A genome-wide analysis of DNA methylation identifies a novel association signal for Lp(a) concentrations in the LPA promoter

Lipoprotein(a) [Lp(a)] is a major cardiovascular risk factor, which is largely genetically determined by one major gene locus, the LPA gene. Many aspects of the transcriptional regulation of LPA are poorly understood and the role of epigenetics has not been addressed yet. Therefore, we conducted an epigenome-wide analysis of DNA methylation on Lp(a) levels in two population-based studies (total n=2208). We identified a CpG site in the LPA promoter which was significantly associated with Lp(a) concentrations. Surprisingly, the identified CpG site was found to overlap the SNP rs76735376. We genotyped this SNP de-novo in three studies (total n=7512). The minor allele of rs76735376 (1.1% minor allele frequency) was associated with increased Lp(a) values (p=1.01e-59) and explained 3.5% of the variation of Lp(a). Statistical mediation analysis showed that the effect on Lp(a) is rather originating from the base change itself and is not mediated by DNA methylation levels. This finding is supported by eQTL data from 153 liver tissue samples from the GTEx project, which shows a significant association of the rs76735376 minor allele with increased LPA expression. In summary, our data supports a functional role of rs76735376 in the regulation of LPA expression.