title: Methylenetetrahydrofolate Dehydrogenase 1 Polymorphisms Modify the Associations of Plasma Glycine and Serine With Risk of Acute Myocardial Infarction in Patients With Stable Angina Pectoris in WENBIT (Western Norway B Vitamin Intervention Trial).
abstract: BACKGROUND
  Serine and glycine interconversion and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1)-mediated 1-carbon transfer are the major sources of methyl groups for 1-carbon metabolism. Recently, plasma glycine and a common polymorphism in MTHFD1 have been associated with risk of acute myocardial infarction (AMI). It is, therefore, of interest to explore if these 2 pathways interact in relation to AMI.
  
  
  RESULTS
  A total of 2571 participants in the WENBIT (Western Norway B Vitamin Intervention Trial) undergoing coronary angiography for stable angina pectoris were studied. Associations of plasma serine and glycine concentrations with risk of AMI across 2 common and functional MTHFD1 polymorphisms (rs2236225 and rs1076991) were explored in Cox regression models. During a median follow-up of 4.7 years, 212 patients (8.2%) experienced an AMI. In age- and sex-adjusted analyses, plasma glycine (P<0.01), but not serine (P=0.52), showed an overall association with AMI. However, interactions of MTHFD1 rs2236225 polymorphism with both plasma serine and glycine were observed (Pinteraction=0.03 for both). Low plasma serine and glycine were associated with an increased risk of AMI among patients carrying the rs2236225 minor A allele. Similarly, low plasma glycine showed stronger risk relationship with AMI in the rs1076991 CC genotype carriers but weaker associations in patients carrying the minor T allele (Pinteraction=0.02).
  
  
  CONCLUSIONS
  Our results showed that 2 common and functional polymorphisms in the MTHFD1 gene modulate the risk associations of plasma serine and glycine with AMI. These findings emphasize the possible role of the MTHFD1 in regulating serine and glycine metabolism in relation to atherosclerotic complications.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00354081.
authors.affiliation: From the Department of Clinical Science (Y.D., E.R.P., P.M.U., O.K.N.), KG Jebsen Center for Diabetes Research, Department of Clinical Science (Ø.H., O.K.N.), and Department of Global Public Health and Primary Care (G.S.T.), University of Bergen, Norway; Department of Heart Disease (G.F.T.S., K.H.L., O.K.N.) and Department of Pediatrics (Ø.H.), Haukeland University Hospital, Bergen, Norway; Laboratory of Clinical Biochemistry, Bergen, Norway (P.M.U.); Food Science and Human Nutrition Department, University of Florida, Gainesville (J.F.G.); Bevital AS (K.M.); and Norwegian Institute of Public Health, Bergen, Norway (G.S.T.). yunpeng.ding@uib.no.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Ding
authors.affiliation: From the Department of Clinical Science (Y.D., E.R.P., P.M.U., O.K.N.), KG Jebsen Center for Diabetes Research, Department of Clinical Science (Ø.H., O.K.N.), and Department of Global Public Health and Primary Care (G.S.T.), University of Bergen, Norway; Department of Heart Disease (G.F.T.S., K.H.L., O.K.N.) and Department of Pediatrics (Ø.H.), Haukeland University Hospital, Bergen, Norway; Laboratory of Clinical Biochemistry, Bergen, Norway (P.M.U.); Food Science and Human Nutrition Department, University of Florida, Gainesville (J.F.G.); Bevital AS (K.M.); and Norwegian Institute of Public Health, Bergen, Norway (G.S.T.).
authors.forename: Eva R
authors.initials: ER
authors.lastname: Pedersen
authors.affiliation: From the Department of Clinical Science (Y.D., E.R.P., P.M.U., O.K.N.), KG Jebsen Center for Diabetes Research, Department of Clinical Science (Ø.H., O.K.N.), and Department of Global Public Health and Primary Care (G.S.T.), University of Bergen, Norway; Department of Heart Disease (G.F.T.S., K.H.L., O.K.N.) and Department of Pediatrics (Ø.H.), Haukeland University Hospital, Bergen, Norway; Laboratory of Clinical Biochemistry, Bergen, Norway (P.M.U.); Food Science and Human Nutrition Department, University of Florida, Gainesville (J.F.G.); Bevital AS (K.M.); and Norwegian Institute of Public Health, Bergen, Norway (G.S.T.).
authors.forename: Gard F T
authors.initials: GF
authors.lastname: Svingen
authors.affiliation: From the Department of Clinical Science (Y.D., E.R.P., P.M.U., O.K.N.), KG Jebsen Center for Diabetes Research, Department of Clinical Science (Ø.H., O.K.N.), and Department of Global Public Health and Primary Care (G.S.T.), University of Bergen, Norway; Department of Heart Disease (G.F.T.S., K.H.L., O.K.N.) and Department of Pediatrics (Ø.H.), Haukeland University Hospital, Bergen, Norway; Laboratory of Clinical Biochemistry, Bergen, Norway (P.M.U.); Food Science and Human Nutrition Department, University of Florida, Gainesville (J.F.G.); Bevital AS (K.M.); and Norwegian Institute of Public Health, Bergen, Norway (G.S.T.).
authors.forename: Øyvind
authors.initials: Ø
authors.lastname: Helgeland
authors.affiliation: From the Department of Clinical Science (Y.D., E.R.P., P.M.U., O.K.N.), KG Jebsen Center for Diabetes Research, Department of Clinical Science (Ø.H., O.K.N.), and Department of Global Public Health and Primary Care (G.S.T.), University of Bergen, Norway; Department of Heart Disease (G.F.T.S., K.H.L., O.K.N.) and Department of Pediatrics (Ø.H.), Haukeland University Hospital, Bergen, Norway; Laboratory of Clinical Biochemistry, Bergen, Norway (P.M.U.); Food Science and Human Nutrition Department, University of Florida, Gainesville (J.F.G.); Bevital AS (K.M.); and Norwegian Institute of Public Health, Bergen, Norway (G.S.T.).
