title: Folate network genetic variation, plasma homocysteine, and global genomic methylation content: a genetic association study.
abstract: BACKGROUND
  Sequence variants in genes functioning in folate-mediated one-carbon metabolism are hypothesized to lead to changes in levels of homocysteine and DNA methylation, which, in turn, are associated with risk of cardiovascular disease.
  
  
  METHODS
  330 SNPs in 52 genes were studied in relation to plasma homocysteine and global genomic DNA methylation. SNPs were selected based on functional effects and gene coverage, and assays were completed on the Illumina Goldengate platform. Age-, smoking-, and nutrient-adjusted genotype--phenotype associations were estimated in regression models.
  
  
  RESULTS
  Using a nominal P ≤ 0.005 threshold for statistical significance, 20 SNPs were associated with plasma homocysteine, 8 with Alu methylation, and 1 with LINE-1 methylation. Using a more stringent false discovery rate threshold, SNPs in FTCD, SLC19A1, and SLC19A3 genes remained associated with plasma homocysteine. Gene by vitamin B-6 interactions were identified for both Alu and LINE-1 methylation, and epistatic interactions with the MTHFR rs1801133 SNP were identified for the plasma homocysteine phenotype. Pleiotropy involving the MTHFD1L and SARDH genes for both plasma homocysteine and Alu methylation phenotypes was identified.
  
  
  CONCLUSIONS
  No single gene was associated with all three phenotypes, and the set of the most statistically significant SNPs predictive of homocysteine or Alu or LINE-1 methylation was unique to each phenotype. Genetic variation in folate-mediated one-carbon metabolism, other than the well-known effects of the MTHFR c.665C>T (known as c.677 C>T, rs1801133, p.Ala222Val), is predictive of cardiovascular disease biomarkers.
authors: Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA.
authors: Susan M
authors: SM
authors: Wernimont
authors: Andrew G
authors: AG
authors: Clark
authors: Patrick J
authors: PJ
authors: Stover
authors: Martin T
authors: MT
authors: Wells
authors: Augusto A
authors: AA
authors: Litonjua
authors: Scott T
authors: ST
authors: Weiss
authors: J Michael
authors: JM
authors: Gaziano
authors: Katherine L
authors: KL
authors: Tucker
authors: Andrea
authors: A
authors: Baccarelli
authors: Joel
authors: J
authors: Schwartz
authors: Valentina
authors: V
authors: Bollati
authors: Patricia A
authors: PA
authors: Cassano
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020087:Alu Elements / Q000235:genetics; D000619:Aminohydrolases / Q000235:genetics; D002318:Cardiovascular Diseases / Q000235:genetics; D019175:DNA Methylation; D005492:Folic Acid / Q000235:genetics*; D005574:Formate-Tetrahydrofolate Ligase / Q000235:genetics; D053263:Gene Regulatory Networks; D056726:Genetic Association Studies; D014644:Genetic Variation; D005838:Genotype; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics; D008297:Male; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D050892:Sarcosine Dehydrogenase / Q000235:genetics; D025101:Vitamin B 6 / Q000378:metabolism
chemical_list: D009097:Multienzyme Complexes; D006710:Homocysteine; C021836:formyl-methenyl-methylenetetrahydrofolate synthetase; D025101:Vitamin B 6; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); C494395:SARDH protein, human; D050892:Sarcosine Dehydrogenase; D000619:Aminohydrolases; D005574:Formate-Tetrahydrofolate Ligase