A genome-wide analysis of DNA methylation identifies a novel association signal for Lp(a) concentrations in the LPA promoter.
Adult
Aged
Aged, 80 and over
CpG Islands
DNA Methylation
Epigenesis, Genetic
Female
Gene Expression Regulation
Gene Frequency
Genome-Wide Association Study
/ methods
Humans
Lipoprotein(a)
/ genetics
Liver
/ metabolism
Male
Middle Aged
Polymorphism, Single Nucleotide
Promoter Regions, Genetic
Quantitative Trait Loci
Whole Genome Sequencing
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2020
2020
Historique:
received:
12
02
2020
accepted:
19
03
2020
entrez:
29
4
2020
pubmed:
29
4
2020
medline:
21
7
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32343731
doi: 10.1371/journal.pone.0232073
pii: PONE-D-20-04259
pmc: PMC7188291
doi:
Substances chimiques
LPA protein, human
0
Lipoprotein(a)
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0232073Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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