Hypermethylation at loci sensitive to the prenatal environment is associated with increased incidence of myocardial infarction

Abstract

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 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.

Figure 1

DNA methylation difference between the female case and control groups (y-axis) at each CpG unit (x-axis) of the loci INS (grey bars) and GNASAS (open bars). Differences were nominally significant for all CpG units when tested individually (P < 0.05), except for CpG 6 of INS. (A) Difference in percentage DNA methylation. (B) Difference in SD-units, a proportion of the standard deviation (SD) from the adjusted mean methylation in the control group. Bars represent the average difference, the whiskers represent the SE of the difference. Numbers under each bar are the CpG units, numbered from the forward primer onward. A positive difference indicates that the case group had a higher average DNA methylation, values are adjusted for bisulphite- and PCR batches, country and age at baseline