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

Abstract

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 DHFRgene 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 DHFRwere 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 DHFR19-bp deletion polymorphism was not associated with overall breast cancer risk, we observed a borderline significant additive interaction (P= 0.06) between the DHFRgenotype 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 (Pfor trend = 0.02) than in multivatimin nonusers. A dose-dependent relation (Pfor trend < 0.001) between DHFRexpression 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 DHFR19-bp deletion polymorphism affects the transcription of DHFRgene in humans. Multivitamin supplements may place a subgroup of women (ie, those with the −19-bp allele) at elevated risk of developing breast cancer.