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Genetic insights into causal effects of lipids and lipid-modifying targets on calcific aortic valve stenosis: a

Chengrong Wu1, Qian Pu2, Yalin Zou1

  • 1Reproductive Center, Guiyang Maternal and Child Care Hospital, Guiyang, 550000, Guizhou, China.

Scientific Reports
|August 13, 2025
PubMed

Insights

Calcific aortic valve stenosis (CAVS) is causally linked to high total and LDL cholesterol. Inhibiting PCSK9, a drug target, may reduce CAVS risk, with ApoB and Lp(a) playing mediating roles.

Area of Science:

  • Cardiovascular Genetics
  • Pharmacogenomics
  • Atherosclerosis Research

Background:

  • Calcific aortic valve stenosis (CAVS) is a growing global health concern with limited pharmacological treatments.
  • Dyslipidemia is a suspected risk factor for CAVS, but its causal role and the efficacy of lipid-modifying drugs remain uncertain.
  • Understanding the genetic underpinnings of CAVS is crucial for developing effective therapeutic strategies.

Purpose of the Study:

  • To investigate the causal relationship between genetically proxied lipid traits and CAVS risk.
  • To evaluate the therapeutic potential of 12 lipid-modifying drug targets for CAVS treatment using Mendelian randomization.
  • To explore potential mediating factors, including lipoprotein a (Lp(a)) and apolipoprotein B (ApoB), in the PCSK9-CAVS pathway.

Main Methods:

  • Utilized Mendelian randomization (MR) to assess the causal effects of lipid traits and drug targets on CAVS.
  • Retrieved genetic variants from the Global Lipids Genetics Consortium (GLGC) and CAVS summary-level data from the TARGET and FinnGen consortia.
  • Performed colocalization, mediation, and sensitivity analyses to validate findings and identify mediators.

Main Results:

  • Total cholesterol and LDL-cholesterol were confirmed as independent causal risk factors for CAVS.
  • Genetic mimicry of PCSK9 inhibition demonstrated a significant reduction in CAVS risk (OR=0.63).
  • ApoB and Lp(a) mediated 55.9% and 4.5% of the total effect of PCSK9 on CAVS risk, respectively.

Conclusions:

  • Total cholesterol and LDL-cholesterol are established causal factors for calcific aortic valve stenosis.
  • Genetically proxied inhibition of PCSK9 presents a promising therapeutic strategy for reducing CAVS risk.
  • ApoB and Lp(a) are significant mediators in the pathway linking PCSK9 to CAVS pathogenesis.

Keywords:
Calcific aortic valve stenosisLDL-CLipids profileMendelian randomizationPCSK9eQTLpQTL

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