Abstract
Circulating 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.
Highlights
As the fourth leading cause of death and the leading cause of disability in American adults, stroke constitutes a major public health burden
MTHFR, which participates in the folate one-carbon metabolism pathway (FOCM) pathway, is tightly related to all the genes products identified in our study and has been implicated in susceptibility to vascular disease, neural tube defects, colon cancer and acute leukemia [19,20,21,22,23,24]
It is interesting to note that a prior genome-wide association (GWAS) in the individual Framingham Heart Study (FHS) and Vitamin Intervention for Stroke Prevention Trial (VISP) cohorts or in a meta-analysis yielded no significant results for baseline tHcy alone
Summary
As the fourth leading cause of death and the leading cause of disability in American adults, stroke constitutes a major public health burden. Epidemiological data consistently demonstrate an association between elevated plasma homocysteine (tHcy) and increased risk for stroke [1], cardiovascular disease [2], and dementia [3], but clinical trials of interventions to lower homocysteine have failed to demonstrate global benefit, with B12 supplementation helping to reduce risk only in subsets of the populations studied [4,5,6] These data support a more complicated relationship than simple biomarker and disease risk and indicate the need for new targets for risk reducing therapies. Dysregulation of this step in the FOCM could have broad implications on many cellular processes, including risk for stroke and cardiovascular disease
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