Exploring PCSK9 Genetic Impact on Lipoprotein(a) via Dual Approaches: Association and Mendelian Randomization

Ya Ching Chang, Lung An Hsu*, Yu Lin Ko

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

1 Scopus citations

Abstract

Previous investigations have suggested an association between the PCSK9 common polymorphism E670G and Lipoprotein(a) (Lp(a)) levels, as well as a link between plasma PCSK9 levels and Lp(a) concentrations. However, the causal relationship between plasma PCSK9 and Lp(a) levels remains uncertain. In this study, we explored the association between PCSK9 E670G polymorphism and Lp(a) levels in 614 healthy Taiwanese individuals. Employing a two-sample Mendelian randomization (MR) analysis using openly accessible PCSK9 and Lp(a) summary statistics from the genome-wide association studies (GWAS) and UK Biobank, we aimed to determine if a causal link exists between plasma PCSK9 levels and Lp(a) concentrations. Our findings reveal that the E670G G allele is independently associated with a decreased likelihood of developing elevated Lp(a) levels. This association persists even after adjusting for common cardiovascular risk factors and irrespective of lipid profile variations. The MR analysis, utilizing six PCSK9 GWAS-associated variants as instrumental variables to predict plasma PCSK9 levels, provides compelling evidence of a causal relationship between plasma PCSK9 levels and Lp(a) concentration. In conclusion, our study not only replicates the association between the PCSK9 E670G polymorphism and Lp(a) levels but also confirms a causative relationship between PCSK9 levels and Lp(a) concentrations through MR analysis.

Original languageEnglish
Article number14668
JournalInternational Journal of Molecular Sciences
Volume24
Issue number19
DOIs
StatePublished - 28 09 2023

Bibliographical note

Publisher Copyright:
© 2023 by the authors.

Keywords

  • Mendelian randomization
  • PCSK9 gene
  • dyslipidemia
  • hyperlipoproteinemia(a)
  • lipoprotein(a)
  • polymorphism
  • Genome-Wide Association Study
  • Humans
  • Proprotein Convertase 9/genetics
  • Lipoprotein(a)/genetics
  • Mendelian Randomization Analysis
  • Polymorphism, Single Nucleotide

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