Dihydrofolate reductase 19-bp deletion polymorphism modifies the association of folate status with memory in a cross-sectional multi-ethnic study of adults

Abstract

Background: 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.

Objective: 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.

Design: 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.

Results: 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).

Conclusions: 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.

Keywords: cognition; dihydrofolate reductase; folate; gene-nutrient interaction; memory.

© 2015 American Society for Nutrition.

Figures

FIGURE 1

Mean (95% CI) adjusted memory scores by quintiles of folate in the pooled cohort. The graph shows results of an ANOVA with Tukey post hoc testing for differences between mean adjusted memory scores by quintiles of plasma folate concentrations. n = 280/quintile. Memory scores were adjusted with the use of a multivariate linear regression for ethnicity, age, sex, education, estimated glomerular filtration rate, diabetes, hypertension, apolipoprotein E4 genotype, plasma total homocysteine, vitamin B-12, and vitamin B-6. Cutoff values between quintiles are marked on the x axis. ***P < 0.001. FACmem, factor score for memory.

FIGURE 2

Interaction of dihydrofolate reductase genotype and plasma folate with respect to memory in the pooled cohort. The graph shows results of a comparison of mean (95% CI) adjusted memory scores by genotype below and above the plasma folate cutoff of 17.8 ng folate/mL. Memory scores were adjusted in the general linear model for ethnicity, age, sex, education, estimated glomerular filtration rate, diabetes, hypertension, apolipoprotein E4 genotype, plasma total homocysteine, vitamin B-12, and vitamin B-6. *P < 0.05, ** P < 0.01. FACmem, factor score for memory.