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Open Access Highly Accessed Research article

Folate network genetic variation, plasma homocysteine, and global genomic methylation content: a genetic association study

Susan M Wernimont1, Andrew G Clark2, Patrick J Stover1, Martin T Wells3, Augusto A Litonjua4, Scott T Weiss4, J Michael Gaziano5, Katherine L Tucker6, Andrea Baccarelli78, Joel Schwartz7, Valentina Bollati8 and Patricia A Cassano9*

Author Affiliations

1 Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA

2 Department of Molecular Biology & Genetics, Cornell University, Ithaca, NY, USA

3 Department of Biological Statistics & Computational Biology, Cornell, Ithaca, NY, USA

4 Channing Laboratory, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA

5 Veterans Administration (VA) Normative Aging Study, VA Boston Healthcare System, and Division of Aging, Brigham & Women's Hospital, Boston, MA, USA

6 Department of Health Sciences, Northeastern University, Boston, MA, USA

7 Departments of Environmental Health and Epidemiology, Harvard University, Boston, MA, USA

8 Center of Molecular and Genetic Epidemiology, Department of Environmental and Occupational Health, Università degli Studi di Milano and IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy

9 209 Savage Hall, Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA

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BMC Medical Genetics 2011, 12:150  doi:10.1186/1471-2350-12-150

Published: 21 November 2011

Abstract

Background

Sequence variants in genes functioning in folate-mediated one-carbon metabolism are hypothesized to lead to changes in levels of homocysteine and DNA methylation, which, in turn, are associated with risk of cardiovascular disease.

Methods

330 SNPs in 52 genes were studied in relation to plasma homocysteine and global genomic DNA methylation. SNPs were selected based on functional effects and gene coverage, and assays were completed on the Illumina Goldengate platform. Age-, smoking-, and nutrient-adjusted genotype--phenotype associations were estimated in regression models.

Results

Using a nominal P ≤ 0.005 threshold for statistical significance, 20 SNPs were associated with plasma homocysteine, 8 with Alu methylation, and 1 with LINE-1 methylation. Using a more stringent false discovery rate threshold, SNPs in FTCD, SLC19A1, and SLC19A3 genes remained associated with plasma homocysteine. Gene by vitamin B-6 interactions were identified for both Alu and LINE-1 methylation, and epistatic interactions with the MTHFR rs1801133 SNP were identified for the plasma homocysteine phenotype. Pleiotropy involving the MTHFD1L and SARDH genes for both plasma homocysteine and Alu methylation phenotypes was identified.

Conclusions

No single gene was associated with all three phenotypes, and the set of the most statistically significant SNPs predictive of homocysteine or Alu or LINE-1 methylation was unique to each phenotype. Genetic variation in folate-mediated one-carbon metabolism, other than the well-known effects of the MTHFR c.665C>T (known as c.677 C>T, rs1801133, p.Ala222Val), is predictive of cardiovascular disease biomarkers.