Philip Dana, Buch Assaf, Moorthy Denish, Scott Tammy M, Parnell Laurence D, Lai Chao-Qiang, Ordovás José M, Selhub Jacob, Rosenberg Irwin H, Tucker Katherine L, Troen Aron M
Nutrition and Brain Health Laboratory, Institute of Biochemistry, Food Science and Nutrition, Robert H Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel;
Neuroscience and Aging Laboratory.
Am J Clin Nutr. 2015 Nov;102(5):1279-88. doi: 10.3945/ajcn.115.111054. Epub 2015 Sep 9.
Folate status has been positively associated with cognitive function in many studies; however, some studies have observed associations of poor cognitive outcomes with high folate. In search of an explanation, we hypothesized that the association of folate with cognition would be modified by the interaction of high-folate status with a common 19-bp deletion polymorphism in the dihydrofolate reductase (DHFR) gene. To our knowledge, the cognitive effects of this gene have not been studied previously.
We examined the association between cognitive outcomes with the 19-bp deletion DHFR polymorphism, folate status, and their interaction with high or normal plasma folate.
This was a pooled cross-sectional study of the following 2 Boston-based cohorts of community living adults: the Boston Puerto Rican Health Study and the Nutrition, Aging, and Memory in Elders study. Individuals were genotyped for the DHFR 19-bp deletion genotype, and plasma folate status was determined. Cognitive outcomes included the Mini-Mental State Examination, Center for Epidemiologic Studies Depression Scale, and factor scores for the domains of memory, executive function, and attention from a set of cognitive tests.
The prevalence of the homozygous deletion (del/del) genotype was 23%. In a multivariable analysis, high folate status (>17.8 ng/mL) was associated with better memory scores than was normal-folate status (fourth-fifth quintiles compared with first-third quintiles: β ± SE = -0.22 ± 0.06, P < 0.01). Carriers of the DHFR del/del genotype had worse memory scores (β ± SE = -0.24 ± 0.10, P < 0.05) and worse executive scores (β = -0.19, P < 0.05) than did those with the del/ins and ins/ins genotypes. Finally, we observed an interaction such that carriers of the del/del genotype with high folate had significantly worse memory scores than those of both noncarriers with high-folate and del/del carriers with normal-folate (β-interaction = 0.26 ± 0.13, P < 0.05).
This study identifies a putative gene-nutrient interaction that, if confirmed, would predict that a sizable minority carrying the del/del genotype might not benefit from high-folate status and could see a worsening of memory. An understanding of how genetic variation affects responses to high-folate exposure will help weigh risks and benefits of folate supplementation for individuals and public health.
在许多研究中，叶酸状态与认知功能呈正相关；然而，一些研究观察到认知结果不佳与高叶酸水平有关。为了寻找解释，我们假设叶酸与认知的关联会因高叶酸状态与二氢叶酸还原酶（DHFR）基因中常见的19碱基对缺失多态性的相互作用而改变。据我们所知，该基因的认知效应此前尚未得到研究。
我们研究了认知结果与19碱基对缺失的DHFR多态性、叶酸状态及其与高或正常血浆叶酸的相互作用之间的关联。
这是一项对以下两个位于波士顿的社区居住成年人队列进行的汇总横断面研究：波士顿波多黎各健康研究和老年人营养、衰老与记忆研究。对个体进行DHFR 19碱基对缺失基因型的基因分型，并测定血浆叶酸状态。认知结果包括简易精神状态检查表、流行病学研究中心抑郁量表，以及一组认知测试中记忆、执行功能和注意力领域的因子得分。
纯合缺失（del/del）基因型的患病率为23%。在多变量分析中，高叶酸状态（>17.8 ng/mL）与比正常叶酸状态更好的记忆得分相关（第四至第五五分位数与第一至第三五分位数相比：β±SE = -0.22±0.06，P<0.01）。与具有del/ins和ins/ins基因型的个体相比，DHFR del/del基因型的携带者记忆得分更差（β±SE = -0.24±0.10，P<0.05），执行得分也更差（β = -0.19，P<0.05）。最后，我们观察到一种相互作用，即高叶酸的del/del基因型携带者的记忆得分显著低于高叶酸的非携带者和正常叶酸的del/del基因型携带者（β相互作用 = 0.26±0.13，P<
