Genetic polymorphism rs6922269 in the MTHFD1L gene is associated with survival and baseline active vitamin B12 levels in post-acute coronary syndromes patients

PLoS One. 2014 Mar 11;9(3):e89029. doi: 10.1371/journal.pone.0089029. eCollection 2014.

Abstract

Background and aims: 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.

Methods and 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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Coronary Syndrome / blood
  • Acute Coronary Syndrome / genetics*
  • Acute Coronary Syndrome / mortality*
  • Alleles*
  • Aminohydrolases / genetics*
  • Biomarkers
  • Cohort Studies
  • Follow-Up Studies
  • Formate-Tetrahydrofolate Ligase / genetics*
  • Genetic Association Studies
  • Genotype
  • Humans
  • Methylenetetrahydrofolate Dehydrogenase (NADP) / genetics*
  • Multienzyme Complexes / genetics*
  • Myocardial Infarction / blood
  • Myocardial Infarction / genetics
  • Myocardial Infarction / mortality
  • Polymorphism, Genetic*
  • Prognosis
  • Survival Analysis
  • Time Factors
  • Vitamin B 12 / blood

Substances

  • Biomarkers
  • Multienzyme Complexes
  • formyl-methenyl-methylenetetrahydrofolate synthetase
  • Methylenetetrahydrofolate Dehydrogenase (NADP)
  • Aminohydrolases
  • Formate-Tetrahydrofolate Ligase
  • Vitamin B 12

Grants and funding

This work was supported by grants from a University of Otago, Health Sciences Division Grant Development Award (BRP), the Health Research Council of NZ, Lotteries Grants Board (Grant#297540 to BRP) and the Heart Foundation of NZ (HFNZ). KLE held a HFNZ Postgraduate Scholarship, APP a Foundation of Research, Science and Technology Postdoctoral Fellowship, SCP a Don and Lorraine Jacquot Fellowship, GAW a HFNZ Senior Fellowship,RND the HFNZ Chair of Heart Health and AMR the HFNZ Chair of Cardiovascular Studies. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.