authors.forename: Jesse F
authors.initials: JF
authors.lastname: Gregory
authors.affiliation: From the Department of Clinical Science (Y.D., E.R.P., P.M.U., O.K.N.), KG Jebsen Center for Diabetes Research, Department of Clinical Science (Ø.H., O.K.N.), and Department of Global Public Health and Primary Care (G.S.T.), University of Bergen, Norway; Department of Heart Disease (G.F.T.S., K.H.L., O.K.N.) and Department of Pediatrics (Ø.H.), Haukeland University Hospital, Bergen, Norway; Laboratory of Clinical Biochemistry, Bergen, Norway (P.M.U.); Food Science and Human Nutrition Department, University of Florida, Gainesville (J.F.G.); Bevital AS (K.M.); and Norwegian Institute of Public Health, Bergen, Norway (G.S.T.).
authors.forename: Kjetil H
authors.initials: KH
authors.lastname: Løland
authors.affiliation: From the Department of Clinical Science (Y.D., E.R.P., P.M.U., O.K.N.), KG Jebsen Center for Diabetes Research, Department of Clinical Science (Ø.H., O.K.N.), and Department of Global Public Health and Primary Care (G.S.T.), University of Bergen, Norway; Department of Heart Disease (G.F.T.S., K.H.L., O.K.N.) and Department of Pediatrics (Ø.H.), Haukeland University Hospital, Bergen, Norway; Laboratory of Clinical Biochemistry, Bergen, Norway (P.M.U.); Food Science and Human Nutrition Department, University of Florida, Gainesville (J.F.G.); Bevital AS (K.M.); and Norwegian Institute of Public Health, Bergen, Norway (G.S.T.).
authors.forename: Klaus
authors.initials: K
authors.lastname: Meyer
authors.affiliation: From the Department of Clinical Science (Y.D., E.R.P., P.M.U., O.K.N.), KG Jebsen Center for Diabetes Research, Department of Clinical Science (Ø.H., O.K.N.), and Department of Global Public Health and Primary Care (G.S.T.), University of Bergen, Norway; Department of Heart Disease (G.F.T.S., K.H.L., O.K.N.) and Department of Pediatrics (Ø.H.), Haukeland University Hospital, Bergen, Norway; Laboratory of Clinical Biochemistry, Bergen, Norway (P.M.U.); Food Science and Human Nutrition Department, University of Florida, Gainesville (J.F.G.); Bevital AS (K.M.); and Norwegian Institute of Public Health, Bergen, Norway (G.S.T.).
authors.forename: Grethe S
authors.initials: GS
authors.lastname: Tell
authors.affiliation: From the Department of Clinical Science (Y.D., E.R.P., P.M.U., O.K.N.), KG Jebsen Center for Diabetes Research, Department of Clinical Science (Ø.H., O.K.N.), and Department of Global Public Health and Primary Care (G.S.T.), University of Bergen, Norway; Department of Heart Disease (G.F.T.S., K.H.L., O.K.N.) and Department of Pediatrics (Ø.H.), Haukeland University Hospital, Bergen, Norway; Laboratory of Clinical Biochemistry, Bergen, Norway (P.M.U.); Food Science and Human Nutrition Department, University of Florida, Gainesville (J.F.G.); Bevital AS (K.M.); and Norwegian Institute of Public Health, Bergen, Norway (G.S.T.).
authors.forename: Per M
authors.initials: PM
authors.lastname: Ueland
authors.affiliation: From the Department of Clinical Science (Y.D., E.R.P., P.M.U., O.K.N.), KG Jebsen Center for Diabetes Research, Department of Clinical Science (Ø.H., O.K.N.), and Department of Global Public Health and Primary Care (G.S.T.), University of Bergen, Norway; Department of Heart Disease (G.F.T.S., K.H.L., O.K.N.) and Department of Pediatrics (Ø.H.), Haukeland University Hospital, Bergen, Norway; Laboratory of Clinical Biochemistry, Bergen, Norway (P.M.U.); Food Science and Human Nutrition Department, University of Florida, Gainesville (J.F.G.); Bevital AS (K.M.); and Norwegian Institute of Public Health, Bergen, Norway (G.S.T.).
authors.forename: Ottar K
authors.initials: OK
authors.lastname: Nygård
mesh_terms: D000368:Aged; D060050:Angina, Stable / Q000097:blood / Q000000981:diagnostic imaging / Q000201:enzymology / Q000235:genetics*; D017023:Coronary Angiography; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005998:Glycine / Q000097:blood*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D016014:Linear Models; D016015:Logistic Models; D008297:Male; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics*; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens / Q000235:genetics*; D015999:Multivariate Analysis; D009203:Myocardial Infarction / Q000097:blood / Q000000981:diagnostic imaging / Q000201:enzymology / Q000235:genetics*; D009664:Norway; D010641:Phenotype; D011110:Polymorphism, Genetic; D011379:Prognosis; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012307:Risk Factors; D012694:Serine / Q000097:blood*; D013997:Time Factors
chemical_list: D015778:Minor Histocompatibility Antigens; D012694:Serine; C539735:MTHFD1 protein, human; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D005998:Glycine
keywords: MTHFD1; association study; coronary artery disease; glycine; myocardial infarction; one-carbon metabolism; serine