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A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
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γGT and PCSK9 variants in subjects with hyper-LDL-cholesterolemia

Kazuhiko Kotani1, Masato Hamasaki2, Snehal Kapse3

  • 1a:1:{s:5:"en_US";s:24:"Jichi Medical University";}. kazukotani@jichi.ac.jp.

Acta Bio-Medica : Atenei Parmensis
|December 19, 2022
PubMed

Insights

Gain-of-function variants in the PCSK9 gene are linked to cardiovascular disease. This study found lower gamma-glutamyl transpeptidase (γGT) activity in individuals with the PCSK9 p.E32K variant, suggesting an inverse association.

Area of Science:

  • Biochemistry and Molecular Biology
  • Cardiovascular Disease Research
  • Genetics and Genomics

Background:

  • Gain-of-function (GOF) variants of the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene are associated with elevated low-density lipoprotein (LDL) cholesterol and increased cardiovascular disease (CVD) risk.
  • Elevated gamma-glutamyl transpeptidase (γGT) activity, a marker of oxidative stress, is also linked to CVD.
  • The potential association between PCSK9 variants and γGT activity warrants investigation in individuals at risk for CVD.

Discussion:

  • This study investigated the relationship between the PCSK9 p.E32K GOF variant and γGT activity in 114 subjects with hyper-LDL-cholesterolemia.
  • Genotyping and enzymatic assays were performed to analyze the association.
  • Multivariate analysis confirmed the findings, indicating a robust relationship.

Key Insights:

  • Subjects with the PCSK9 p.E32K variant exhibited significantly lower γGT activity (median, 21 IU/L) compared to those without the variant (median, 30 IU/L).
  • A statistically significant inverse association was observed between γGT activity and the presence of the PCSK9 p.E32K GOF variant.
  • This inverse relationship was maintained after adjusting for other factors in multivariate analysis.

Outlook:

  • Further research into the underlying mechanisms connecting PCSK9 variants and γGT activity is crucial.
  • Understanding this association may provide new insights into the pathogenesis of CVD driven by PCSK9 variants.
  • This knowledge could potentially inform novel therapeutic strategies targeting PCSK9 and oxidative stress in CVD prevention.
Abstract

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