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


METHODS
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.
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;
Dana
D
Philip
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;
Assaf
A
Buch
Neuroscience and Aging Laboratory.
Denish
D
Moorthy
Neuroscience and Aging Laboratory.
Tammy M
TM
Scott
Nutritional Genomics Laboratory.
Laurence D
LD
Parnell
Nutritional Genomics Laboratory.
Chao-Qiang
CQ
Lai
Nutritional Genomics Laboratory.
José M
JM
Ordovás
Vitamin Metabolism Laboratory, and.
Jacob
J
Selhub
Neuroscience and Aging Laboratory.
Irwin H
IH
Rosenberg
Nutritional Epidemiology Program, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA; and Department of Clinical Laboratory and Nutritional Sciences at University of Massachusetts, Lowell, MA.
Katherine L
KL
Tucker
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, aron.troen@mail.huji.ac.il.
Aron M
http://orcid.org/0000-0001-9738-2524
AM
Troen
D001741:Black or African American; D000368:Aged; D000369:Aged, 80 and over; D001900:Boston / Q000453:epidemiology; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005260:Female; D005492:Folic Acid / Q000506:poisoning; D005494:Folic Acid Deficiency / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D017353:Gene Deletion; D056726:Genetic Association Studies; D006630:Hispanic or Latino; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000453:epidemiology / Q000209:etiology*; D008875:Middle Aged; D054647:Nutrigenomics / Q000379:methods; D009752:Nutritional Status; D011110:Polymorphism, Genetic; D015995:Prevalence; D011647:Puerto Rico / Q000208:ethnology; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D044465:White People
D005492:Folic Acid; D013762:Tetrahydrofolate Dehydrogenase
cognition; dihydrofolate reductase; folate; gene-nutrient interaction; memory