AUTHOR=Keene Keith L., Chen Wei-Min , Chen Fang , Williams Stephen R., Elkhatib Stacey D., Hsu Fang-Chi , Mychaleckyj Josyf C., Doheny Kimberley F., Pugh Elizabeth W., Ling Hua , Laurie Cathy C., Gogarten Stephanie M., Madden Ebony B., Worrall Bradford B., Sale Michele M.

TITLE=Genetic associations with plasma B12, B6, and folate levels in an ischemic stroke population from the Vitamin Intervention for Stroke Prevention (VISP) trial

JOURNAL=Frontiers in Public Health

VOLUME=2

YEAR=2014

URL=https://www.frontiersin.org/journals/public-health/articles/10.3389/fpubh.2014.00112

DOI=10.3389/fpubh.2014.00112

ISSN=2296-2565

ABSTRACT=<p><bold>Background:</bold> 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<sub>6</sub>, and B<sub>12</sub> reduce recurrent cerebral infarction.</p><p><bold>Methods:</bold> 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<sub>12</sub>, and B<sub>6</sub> were completed using linear regression approaches, implemented in PLINK.</p><p><bold>Results:</bold> Six associations met or exceeded genome-wide significance (<italic>P</italic> ≤ 5 × 10<sup>−08</sup>). For baseline Vitamin B<sub>12</sub>, the strongest association was observed with a non-synonymous SNP (nsSNP) located in the <italic>CUBN</italic> gene (<italic>P</italic> = 1.76 × 10<sup>−13</sup>). Two additional <italic>CUBN</italic> intronic SNPs demonstrated strong associations with B<sub>12</sub> (<italic>P</italic> = 2.92 × 10<sup>−10</sup> and 4.11 × 10<sup>−10</sup>), while a second nsSNP, located in the <italic>TCN1</italic> gene, also reached genome-wide significance (<italic>P</italic> = 5.14 × 10<sup>−11</sup>). For baseline measures of Vitamin B<sub>6</sub>, we identified genome-wide significant associations for SNPs at the <italic>ALPL</italic> locus (rs1697421; <italic>P</italic> = 7.06 × 10<sup>−10</sup> and rs1780316; <italic>P</italic> = 2.25 × 10<sup>−08</sup>). In addition to the six genome-wide significant associations, nine SNPs (two for Vitamin B<sub>6</sub>, six for Vitamin B<sub>12</sub>, and one for folate measures) provided suggestive evidence for association (<italic>P</italic> ≤ 10<sup>−07</sup>).</p><p><bold>Conclusion:</bold> 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.</p>