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Investigating Aortic Valve Calcification via Isolation and Culture of T Lymphocytes using Feeder Cells from Irradiated Buffy Coat
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Complement Component C4B Prioritization Through Drug‒Target Mendelian Randomization and Proteomic Analysis Reveals a

Weijie Li1,2, Ting Zhou1, Songyuan Luo1

  • 1Department of Cardiology, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, P. R. China.

Cardiovascular Drugs and Therapy
|July 7, 2026
PubMed
Abstract

Insights

This study identified C4B as a potential therapeutic target for calcific aortic valve stenosis (CAVS) by analyzing multi-omic data. C4B is a prioritized candidate for developing new CAVS treatments.

Area of Science:

  • Genetics and genomics
  • Cardiovascular research
  • Drug discovery

Background:

  • Calcific aortic valve stenosis (CAVS) lacks effective pharmacotherapies to halt its progression.
  • Multi-omic analyses are crucial for identifying novel drug targets in complex diseases like CAVS.

Purpose of the Study:

  • To leverage multi-omic data to identify and validate potential drug targets for CAVS.
  • To investigate the role of the immune-complement system in CAVS pathogenesis.

Main Methods:

  • Integrated druggable genome data with cis-expression quantitative trait loci (eQTLs).
  • Performed Mendelian randomization (MR) analysis using two independent genome-wide association study (GWAS) datasets for CAVS.
  • Utilized Bayesian colocalization, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes enrichment analyses.
  • Verified candidate genes through proteomic (LC-MS/MS) and immunohistochemical (IHC) analyses.
  • Conducted phenome-wide association study (PheWAS) and reverse MR analysis to assess pleiotropy and causality.

Main Results:

  • Seven druggable genes were significantly associated with CAVS, with C4A and C4B showing robust colocalization.
  • LC-MS/MS confirmed upregulation of C4A and C4B proteins in CAVS.
  • C4B was identified as a risk factor for CAVS (OR: 1.04, p < 10^-9) and its causal effect was validated by reverse MR.
  • IHC showed significantly higher C4B expression in calcific aortic valves, predominantly in interstitial cells.

Conclusions:

  • The study provides a genetically anchored therapeutic hypothesis implicating the immune-complement system in CAVS.
  • C4B is identified as a prioritized candidate target with significant therapeutic potential for CAVS.
Keywords:
C4BCalcific aortic valve stenosisDrug targetImmunohistochemical analysisMendelian randomizationProteomic analysis

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