title: Genetic Associations with Plasma B12, B6, and Folate Levels in an Ischemic Stroke Population from the Vitamin Intervention for Stroke Prevention (VISP) Trial.
abstract: BACKGROUND
  B vitamins play an important role in homocysteine metabolism, with vitamin deficiencies resulting in increased levels of homocysteine and increased risk for stroke. We performed a genome-wide association study (GWAS) in 2,100 stroke patients from the Vitamin Intervention for Stroke Prevention (VISP) trial, a clinical trial designed to determine whether the daily intake of high-dose folic acid, vitamins B6, and B12 reduce recurrent cerebral infarction.
  
  
  METHODS
  Extensive quality control (QC) measures resulted in a total of 737,081 SNPs for analysis. Genome-wide association analyses for baseline quantitative measures of folate, Vitamins B12, and B6 were completed using linear regression approaches, implemented in PLINK.
  
  
  RESULTS
  Six associations met or exceeded genome-wide significance (P ≤ 5 × 10(-08)). For baseline Vitamin B12, the strongest association was observed with a non-synonymous SNP (nsSNP) located in the CUBN gene (P = 1.76 × 10(-13)). Two additional CUBN intronic SNPs demonstrated strong associations with B12 (P = 2.92 × 10(-10) and 4.11 × 10(-10)), while a second nsSNP, located in the TCN1 gene, also reached genome-wide significance (P = 5.14 × 10(-11)). For baseline measures of Vitamin B6, we identified genome-wide significant associations for SNPs at the ALPL locus (rs1697421; P = 7.06 × 10(-10) and rs1780316; P = 2.25 × 10(-08)). In addition to the six genome-wide significant associations, nine SNPs (two for Vitamin B6, six for Vitamin B12, and one for folate measures) provided suggestive evidence for association (P ≤ 10(-07)).
  
  
  CONCLUSIONS
  Our GWAS study has identified six genome-wide significant associations, nine suggestive associations, and successfully replicated 5 of 16 SNPs previously reported to be associated with measures of B vitamins. The six genome-wide significant associations are located in gene regions that have shown previous associations with measures of B vitamins; however, four of the nine suggestive associations represent novel finding and warrant further investigation in additional populations.
authors.affiliation: Center for Public Health Genomics, University of Virginia , Charlottesville, VA , USA ; Department of Biology, Center for Health Disparities, East Carolina University , Greenville, NC , USA.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Keene
authors.affiliation: Center for Public Health Genomics, University of Virginia , Charlottesville, VA , USA ; Department of Public Health Sciences, University of Virginia , Charlottesville, VA , USA.
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Chen
authors.affiliation: Center for Public Health Genomics, University of Virginia , Charlottesville, VA , USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Chen
authors.affiliation: Center for Public Health Genomics, University of Virginia , Charlottesville, VA , USA.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Williams
authors.affiliation: Center for Public Health Genomics, University of Virginia , Charlottesville, VA , USA.
authors.forename: Stacey D
authors.initials: SD
authors.lastname: Elkhatib
authors.affiliation: Department of Biostatistical Sciences, Wake Forest School of Medicine , Winston Salem, NC , USA.
authors.forename: Fang-Chi
authors.initials: FC
authors.lastname: Hsu
authors.affiliation: Center for Public Health Genomics, University of Virginia , Charlottesville, VA , USA ; Department of Public Health Sciences, University of Virginia , Charlottesville, VA , USA.
authors.forename: Josyf C
authors.initials: JC
authors.lastname: Mychaleckyj
authors.affiliation: Center for Inherited Disease Research, Johns Hopkins University School of Medicine , Baltimore, MD , USA.
authors.forename: Kimberly F
authors.initials: KF
authors.lastname: Doheny
authors.affiliation: Center for Inherited Disease Research, Johns Hopkins University School of Medicine , Baltimore, MD , USA.
authors.forename: Elizabeth W
authors.initials: EW
authors.lastname: Pugh
authors.affiliation: Center for Inherited Disease Research, Johns Hopkins University School of Medicine , Baltimore, MD , USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Ling
authors.affiliation: Department of Biostatistics, University of Washington , Seattle, WA , USA.
authors.forename: Cathy C
authors.initials: CC
authors.lastname: Laurie
authors.affiliation: Department of Biostatistics, University of Washington , Seattle, WA , USA.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Gogarten
authors.affiliation: National Human Genome Research Institute, National Institutes of Health , Bethesda, MD , USA.
authors.forename: Ebony B
authors.initials: EB
authors.lastname: Madden
authors.affiliation: Department of Public Health Sciences, University of Virginia , Charlottesville, VA , USA ; Department of Neurology, University of Virginia , Charlottesville, VA , USA.
authors.forename: Bradford B
authors.initials: BB
authors.lastname: Worrall
authors.affiliation: Center for Public Health Genomics, University of Virginia , Charlottesville, VA , USA ; Department of Public Health Sciences, University of Virginia , Charlottesville, VA , USA ; Department of Biochemistry & Molecular Genetics, University of Virginia , Charlottesville, VA , USA.
authors.forename: Michele M
authors.initials: MM
authors.lastname: Sale
keywords: B12; B6; GWAS; VISP; association; folate; one-carbon metabolism