title: Common Polymorphisms That Affect Folate Transport or Metabolism Modify the Effect of the MTHFR 677C > T Polymorphism on Folate Status.
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.
authors.affiliation: 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;
authors.forename: Olalla
authors.initials: O
authors.lastname: Bueno
authors.affiliation: Schools of Medicine and Biochemistry and Immunology, Trinity College, Dublin, Ireland;
authors.forename: Anne M
authors.initials: AM
authors.lastname: Molloy
authors.affiliation: 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;
authors.forename: Joan D
authors.initials: JD
authors.lastname: Fernandez-Ballart
authors.affiliation: 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;
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: García-Minguillán
authors.affiliation: Biomedical Research Network, Pathophysiology of Obesity and Nutrition (CIBEROBN), Institute of Health Carlos III, Madrid, Spain; Primary Health Center, El Morell, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Ceruelo
authors.affiliation: Primary Health Center, Cambrils, Tarragona, Spain;
authors.forename: Lídia
authors.initials: L
authors.lastname: Ríos
authors.affiliation: University of Bergen, Section of Pharmacology, Department of Clinical Science, Bergen, Norway; and.
authors.forename: Per M
authors.initials: PM
authors.lastname: Ueland
authors.affiliation: Bevital A/S, Bergen, Norway.
authors.forename: Klaus
authors.initials: K
authors.lastname: Meyer
authors.affiliation: 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.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Murphy
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D003430:Cross-Sectional Studies; D005215:Fasting; D005260:Female; D005492:Folic Acid / Q000097:blood*; D005494:Folic Acid Deficiency / Q000097:blood / Q000235:genetics; D005787:Gene Frequency; D005838:Genotype; D006710:Homocysteine / Q000097:blood; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic; D016016:Proportional Hazards Models; D013030:Spain; D055815:Young Adult
chemical_list: D006710:Homocysteine; D005492:Folic Acid; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)
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