title: Genetic polymorphism rs6922269 in the MTHFD1L gene is associated with survival and baseline active vitamin B12 levels in post-acute coronary syndromes patients.
abstract: OBJECTIVE
  The methylene-tetrahydrofolate dehydrogenase (NADP+ dependent) 1-like (MTHFD1L) gene is involved in mitochondrial tetrahydrofolate metabolism. Polymorphisms in MTHFD1L, including rs6922269, have been implicated in risk for coronary artery disease (CAD). We investigated the association between rs6922269 and known metabolic risk factors and survival in two independent cohorts of coronary heart disease patients.
  
  
  RESULTS
  DNA and plasma from 1940 patients with acute coronary syndromes were collected a median of 32 days after index hospital admission (Coronary Disease Cohort Study, CDCS). Samples from a validation cohort of 842 patients post-myocardial infarction (PMI) were taken 24-96 hours after hospitalization. DNA samples were genotyped for rs6922269, using a TaqMan assay. Homocysteine and active vitamin B12 were measured by immunoassay in baseline CDCS plasma samples, but not PMI plasma. All cause mortality was documented over follow-up of 4.1 (CDCS) and 8.8 (PMI) years, respectively. rs6922269 genotype frequencies were AA n = 135, 7.0%; GA n = 785, 40.5% and GG n = 1020, 52.5% in the CDCS and similar in the PMI cohort. CDCS patients with AA genotype for rs6922269 had lower levels of co-variate adjusted baseline plasma active vitamin B12 (p = 0.017) and poorer survival than patients with GG or GA genotype (mortality: AA 19.6%, GA 12.0%, GG 11.6%; p = 0.007). In multivariate analysis, rs6922269 genotype predicted survival, independent of established covariate predictors (p = 0.03). However the association between genotype and survival was not validated in the PMI cohort.
  
  
  CONCLUSIONS
  MTHFD1L rs6922269 genotype is associated with active vitamin B12 levels at baseline and may be a marker of prognostic risk in patients with established coronary heart disease.
authors.affiliation: Christchurch Heart Institute, Department of Medicine, University of Otago, Christchurch, New Zealand; Genetics Otago, University of Otago, Christchurch, New Zealand; Institute of Food, Nutrition & Human Health, Massey University, Wellington, New Zealand.
authors.forename: Barry R
authors.initials: BR
authors.lastname: Palmer
authors.affiliation: Pathology Department, University of Otago, Christchurch, New Zealand; Clinical Biochemistry Unit, Canterbury Health Laboratories, Christchurch, New Zealand.
authors.forename: Sandy
authors.initials: S
authors.lastname: Slow
authors.affiliation: Christchurch Heart Institute, Department of Medicine, University of Otago, Christchurch, New Zealand.
authors.forename: Katrina L
authors.initials: KL
authors.lastname: Ellis
authors.affiliation: Christchurch Heart Institute, Department of Medicine, University of Otago, Christchurch, New Zealand.
authors.forename: Anna P
authors.initials: AP
authors.lastname: Pilbrow
authors.affiliation: Christchurch Heart Institute, Department of Medicine, University of Otago, Christchurch, New Zealand.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Skelton
authors.affiliation: Christchurch Heart Institute, Department of Medicine, University of Otago, Christchurch, New Zealand.
authors.forename: Chris M
authors.initials: CM
authors.lastname: Frampton
authors.affiliation: Christchurch Heart Institute, Department of Medicine, University of Otago, Christchurch, New Zealand.
authors.forename: Suetonia C
authors.initials: SC
authors.lastname: Palmer
authors.affiliation: Christchurch Heart Institute, Department of Medicine, University of Otago, Christchurch, New Zealand.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Troughton
authors.affiliation: Christchurch Heart Institute, Department of Medicine, University of Otago, Christchurch, New Zealand.
authors.forename: Tim G
authors.initials: TG
authors.lastname: Yandle
authors.affiliation: Department of Medicine, Faculty of Medicine & Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Rob N
authors.initials: RN
authors.lastname: Doughty
authors.affiliation: Department of Medicine, Faculty of Medicine & Health Sciences, University of Auckland, Auckland, New Zealand; Department of Medical Imaging, Unitec Institute of Technology, Auckland, New Zealand.
authors.forename: Gillian A
authors.initials: GA
authors.lastname: Whalley
authors.affiliation: Pathology Department, University of Otago, Christchurch, New Zealand; Clinical Biochemistry Unit, Canterbury Health Laboratories, Christchurch, New Zealand.
authors.forename: Michael
authors.initials: M
authors.lastname: Lever
authors.affiliation: Pathology Department, University of Otago, Christchurch, New Zealand; Clinical Biochemistry Unit, Canterbury Health Laboratories, Christchurch, New Zealand.
authors.forename: Peter M
authors.initials: PM
authors.lastname: George
authors.affiliation: Clinical Biochemistry Unit, Canterbury Health Laboratories, Christchurch, New Zealand.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Chambers
authors.affiliation: Department of Medicine, Faculty of Medicine & Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Chris
authors.initials: C
authors.lastname: Ellis
authors.affiliation: Christchurch Heart Institute, Department of Medicine, University of Otago, Christchurch, New Zealand.
authors.forename: A Mark
authors.initials: AM
authors.lastname: Richards
authors.affiliation: Christchurch Heart Institute, Department of Medicine, University of Otago, Christchurch, New Zealand; Genetics Otago, University of Otago, Christchurch, New Zealand.
authors.forename: Vicky A
authors.initials: VA
authors.lastname: Cameron
mesh_terms: D054058:Acute Coronary Syndrome / Q000097:blood / Q000235:genetics* / Q000401:mortality*; D000483:Alleles; D000619:Aminohydrolases / Q000235:genetics*; D015415:Biomarkers; D015331:Cohort Studies; D005500:Follow-Up Studies; D005574:Formate-Tetrahydrofolate Ligase / Q000235:genetics*; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics*; D009097:Multienzyme Complexes / Q000235:genetics*; D009203:Myocardial Infarction / Q000097:blood / Q000235:genetics / Q000401:mortality; D011110:Polymorphism, Genetic; D011379:Prognosis; D016019:Survival Analysis; D013997:Time Factors; D014805:Vitamin B 12 / Q000097:blood
chemical_list: D015415:Biomarkers; D009097:Multienzyme Complexes; C021836:formyl-methenyl-methylenetetrahydrofolate synthetase; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D000619:Aminohydrolases; D005574:Formate-Tetrahydrofolate Ligase; D014805:Vitamin B 12