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J Nutr. 2016 Jan;146(1):1-8. doi: 10.3945/jn.115.223685. Epub 2015 Nov 11.

Common Polymorphisms That Affect Folate Transport or Metabolism Modify the Effect of the MTHFR 677C > T Polymorphism on Folate Status.

Author information

1
Area of Preventive Medicine and Public Health, Faculty of Medicine and Health Sciences, Pere Virgili Institute for Health Research, Rovira i Virgili University, Reus, Spain; Biomedical Research Network, Pathophysiology of Obesity and Nutrition (CIBEROBN), Institute of Health Carlos III, Madrid, Spain;
2
Schools of Medicine and Biochemistry and Immunology, Trinity College, Dublin, Ireland;
3
Biomedical Research Network, Pathophysiology of Obesity and Nutrition (CIBEROBN), Institute of Health Carlos III, Madrid, Spain; Primary Health Center, El Morell, Spain.
4
Primary Health Center, Cambrils, Tarragona, Spain;
5
University of Bergen, Section of Pharmacology, Department of Clinical Science, Bergen, Norway; and.
6
Bevital A/S, Bergen, Norway.
7
Area of Preventive Medicine and Public Health, Faculty of Medicine and Health Sciences, Pere Virgili Institute for Health Research, Rovira i Virgili University, Reus, Spain; Biomedical Research Network, Pathophysiology of Obesity and Nutrition (CIBEROBN), Institute of Health Carlos III, Madrid, Spain; michelle.murphy@urv.cat.

Abstract

BACKGROUND:

Although combinations of biologically relevant polymorphic variants affect folate status, most studies have focused on the effects of individual polymorphisms; however, these effects may be altered by interactions between polymorphisms.

OBJECTIVE:

We investigated the individual and combined effects of polymorphisms that affect folate transport or metabolism on folate status.

METHODS:

The associations between the methylenetetrahydrofolate reductase (MTHFR) 677C > T, methionine transferase reductase (MTRR) 66A > G, MTRR 524C > T, 5,10-methylenetetrahydrofolate dehydrogenase-5,10-methylenetetrahydrofolate cyclohydrolase-10-formyltetrahydrofolate synthetase (MTHFD1) 1958G > A, MTHFD1 -105C > T, dihydrofolate reductase (DHFR) 19-bp insertion/deletion, and solute carrier family 19A, member 1 (SLC19A1) 80G > A polymorphisms and fasting plasma folate (PF), red cell folate (RCF), and plasma total homocysteine (tHcy) were tested by ANCOVA and Cox regression analysis in 781 Spanish adults.

RESULTS:

Folate deficiency (PF <7 nmol/L) was observed in 18.8% of the participants. Geometric mean PF (nmol/L) was lower in MTHFR 677TT (10.0; 95% CI: 9.2, 11.9) compared with 677CC (12.4; 95% CI: 11.6, 13.2; P < 0.001). RCF (nmol/L) was lower in MTHFR 677TT (652; 95% CI: 611, 695) compared with 677CC (889; 95% CI: 851, 929; P < 0.001) and in SLC19A1 80AA (776; 95% CI: 733, 822) compared with 80GG (861; 95% CI: 815, 910; P < 0.01). RCF and tHcy (μmol/L) did not differ in MTHFR + MTRR 677TT/524TT compared with 677CC/524CC: 780 (95% CI: 647, 941) compared with 853 (95% CI: 795, 915; P = 0.99) and 10.2 (95% CI: 8.4, 12.3) compared with 8.9 (95% CI: 8.5, 9.4; P = 0.99), respectively. The RR of lowest-tertile RCF (≤680 nmol/L) was 2.1 (95% CI: 1.0, 4.5) for MTHFR + MTRR 677TT/66GG compared with 677CC/66AA, 2.2 (95% CI: 1.2, 4.1) for MTHFR + MTHFD1 677TT/1958AA compared with 677CC/1958GG, 2.9 (95% CI: 1.4, 6.0) for MTHFR + MTHFD1 677TT/-105TT compared with 677CC/-105CC, and 3.5 (95% CI: 1.5, 8.1) for MTHFR + SLC19A1 677TT/80AA compared with 677CC/80GG. Confining the analysis to the MTHFR 677TT genotype, the risk of lowest-tertile RCF was reduced for MTHFR + MTRR 677TT/66GG compared with 677TT/66AA (RR: 0.5; 95% CI: 0.3, 0.9).

CONCLUSIONS:

Folate status was lower in the MTHFR 677TT and SLC19A1 80AA genotypes compared with corresponding reference genotypes. Low folate status risk associated with the MTHFR 677TT genotype varied depending on its combination with other polymorphisms.

KEYWORDS:

MTHFD1 -105C > T; MTHFD1 1958G > A; MTHFR 677C > T; MTRR 524C > T; MTRR 66A > G; SLC19A1 80G > A; homocysteine; plasma folate; population study; red cell folate

PMID:
26561410
DOI:
10.3945/jn.115.223685
[Indexed for MEDLINE]

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