Epigenetic mechanisms regulate cellular gene expression potential without changing the genetic code. Like the genetic sequence, epigenetic marks are faithfully transmitted during mitosis and are... Show moreEpigenetic mechanisms regulate cellular gene expression potential without changing the genetic code. Like the genetic sequence, epigenetic marks are faithfully transmitted during mitosis and are generally stable in differentiated cells, but in contrast with the static genome, the epigenome retains the capacity for dynamic changes in each individual cell. Epigenetic variation is therefore a topic of interest for research on ageing and its related common diseases. In this thesis we focus on DNA methylation, which is the most studied layer of epigenetic information,and is correlated to the other epigenetic layers. We used a combination of successive studies to investigate aspects of variation in DNA methylation, various sources generating such variation and its relation with risk for myocardial infarction (MI) at candidate loci for cardiovascular and metabolic diseases Show less
Slieker, R.C.; Bos, S.D.; Goeman, J.J.; Bovee, J.V.M.G.; Talens, R.P.; Breggen, R. van der; ... ; Heijmans, B.T. 2013
Percutaneous coronary intervention (PCI) has become an effective therapy to treat obstructive coronary artery diseases (CAD). However, one of the major drawbacks of PCI is the occurrence of... Show morePercutaneous coronary intervention (PCI) has become an effective therapy to treat obstructive coronary artery diseases (CAD). However, one of the major drawbacks of PCI is the occurrence of restenosis in 5-25% of all initially treated patients. Restenosis is defined as the re-narrowing of the lumen of the blood vessel, resulting in renewed symptoms and the need for repeated intervention. To identify genetic variants that are associated with restenosis, a genome-wide association study (GWAS) was conducted in 295 patients who developed restenosis (cases) and 571 who did not (controls) from the GENetic Determinants of Restenosis (GENDER) study. Analysis of ~550 000 single nucleotide polymorphisms (SNPs) in GENDER was followed by a replication phase in three independent case-control populations (533 cases and 3067 controls). A potential susceptibility locus for restenosis at chromosome 12, including rs10861032 (P(combined) = 1.11 × 10(-7)) and rs9804922 (P(combined) = 1.45 × 10(-6)), was identified in the GWAS and replication phase. In addition, both SNPs were also associated with coronary events (rs10861032, P(additive) = 0.005; rs9804922, P(additive) = 0.023) in a trial based cohort set of elderly patients with (enhanced risk of) CAD (PROSPER) and all-cause mortality in PROSPER (rs10861032, P(additive) = 0.007; rs9804922, P(additive) = 0.013) and GENDER (rs10861032, P(additive) = 0.005; rs9804922, P(additive) = 0.023). Further analysis suggests that this locus could be involved in regulatory functions. Show less
BACKGROUND: Human epidemiological studies suggest that small size at birth and food deprivation during gestation confer an excess risk of coronary heart diseases (CHD) in adulthood, frequently in a... Show moreBACKGROUND: Human epidemiological studies suggest that small size at birth and food deprivation during gestation confer an excess risk of coronary heart diseases (CHD) in adulthood, frequently in a sex-specific manner. Prior epigenetic studies indicate that such prenatal conditions are marked by persistent and sometimes sex-specific changes in DNA methylation. Here, we have investigated the association between DNA methylation and myocardial infarction (MI) at six loci sensitive to prenatal nutrition, anticipating potential sex-specificity.Method Within the placebo group of the PROSPER trial on pravastatin and the risk of CHD, we compared all individuals who were event free at baseline and developed MI during 3 years' follow-up (n = 122) with a similar-sized control group. Methylation at IL10, LEP, ABCA1, IGF2, INS and GNASAS was measured in DNA extracted from leucocytes using mass spectrometry. RESULTS: DNA methylation at GNASAS was modestly higher in MI cases compared with controls (P = 0.030). A significant sex interaction was observed for INS (P = 0.014) and GNASAS (P = 0.031). Higher DNA methylation at these loci was associated with MI among women (INS: +2.5%, P = 0.002; GNASAS: +4.2%, P = 0.001). Hypermethylation at one locus and at both loci was associated with odds ratios (ORs) of 2.8 and 8.6, respectively (P(trend) = 3.0 × 10(-4)). No association was observed among men. CONCLUSIONS: The risk of MI in women is associated with DNA methylation marks at specific loci previously shown to be sensitive to prenatal conditions. This observation may reflect a developmental component of MI. Show less
The prospect of finding epigenetic risk factors for complex diseases would be greatly enhanced if DNA from existing biobanks, which is generally extracted from whole blood, could be used to perform... Show moreThe prospect of finding epigenetic risk factors for complex diseases would be greatly enhanced if DNA from existing biobanks, which is generally extracted from whole blood, could be used to perform epigenetic association studies. We characterized features of DNA methylation at 16 candidate loci, 8 of which were imprinted, in DNA samples from the Netherlands Twin Register biobank. Except for un-methylated or fully methylated sites, CpG methylation varied considerably in a sample of 30 unrelated individuals. This variation remained after accounting for the cellular heterogeneity of blood. Methylation of CpG sites was correlated within loci and, for 4 imprinted loci, across chromosomes. In 34 additional individuals, we investigated the DNA methylation of 8 representative loci in 2 longitudinal blood and 2 longitudinal buccal cell samples (follow-up 11-20 and 2-8 yr, respectively). Five of 8 loci were stable over time (rho > 0.75) in both tissues, indicating that prospective epigenetic studies may be possible. For 4 loci, the DNA methylation in blood (mesoderm) correlated with that in the buccal cells (ectoderm) (rho > 0.75). Our data suggest that epigenetic studies on complex diseases may be feasible for a proportion of genomic loci provided that they are carefully designed.-Talens, R. P., Boomsma, D. I., Tobi, E. W., Kremer, D., Jukema, J. W., Willemsen, G., Putter, H., Slagboom, P. E., Heijmans, B. T. Variation, patterns, and temporal stability of DNA methylation: considerations for epigenetic epidemiology. FASEB J. 24, 3135-3144 (2010). www.fasebj.org Show less
