Genome-Wide Meta-Analysis of Homocysteine and Methionine Metabolism Identifies Five One Carbon Metabolism Loci and a Novel Association of with Ischemic Stroke

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dc.contributor.authorWilliams, Stephen R.
dc.contributor.authorYang, Qiong
dc.contributor.authorChen, Fang
dc.contributor.authorLiu, Xuan
dc.contributor.authorKeene, Keith L.
dc.contributor.authorJacques, Paul
dc.contributor.authorChen, Wei-Min
dc.contributor.authorWeinstein, Galit
dc.contributor.authorHsu, Fang-Chi
dc.contributor.authorBeiser, Alexa
dc.contributor.authorWang, Liewei
dc.contributor.authorBookman, Ebony
dc.contributor.authorDoheny, Kimberly F.
dc.contributor.authorWolf, Philip A.
dc.contributor.authorZilka, Michelle
dc.contributor.authorSelhub, Jacob
dc.contributor.authorNelson, Sarah
dc.contributor.authorGogarten, Stephanie M.
dc.contributor.authorWorrall, Bradford B.
dc.contributor.authorSeshadri, Sudha
dc.contributor.authorSale, Michèle M.
dc.date.accessioned2016-06-06T16:02:19Z
dc.date.available2016-06-06T16:02:19Z
dc.date.issued2014-03
dc.description.abstractCirculating homocysteine levels (tHcy), a product of the folate one carbon metabolism pathway (FOCM) through the demethylation of methionine, are heritable and are associated with an increased risk of common diseases such as stroke, cardiovascular disease (CVD), cancer and dementia. The FOCM is the sole source of de novo methyl group synthesis, impacting many biological and epigenetic pathways. However, the genetic determinants of elevated tHcy (hyperhomocysteinemia), dysregulation of methionine metabolism and the underlying biological processes remain unclear. We conducted independent genome-wide association studies and a meta-analysis of methionine metabolism, characterized by post-methionine load test tHcy, in 2,710 participants from the Framingham Heart Study (FHS) and 2,100 participants from the Vitamin Intervention for Stroke Prevention (VISP) clinical trial, and then examined the association of the identified loci with incident stroke in FHS. Five genes in the FOCM pathway (GNMT [p = 1.60×10−63], CBS [p = 3.15×10−26], CPS1 [p = 9.10×10−13], ALDH1L1 [p = 7.3×10−13] and PSPH [p = 1.17×10−16]) were strongly associated with the difference between pre- and post-methionine load test tHcy levels (ΔPOST). Of these, one variant in the ALDH1L1 locus, rs2364368, was associated with incident ischemic stroke. Promoter analyses reveal genetic and epigenetic differences that may explain a direct effect on GNMT transcription and a downstream affect on methionine metabolism. Additionally, a genetic-score consisting of the five significant loci explains 13% of the variance of ΔPOST in FHS and 6% of the variance in VISP. Association between variants in FOCM genes with ΔPOST suggest novel mechanisms that lead to differences in methionine metabolism, and possibly the epigenome, impacting disease risk. These data emphasize the importance of a concerted effort to understand regulators of one carbon metabolism as potential therapeutic targets.en_US
dc.identifier.citationPLoS Genetics; 10:3 p. 1-13en_US
dc.identifier.doi10.1371/journal.pgen.1004214
dc.identifier.issn1553-7390
dc.identifier.pmidpmc3961178en_US
dc.identifier.urihttp://hdl.handle.net/10342/5464
dc.relation.urihttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961178/en_US
dc.titleGenome-Wide Meta-Analysis of Homocysteine and Methionine Metabolism Identifies Five One Carbon Metabolism Loci and a Novel Association of with Ischemic Strokeen_US
dc.typeArticleen_US
ecu.journal.issue3en_US
ecu.journal.namePLoS Geneticsen_US
ecu.journal.pages1-13en_US
ecu.journal.volume10en_US

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