Genetic associations with plasma B12, B6, and folate levels in an ischemic stroke population from the vitamin intervention for stroke prevention (VISP) trial

on behalf of the GARNET Collaborative Research Group

Research output: Contribution to journalArticle

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 = 706 × 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.

Original languageEnglish (US)
Article number112
JournalFrontiers in Public Health
Volume2
Issue numberAUG
DOIs
StatePublished - Aug 6 2014

Fingerprint

Folic Acid
Vitamins
Single Nucleotide Polymorphism
Stroke
Vitamin B 6
Genome
Vitamin B 12
Vitamin B Complex
Genome-Wide Association Study
Population
Homocysteine
Genes
Avitaminosis
Cerebral Infarction
Quality Control
Linear Models
Clinical Trials

Keywords

  • Association
  • B12
  • B6
  • Folate
  • GWAS
  • One-carbon metabolism
  • VISP

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health

Cite this

Genetic associations with plasma B12, B6, and folate levels in an ischemic stroke population from the vitamin intervention for stroke prevention (VISP) trial. / on behalf of the GARNET Collaborative Research Group.

In: Frontiers in Public Health, Vol. 2, No. AUG, 112, 06.08.2014.

Research output: Contribution to journalArticle

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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 = 706 × 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 = "Association, B12, B6, Folate, GWAS, One-carbon metabolism, VISP",
author = "{on behalf of the GARNET Collaborative Research Group} and Keene, {Keith L.} and Chen, {Wei Min} and Fang Chen and Williams, {Stephen R.} and Elkhatib, {Stacey D.} and Hsu, {Fang Chi} and Mychaleckyj, {Josyf C.} and Kimberly Doheny and Elizabeth Pugh and Hua Ling and Laurie, {Cathy C.} and Gogarten, {Stephanie M.} and Madden, {Ebony B.} and Worrall, {Bradford B.} and Sale, {Michele M.}",
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AU - on behalf of the GARNET Collaborative Research Group

AU - Keene, Keith L.

AU - Chen, Wei Min

AU - Chen, Fang

AU - Williams, Stephen R.

AU - Elkhatib, Stacey D.

AU - Hsu, Fang Chi

AU - Mychaleckyj, Josyf C.

AU - Doheny, Kimberly

AU - Pugh, Elizabeth

AU - Ling, Hua

AU - Laurie, Cathy C.

AU - Gogarten, Stephanie M.

AU - Madden, Ebony B.

AU - Worrall, Bradford B.

AU - Sale, Michele M.

PY - 2014/8/6

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N2 - 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 = 706 × 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.

AB - 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 = 706 × 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.

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