Short CommmunicationsLinkage disequilibrium between the 677C > T and 1298A > C polymorphisms in human methylenetetrahydrofolate reductase gene and their contributions to risk of colorectal cancerChen, Jiaa; Ma, Jingb; Stampfer, Meir J.b,c,d; Palomeque, Carolinea; Selhub, Jacobe; Hunter, David J.b,cAuthor Information aDepartment of Community and Preventive Medicine, Mount Sinai School of Medicine, New York, NY, USA, bChanning Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA, Departments of cEpidemiology and dNutrition, Harvard School of Public Health, Boston, MA, USA and eJean Mayer USDA Human Nutrition Center on Aging at Tufts University, Boston, MA, USA Correspondence and requests for reprints to Jia Chen, Department of Community and Preventive Medicine, Box 1043, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA Tel.: +1 212-241-7519; fax: +1 212-360-6965; e-mail: [email protected] Received 25 February 2002 Accepted 20 March 2002 Pharmacogenetics: June 2002 - Volume 12 - Issue 4 - p 339-342 Buy 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. © 2002 Lippincott Williams & Wilkins, Inc.