.lastname: Valcin
authors.forename: Wendy
authors.initials: W
authors.lastname: Chan
authors.forename: James G
authors.initials: JG
authors.lastname: Wetmur
authors.forename: Jacob
authors.initials: J
authors.lastname: Selhub
authors.forename: David J
authors.initials: DJ
authors.lastname: Hunter
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000954:Antigens, Surface / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D004311:Double-Blind Method; D005492:Folic Acid / Q000097:blood*; D043425:Glutamate Carboxypeptidase II / Q000235:genetics*; D012696:Glycine Hydroxymethyltransferase / Q000235:genetics*; D006801:Humans; D008297:Male; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011446:Prospective Studies
chemical_list: D000954:Antigens, Surface; D005492:Folic Acid; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D012696:Glycine Hydroxymethyltransferase; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II