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Title: A 19-base pair deletion polymorphism in dihydrofolate reductase is associated with increased unmetabolized folic acid in plasma and decreased red blood cell folate

Author
item SELHUB, JACOB - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item KALMBACH, RENEE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item CHOUMENKOVITCH, SILVINA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item TROEN, ARON - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item JACQUES, PAUL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item D'AGOSTINO, RALPH - Boston University Medical School

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/2/2008
Publication Date: 12/1/2008
Citation: Selhub, J., Kalmbach, R., Choumenkovitch, S., Troen, A., Jacques, P., D'Agostino, R. 2008. A 19-base pair deletion polymorphism in dihydrofolate reductase is associated with increased unmetabolized folic acid in plasma and decreased red blood cell folate. Journal of Nutrition. 138:2323-2327.

Interpretive Summary: A deletion in dihydrofolate reductase (DHFR), an enzyme important for folate metabolism, has been implicated to play a causal role in neural tube defects and cancer. The functional significance of this polymorphism has not yet been demonstrated. Our objective was to determine the effects of the DHFR mutation with respect to folate status. Our findings indicate there was a significant interaction between the DHFR polymorphism and folic acid intake with respect to the number of people who had the highest amounts of folic acid in their blood. When folic acid intake was >/= 500ug, people who had the deletion in DHFR were more likely to have the highest amounts of folic acid in their blood compared to those who did not have the deletion. Also, when folic acid intake was low, those with the deletion had significantly lower RBC folate compared to those with no deletion. Our results suggest the deletion in DHFR is a functional polymorphism as it limits assimilation of folic acid into cellular folate stores at both high and low folic acid intakes.

Technical Abstract: Dihydrofolate reductase (DHFR) catalyzes the reduction of folic acid to tetrahydrofolate (THF). A 19-bp noncoding deletion allele maps to intron 1, beginning 60 bases from the splice donor site, and has been implicated in neural tube defects and cancer, presumably by influencing folate metabolism. The functional impact of this polymorphism has not yet been demonstrated. The objective of this research was to determine the effects of the DHFR mutation with respect to folate status and assess influence of folic acid intake on these relations. The relationship between DHFR genotype and plasma concentrations of circulating folic acid, total folate, total homocysteine, and concentrations of RBC folate was determined in 1215 subjects from the Framingham Offspring Study. There was a significant interaction between DHFR genotype and folic acid intake with respect to the prevalence of high circulating unmetabolized folic acid (defined as .85th percentile). Folic acid intake of $500 mg/d increased the prevalence of high circulating unmetabolized folic acid in subjects with the deletion (del/del genotype (47.0%) compared with the wild type (WT)/del (21.4%) and wild type (WT)/WT genotypes (24.4%) (P for interaction 1/4 0.03). Interaction between the DHFR polymorphism and folic acid intake was also seen with respect to RBC folate (P for interaction 1/4 0.01). When folic acid intake was ,250 mg/d, the del/del genotype was associated with significantly lower RBC folate (732.3 nmol/L) compared with the WT/WT genotype (844.4 nmol/L). Our results suggest the del/del polymorphism in DHFR is a functional polymorphism, because it limits assimilation of folic acid into cellular folate stores at high and low folic acid intakes.