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 public databases and SNPs from the Finnish database. 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 NELL 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 within normal heart and limited NELL1 expression. Immune infiltration analysis revealed decreased neutrophil in diabetic cardiomyopathy. CTD analysis identified sets of small molecules affecting LILRA5 expression, parts could stably bind with LILRA5.
Conclusion
LILRA5 and NELL1 are potential key therapeutic targets for NISCM, with LILRA5 showing particularly promising prospects in diabetic cardiomyopathy. Several small molecules interact with LILRA5, implying potential clinical implication.