Abstract
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 208 liver tissue samples from the GTEx project, which shows a significant association of the rs76735376 minor allele with increased LPA expression. To evaluate, whether the association signal at rs76735376 may actually be derived from a stronger eQTL signal in LD with this SNP, eQTL association results of all correlated SNPs (r2≥0.1) were integrated with genetic association results. This analysis pinpointed to rs10455872 as the potential trigger of the effect of rs76735376. Furthermore, both SNPs coincide with short apo(a) isoforms. Adjusting for both, rs10455872 and the apo(a) isoforms diminished the effect size of rs76735376 to 5.38 mg/dL (p = 0.0463). This indicates that the effect of rs76735376 can be explained by both an independent effect of the SNP and a strong correlation with rs10455872 and apo(a) isoforms.
Highlights
High Lipoprotein(a) [Lp(a)] concentrations represent a major risk factor for several cardiovascular diseases that is widely present in the population [1,2,3]
Since rs76735376 is in close vicinity to the well-known LPA pentanucleotide-repeat (PNR) polymorphism[30,38,39,53], we evaluated in KORA F4 and SAPHIR, whether the association of the pentanucleotide repeat (PNR) with Lp(a) concentrations can be explained by rs76735376 or vice versa
Research on Lp(a) has experienced two revivals: the first by genetic studies providing strong support for a causal association with cardiovascular outcomes and the second, more recently, due to Lp(a)-lowering agents becoming available in the form of PCSK9 inhibitors and mRNA antisense therapy
Summary
High Lipoprotein(a) [Lp(a)] concentrations represent a major risk factor for several cardiovascular diseases that is widely present in the population [1,2,3]. Depending on the cut-off used to define the normal range (30 mg/dL (reviewed in [4]) or 50 mg/dL[5]), 15% to 25% percent of the Caucasian population present Lp(a) concentrations that put them at increased cardiovascular risk[1,2,3]. Lp(a) concentrations are mostly genetically determined by one major gene locus, the LPA gene[20], which presents a peculiar structure consisting of several so-called kringle domains (kringle 4 type one to type 10 and kringle 5; abbreviated KIV-1 to -10 and KV). In Caucasians, low molecular weight isoforms (11–22 KIV repeats) are associated with 4–5 times higher Lp(a) than high molecular isoforms with >22 repeats
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