Abstract
Myocardial infarction patients had decreased methylation at four growth differentiating factor-15 (GDF-15) related CpG sites (cg13033858, cg16936953, cg17150809, and cg18608055). These sites had not been studied for their association with cardiovascular disease (CVD) deaths. Thus, we aimed to assess the associations independent of genes, shared environment, and traditional CVD risk factors. Nineteen white, male, monozygotic twin pairs discordant for CVD deaths were included from the National Heart, Lung and Blood Institute Twin Study (NHLBI) initiated in 1969. Data on vital status was collected through December 31, 2014. Methylation of buffy coat DNA at exam 3 (1986–87) was measured using the Illumina HumanMethylation450 BeadChip. Principal component analysis was used to generate a score representing blood leukocyte composition and baseline CVD risk factors and predominated with natural killer cells, CD4+ T cells, and Framingham risk score. Conditional logistic regression demonstrated that methylation at the four CpG sites was not associated with CVD deaths before (all p > 0.05, bootstrapped p > 0.05) and after adjustment for the score (all p > 0.05). Joint influences of cg16936953 and the score were statistically significant (p < 0.05). In conclusion, joint influences of methylation at the site cg16936953 and the score are prospectively associated with CVD deaths independent of germline and common environment.ClinicalTrials.gov Identifier for NHLBI Twin Study: NCT00005124.
Highlights
Myocardial infarction patients had decreased methylation at four growth differentiating factor-15 (GDF-15) related CpG sites
We aimed to assess whether methylation at the four genomic CpG sites linked to circulating GDF-15 levels was prospectively associated with cardiovascular disease (CVD) death risk independent of germline, shared environmental factors, blood leukocyte composition, and known traditional CVD risk factors
The joint influence of cg16936953 and the score was statistically significantly associated with CVD death (p < 0.05), and the adjusted hazard ratio (HR) was marginally statistically significant for cg16936953 [HR 4.38, 95% confidence intervals (CI) 0.79–24.3, p = 0.09] and the score (p = 0.06), respectively
Summary
Myocardial infarction patients had decreased methylation at four growth differentiating factor-15 (GDF-15) related CpG sites (cg13033858, cg16936953, cg17150809, and cg18608055). These sites had not been studied for their association with cardiovascular disease (CVD) deaths. Joint influences of methylation at the site cg16936953 and the score are prospectively associated with CVD deaths independent of germline and common environment. Epigenetic changes to the genome are stable across mitotic divisions[4] They involve chemical modifications to DNA or associated proteins, such as the methylation of 5-cytosine in CpG (cytosine-phosphate-guanine) DNA dinucleotide pairs in the genome via the transfer of a methyl group to the pyrimidine ring of the cytosine[4]. While most variation in DNA methylation patterns between individuals is due to environmental factors, genetic influences on DNA methylation are high at certain genomic sites, especially those exhibiting high levels of variability in m ethylation[6]
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