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Front Public Health. 2014 Aug 6;2:112. doi: 10.3389/fpubh.2014.00112. eCollection 2014.

Genetic Associations with Plasma B12, B6, and Folate Levels in an Ischemic Stroke Population from the Vitamin Intervention for Stroke Prevention (VISP) Trial.

Author information

1
Center for Public Health Genomics, University of Virginia , Charlottesville, VA , USA ; Department of Biology, Center for Health Disparities, East Carolina University , Greenville, NC , USA.
2
Center for Public Health Genomics, University of Virginia , Charlottesville, VA , USA ; Department of Public Health Sciences, University of Virginia , Charlottesville, VA , USA.
3
Center for Public Health Genomics, University of Virginia , Charlottesville, VA , USA.
4
Department of Biostatistical Sciences, Wake Forest School of Medicine , Winston Salem, NC , USA.
5
Center for Inherited Disease Research, Johns Hopkins University School of Medicine , Baltimore, MD , USA.
6
Department of Biostatistics, University of Washington , Seattle, WA , USA.
7
National Human Genome Research Institute, National Institutes of Health , Bethesda, MD , USA.
8
Department of Public Health Sciences, University of Virginia , Charlottesville, VA , USA ; Department of Neurology, University of Virginia , Charlottesville, VA , USA.
9
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.

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)).

CONCLUSION:

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.

KEYWORDS:

B12; B6; GWAS; VISP; association; folate; one-carbon metabolism

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