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

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 B(6), and B(12) 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 B(12), and B(6) 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 B(12), 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 B(12) (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 B(6), 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 B(6), six for Vitamin B(12), 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.