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Lymphocyte activation gene-3-associated protein networks are associated with HDL-cholesterol and mortality in the
Ani Manichaikul1, Honghuang Lin2, Chansuk Kang1
1Center for Public Heath Genomics, University of Virginia, Charlottesville, VA, USA.
Insights
Low lymphocyte-activation gene-3 (LAG3) protein levels link to higher HDL-cholesterol and heart attack risk. Genetic variants near LAG3 influence LAG3 protein levels and associated proteins impacting cardiovascular health.
Area of Science:
- Genetics
- Immunology
- Cardiovascular Science
Background:
- Lymphocyte-activation gene-3 (LAG3) deficiency is linked to elevated HDL-cholesterol (HDL-C) and increased myocardial infarction risk.
- Understanding the genetic and proteomic landscape surrounding LAG3 is crucial for elucidating its role in cardiovascular disease.
Purpose of the Study:
- To investigate the association between genetic variants near LAG3 and plasma LAG3 protein levels.
- To identify LAG3-associated plasma proteins and their relationship with HDL-C and clinical outcomes, including cardiovascular disease and mortality.
Main Methods:
- Utilized whole genome sequencing and plasma proteomics from the Multi-Ethnic Study of Atherosclerosis (MESA) and Framingham Heart Study (FHS) cohorts.
- Employed in situ Hi-C chromatin capture to analyze interactions between LAG3 and other genes.
- Conducted genetic association analyses and tested LAG3-associated protein networks for associations with HDL-C and mortality.
Main Results:
- Identified a significant association between the LAG3 rs3782735 variant and plasma LAG3 protein levels.
- Discovered 183 proteins associated with LAG3, with four proteins linked to HDL-C.
- Found significant cis and trans interactions involving LAG3 and other genes (C1S, LRIG3, TNFRSF1A, B2M) via chromatin capture.
- A LAG3-associated protein network showed significant links to HDL-C and mortality.
Conclusions:
- Genetic variants near LAG3 influence its plasma protein levels.
- LAG3-associated proteins play a role in regulating HDL-C and are implicated in cardiovascular mortality.
- These findings provide insights into the molecular mechanisms linking LAG3 to cardiovascular health.
Abstract:
Deficiency of the immune checkpoint lymphocyte activation gene-3 (LAG3) protein is significantly associated with both elevated HDL-cholesterol (HDL-C) and myocardial infarction risk. We determined the association of genetic variants within ±500 kb of LAG3 with plasma LAG3 and defined LAG3-associated plasma proteins with HDL-C and clinical outcomes. Whole genome sequencing and plasma proteomics were obtained from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Framingham Heart Study (FHS) cohorts as part of the Trans-Omics for Precision Medicine program. In situ Hi-C chromatin capture was performed in EBV-transformed cell lines isolated from four MESA participants. Genetic association analyses were performed in MESA using multivariate regression models, with validation in FHS. A LAG3-associated protein network was tested for association with HDL-C, coronary heart disease, and all-cause mortality. We identify an association between the LAG3 rs3782735 variant and plasma LAG3 protein. Proteomics analysis reveals 183 proteins significantly associated with LAG3 with four proteins associated with HDL-C. Four proteins discovered for association with all-cause mortality in FHS shows nominal associations in MESA. Chromatin capture analysis reveals significant cis interactions between LAG3 and C1S, LRIG3, TNFRSF1A, and trans interactions between LAG3 and B2M. A LAG3-associated protein network has significant associations with HDL-C and mortality.
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