Evidence map›Paper›PMID 42412152›Full record

ArticleCardiovascular drugs and therapy2026

Complement Component C4B Prioritization Through Drug‒Target Mendelian Randomization and Proteomic Analysis Reveals a Novel Therapeutic Target for Calcific Aortic Valve Stenosis.

Weijie Li, Ting Zhou, Songyuan Luo, Jiaohua Chen, Zejia Wu, Wenhui Lin, Xiaolu Hu, Xinyue Yang, Jie Li, Zhaoyan Xu and 1 more

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Article in Cardiovascular drugs and therapy, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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1 · What the graph read from it

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5 · Who and what money

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11 authors.

Weijie Li *Department 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.
Ting Zhou *Department 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.
Songyuan LuoDepartment 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.
Jiaohua ChenDepartment 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.
Zejia WuDepartment 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.
Wenhui LinDepartment 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.
Xiaolu HuDepartment 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.
Xinyue YangDepartment 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.
Jie LiDepartment 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.
Zhaoyan XuDepartment of Cardiology, The First People's Hospital of Foshan (Foshan Hospital Affiliated to Southern University of Science and Technology), School of Medicine, Southern University of Science and Technology, Guangdong, Foshan, Guangdong, P. R. China. yannihu@126.com.
Jianfang LuoDepartment 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. jianfangluo@sina.com.

Funding

Foshan Municipal Science and Technology Innovation Project 2520001002968National Natural Science Foundation of China 82200519
6 · The paper itself

Abstract

objectivesNo pharmacotherapies effectively halt the progression of calcific aortic valve stenosis (CAVS). We leveraged multi-omic analyses to identify potential drug targets of CAVS.

methodsWe integrated druggable genome with cis-expression quantitative trait locus (eQTLs) data from the eQTLGen Consortium to identify instrumentable genes. Two independent genome-wide association study (GWAS) datasets for CAVS were used for Mendelian randomization (MR) analysis (Finngen dataset for discovery, a genome-wide meta-analysis cohort for replication). Genes showing significant associations in both cohorts underwent Bayesian colocalization, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Candidates were verified by proteomic analysis (liquid chromatography-tandem mass spectrometry, LC-MS/MS) and immunohistochemical (IHC) analysis of human aortic valves. Additionally, a phenome-wide association study (PheWAS) was conducted to assess the horizontal pleiotropy. A reverse MR analysis was performed to assess potential reverse causality.

resultsSeven druggable genes were significantly associated with CAVS in both cohorts. Among these, C4A and C4B exhibited robust colocalization evidence (both posterior probabilities PP.H4 > 80%). While LC-MS/MS confirmed the significant upregulation of C4A and C4B at the protein level (fold changes of 1.58 and 1.51, respectively; p < 0.05), only C4B was established as a risk factor for CAVS (odds ratio: 1.04, 95% confidence interval: 1.03-1.06, p = 3.49 × 10

conclusionOur study offers a genetically anchored therapeutic hypothesis involving the immune-complement system and identifies C4B as a prioritized candidate with therapeutic potential for CAVS.

Indexed as

C4BCalcific aortic valve stenosisDrug targetImmunohistochemical analysisMendelian randomizationProteomic analysis

Identifiers

PMID42412152

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.