Kalmbach Renee D, Choumenkovitch Silvina F, Troen Aron P, Jacques Paul F, D'Agostino Ralph, Selhub Jacob
Vitamin Metabolism and Aging Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA.
J Nutr. 2008 Dec;138(12):2323-7. doi: 10.3945/jn.108.096404.
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 >or=500 microg/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 = 0.03). Interaction between the DHFR polymorphism and folic acid intake was also seen with respect to RBC folate (P for interaction = 0.01). When folic acid intake was <250 microg/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.
二氢叶酸还原酶（DHFR）催化叶酸还原为四氢叶酸（THF）。一个19碱基对的非编码缺失等位基因定位于内含子1，起始于距剪接供体位点60个碱基处，据推测它通过影响叶酸代谢与神经管缺陷和癌症有关。这种多态性的功能影响尚未得到证实。本研究的目的是确定DHFR突变对叶酸状态的影响，并评估叶酸摄入对这些关系的影响。在弗雷明汉后代研究的1215名受试者中，确定了DHFR基因型与循环叶酸、总叶酸、总同型半胱氨酸的血浆浓度以及红细胞叶酸浓度之间的关系。就高循环未代谢叶酸（定义为>第85百分位数）的患病率而言，DHFR基因型与叶酸摄入之间存在显著相互作用。叶酸摄入量≥500微克/天会增加缺失型（del/del基因型（47.0%））受试者高循环未代谢叶酸的患病率，相比野生型（WT）/del（21.4%）和野生型（WT）/WT基因型（24.4%）（相互作用P值 = 0.03）。在红细胞叶酸方面也观察到DHFR多态性与叶酸摄入之间的相互作用（相互作用P值 = 0.01）。当叶酸摄入量<250微克/天时，与WT/WT基因型（844.4纳摩尔/升）相比，del/del基因型与显著更低的红细胞叶酸（732.3纳摩尔/升）相关。我们的结果表明，DHFR中的del/del多态性是一种功能性多态性，因为它在高叶酸摄入量和低叶酸摄入量时都会限制叶酸向细胞叶酸储存库的同化。
