A study in familial hypercholesterolemia suggests reduced methylomic plasticity in men with coronary artery disease

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From: Epigenomics(Vol. 7, Issue 1)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 10,422 words
Lexile Measure: 1610L

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Author(s): Simon-Pierre Guay aff1 aff2 , Diane Brisson aff2 aff3 , Patrick Mathieu aff4 , Yohan Bossé aff4 aff5 , Daniel Gaudet aff2 aff3 , Luigi Bouchard [*] aff1 aff2


arterial remodeling; candidate genes; cardiovascular diseases; DNA methylation; epigenome-wide association study; gene expression; missing heritability

Familial hypercholesterolemia (FH) is a common autosomal dominant disorder characterized by a high level of low-density lipoprotein cholesterol (LDL-C), early atherosclerosis and premature occurrence of coronary artery disease (CAD) [1 ]. FH is commonly caused by mutations in the LDL receptor (LDLR ) gene [1 ]. Less frequently, FH is caused by mutations within APOB, PCSK9 or LDLRAP1 genes [1 ]. Although FH subjects are at higher risk of CAD compared with non-FH subjects, the age of onset and severity of CAD varies considerably between FH patients, even among those who share the same causal mutation [2-5 ].

Many heritable and environmental factors have been associated with CAD [ 2-4 ]. A previous retrospective multicenter cohort study of 2400 FH patients showed that classical metabolic CAD risk factors explain 21.3% of the CAD occurrence in FH [2 ]. Heritable factors also seem to play a significant role in the development of CAD, as CAD occurrence clusters within FH kindred [6 ]. Although heritability estimates of CAD are about 40%, so far only 10% of the variation in CAD occurrence has been explained by common genetic variants according to the most recent genome-wide association study (GWAS) [ 7,8 ]. Therefore, the unaccountable heritability (or missing heritability) could be explained by nontraditional heritable factors such as DNA methylation, one of the most studied epigenetic mechanisms [9-15 ]. DNA methylation refers to the addition of a methyl group by DNA methyltransferases at the position 5' of the cytosine pyrimidine ring, most exclusively when the cytosines are located upstream of a guanine (sequence called CpG dinucleotides) and is associated with gene transcription regulation [16 ]. Previous epigenetic studies have suggested that DNA methylation could contribute to explain the missing heritability of most complex traits, including CAD and its related risk factors [10-15 ].

So far, association results between global DNA methylation levels measured in leucocytes and CAD remain inconsistent. In previous studies, both a global hypomethylation and hypermethylation of the genome have been associated with CAD and its related risk factors [12,17-19 ]. The most important limitation of these studies is the analytical strategy that has not allowed the identification of specific loci where DNA methylation might be associated with CAD expression. We recently observed that FH subjects with a previous history of CAD had higher ABCA1 and LIPC DNA methylation levels in leucocytes as compared with FH subjects without CAD [10,11 ]. A few studies have identified associations between CAD and DNA methylation levels with a candidate gene approach [13,20-22 ]. So far, only one study investigating epigenetic marks in leucocytes according to CAD used genome-wide profiling [14 ]. However, this latter work focus only on hypermethylated loci [14 ]. Therefore, no study has yet assessed the association between CAD and DNA methylation levels in leucocytes...

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Gale Document Number: GALE|A409374825