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A functional 19-base pair deletion polymorphism of dihydrofolate reductase (DHFR) and risk of breast cancer in multivitamin users^1,2,3

¹ From the Departments of Community and Preventive Medicine (XX, MR, JC, SLT, and JAB) and Microbiology (JGW), Mount Sinai School of Medicine, New York, NY; the Department of Epidemiology, University of North Carolina, Chapel Hill, NC (MDG and MMG); and the Departments of Environmental Health Sciences (RMS) and Epidemiology and Medicine (AIN), Columbia University, New York, NY

Background:Dihydrofolate reductase (DHFR) converts dihydrofolate (DHF) into tetrahydrofolate (THF) and plays an essential role in cell metabolism and cellular growth. Folic acid from multivitamins needs to be reduced by DHFR before it participates in cellular reactions.

Objectives:We examined the relation of a 19-base pair (bp) deletion polymorphism of the DHFR gene with the risk of breast cancer by using data from the Long Island Breast Cancer Study Project, a population-based case-control study. We also investigated the transcriptional effect of this deletion polymorphism.

Design:Dietary data and habitual use of multivitamins were assessed from a modified Block food-frequency questionnaire (FFQ). Genotypes of DHFR were ascertained from 1062 case subjects and 1099 control subjects by allele-specific polymerase chain reaction. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% CIs.

Result:Although the DHFR 19-bp deletion polymorphism was not associated with overall breast cancer risk, we observed a borderline significant additive interaction (P = 0.06) between the DHFR genotype and multivitamin use. The –19-bp allele was associated with greater breast cancer risk in multivitamin users (51.2% of the study population) with an OR of 1.26 (95% CI: 0.96, 1.66) and 1.52 (95% CI: 1.08, 2.13) for the +/– and –/– genotypes, respectively (P for trend = 0.02) than in multivatimin nonusers. A dose-dependent relation (P for trend < 0.001) between DHFR expression and the deletion genotype was observed. Compared with the subjects with the 19-bp +/+ genotype, subjects with the –/– genotype had 4.8-fold DHFR mRNA levels.

Conclusions:The DHFR 19-bp deletion polymorphism affects the transcription of DHFR gene in humans. Multivitamin supplements may place a subgroup of women (ie, those with the –19-bp allele) at elevated risk of developing breast cancer.

Key Words: Folate • dihydrofolate reductase • DHFR • one-carbon metabolism • breast cancer • multivitamins • prospective study • epidemiology • diet

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				R. D. Kalmbach, S. F. Choumenkovitch, A. P. Troen, P. F. Jacques, R. D'Agostino, and J. Selhub A 19-Base Pair Deletion Polymorphism in Dihydrofolate Reductase Is Associated with Increased Unmetabolized Folic Acid in Plasma and Decreased Red Blood Cell Folate J. Nutr., December 1, 2008; 138(12): 2323 - 2327. [Abstract] [Full Text] [PDF]

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