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Tracking Drug-induced Changes in Receptor Post-internalization Trafficking by Colocalizational Analysis
Published on: July 3, 2015
Instrumental variable and colocalization analyses identify endotrophin and HTRA1 as potential therapeutic targets for
Paul C Lee1, In-Hyuk Jung1, Shreeya Thussu1
1Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA.
Abstract:
Coronary artery disease (CAD) remains a leading cause of disease burden globally, and there is a persistent need for new therapeutic targets. Instrumental variable (IV) and genetic colocalization analyses can help identify novel therapeutic targets for human disease by nominating causal genes in genome-wide association study (GWAS) loci. We conducted cis-IV analyses for 20,125 genes and 1,746 plasma proteins with CAD using molecular trait quantitative trait loci variant (QTLs) data from three different studies. 19 proteins and 119 genes were significantly associated with CAD risk by IV analyses and demonstrated evidence of genetic colocalization. Notably, our analyses validated well-established targets such as PCSK9 and ANGPTL4 while also identifying HTRA1 and endotrophin (a cleavage product of COL6A3) as proteins whose levels are causally associated with CAD risk. Further experimental studies are needed to confirm the causal role of the genes and proteins identified through our multiomic cis-IV analyses on human disease.
Insights
This study used genetic analysis to find new therapeutic targets for coronary artery disease (CAD). It identified several genes and proteins, including HTRA1 and endotrophin, causally linked to CAD risk.
Area of Science:
- Genetics
- Cardiovascular Disease Research
- Pharmacogenomics
Background:
- Coronary artery disease (CAD) is a major global health concern with ongoing need for novel therapeutic strategies.
- Genome-wide association studies (GWAS) identify genetic loci associated with disease, but determining causal genes requires advanced methods.
- Instrumental variable (IV) and genetic colocalization analyses are powerful tools for nominating causal genes within GWAS loci.
Purpose of the Study:
- To identify novel, potentially causal genes and proteins associated with coronary artery disease (CAD) risk.
- To leverage multi-omic data and advanced genetic analyses to nominate therapeutic targets for CAD.
- To validate established CAD targets and discover new ones using a robust analytical framework.
Main Methods:
- Conducted cis-instrumental variable (cis-IV) analyses integrating molecular quantitative trait loci (QTLs) data for 20,125 genes and 1,746 plasma proteins with CAD.
- Employed genetic colocalization to confirm shared genetic architecture between identified molecular traits and CAD risk.
- Utilized data from three distinct molecular QTL studies for comprehensive analysis.
Main Results:
- Identified 19 proteins and 119 genes significantly associated with CAD risk through IV analyses, with evidence of genetic colocalization.
- Validated known therapeutic targets for CAD, such as PCSK9 and ANGPTL4.
- Discovered novel candidate targets, including HTRA1 and endotrophin (COL6A3 cleavage product), causally linked to CAD risk.
Conclusions:
- The study successfully nominated multiple genes and proteins with a potential causal role in coronary artery disease.
- Findings highlight HTRA1 and endotrophin as promising new targets for therapeutic development in CAD.
- Further experimental validation is crucial to confirm the identified causal relationships and their therapeutic potential.
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