title: Linkage disequilibrium between the 677C>T and 1298A>C polymorphisms in human methylenetetrahydrofolate reductase gene and their contributions to risk of colorectal cancer.
abstract: A common polymorphism in a folate-metabolizing gene, methylenetetrahydrofolate reductase (MTHFR) 677C>T has been associated with reduced risk of colorectal cancer. In this study, we investigated whether a second common polymorphism of the gene, MTHFR 1298A>C, is an independent risk factor for colorectal cancer and if it is associated with plasma folate and total homocysteine (tHcy) levels. We also examined whether the 677C>T and 1298A>C polymorphisms are in linkage disequilibrium and whether combined heterozygosity confers additional (or reduced) risk of colorectal cancer. We conducted a nested case-control study of 211 incident colorectal cancer cases and 343 controls in the prospective Physicians' Health Study. The MTHFR 677C>T and 1298A>C polymorphisms were in linkage disequilibrium in this population. Compared to MTHFR 1298AA genotype, multivariate-adjusted relative risk of colorectal cancer was 0.73 (95% CI 0.37-1.43) for the MTHFR 1298CC genotype. The slight reduction in risk was not a result of its linkage disequilibrium with the 677C>T polymorphism. This polymorphism was not significantly correlated with the plasma folate and tHcy levels. The combined heterozygosity did not modify the cancer risk; nor did it change the plasma folate and tHcy significantly. We conclude that the MTHFR 1298A>C polymorphism is a less substantial independent risk factor for colorectal cancer compared to the 677C>T polymorphism.
authors.affiliation: Department of Community and Preventive Medicine, Mount Sinai School of Medicine, New York, NY, USA. jia.chen@mssm.edu
authors.forename: Jia
authors.initials: J
authors.lastname: Chen
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.forename: Meir J
authors.initials: MJ
authors.lastname: Stampfer
authors.forename: Caroline
authors.initials: C
authors.lastname: Palomeque
authors.forename: Jacob
authors.initials: J
authors.lastname: Selhub
authors.forename: David J
authors.initials: DJ
authors.lastname: Hunter
mesh_terms: D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics*; D004311:Double-Blind Method; D005492:Folic Acid / Q000097:blood*; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D015994:Incidence; D015810:Linkage Disequilibrium; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics*; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D011795:Surveys and Questionnaires
chemical_list: D005492:Folic Acid; D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2)