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Journal Article Research Support, Non-U.S. Gov't Epublish 1 citation

PubMed: 39267096 DOI: 10.1186/s12933-024-02431-8

Identification of potential therapeutic targets for nonischemic cardiomyopathy in European ancestry: an integrated multiomics analysis.

Cardiovasc Diabetol 23(1):338

Authors: Kaijia Shi, Xu Chen, Yangyang Zhao, Peihu Li, Jinxuan Chai, Jianmin Qiu, Zhihua Shen, Junli Guo, Wei Jie

Affiliations

  • Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory for Tropical Cardiovascular Diseases Research of Hainan Province, School of Public Health, Hainan Medical University, Haikou, 571199, China.
  • Department of Intensive Care Unit, Yuhuangding Hospital, Yantai, 264000, China.
  • Department of Pathology and Pathophysiology, School of Basic Medicine Sciences, Guangdong Medical University, Zhanjiang, 524023, China.
  • Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory for Tropical Cardiovascular Diseases Research of Hainan Province, School of Public Health, Hainan Medical University, Haikou, 571199, China.
  • Key Laboratory of Tropical Translational Medicine of Ministry of Education & Key Laboratory for Tropical Cardiovascular Diseases Research of Hainan Province, School of Public Health, Hainan Medical University, Haikou, 571199, China.

Abstract

BACKGROUND

Nonischemic cardiomyopathy (NISCM) is a clinical challenge with limited therapeutic targets. This study aims to identify promising drug targets for NISCM.

METHODS

We utilized cis-pQTLs from the deCODE study, which includes data from 35,559 Icelanders, and SNPs from the FinnGen study, which includes data from 1,754 NISCM cases and 340,815 controls of Finnish ancestry. Mendelian randomization (MR) analysis was performed to estimate the causal relationship between circulating plasma protein levels and NISCM risk. Proteins with significant associations underwent false discovery rate (FDR) correction, followed by Bayesian colocalization analysis. The expression of top two proteins, LILRA5 and NELL1, was further analyzed using various NISCM datasets. Descriptions from the Human Protein Atlas (HPA) validated protein expression. The impact of environmental exposures on LILRA5 was assessed using the Comparative Toxicogenomics Database (CTD), and molecular docking identified the potential small molecule interactions.

RESULTS

MR analysis identified 255 circulating plasma proteins associated with NISCM, with 16 remaining significant after FDR correction. Bayesian colocalization analysis identified LILRA5 and NELL1 as significant, with PP.H4 > 0.8. LILRA5 has a protective effect (OR = 0.758, 95% CI, 0.670-0.857) while NELL1 displays the risk effect (OR = 1.290, 95% CI, 1.199-1.387) in NISCM. Decreased LILRA5 expression was found in NISCM such as diabetic, hypertrophic, dilated, and inflammatory cardiomyopathy, while NELL1 expression increased in hypertrophic cardiomyopathy. HPA data indicated high LILRA5 expression in neutrophils, macrophages and endothelial cells within normal heart and limited NELL1 expression. Immune infiltration analysis revealed decreased neutrophil in diabetic cardiomyopathy. CTD analysis identified several small molecules that affect LILRA5 mRNA expression. Among these, Estradiol, Estradiol-3-benzoate, Gadodiamide, Topotecan, and Testosterone were found to stably bind to the LILRA5 protein at the conserved VAL-15 or THR-133 residues in the Ig-like C2 domain.

CONCLUSION

Based on European Ancestry Cohort, this study reveals that LILRA5 and NELL1 are potential therapeutic targets for NISCM, with LILRA5 showing particularly promising prospects in diabetic cardiomyopathy. Several small molecules interact with LILRA5, implying potential clinical implication.

MeSH

Diabetic Cardiomyopathies, Neutrophils, Therapeutics, Diabetes Complications, Cardiomyopathies, Plasma, Small Molecules

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