Lymphocyte activation gene-3-associated protein networks are associated with HDL-cholesterol and mortality in the Trans-omics for Precision Medicine program

• Main Authors: Adrienne Cupples, L. (Author), Blackwell, T. (Author), Clish, C.B (Author), Conomos, M.P (Author), Cornell, E. (Author), Craig Johnson, W. (Author), Gerszten, R.E (Author), Guo, X. (Author), Jain, D. (Author), Kang, C. (Author), Lin, H. (Author), Liu, Y. (Author), Manichaikul, A. (Author), Papanicolaou, G.J (Author), Peter Durda, J. (Author), Rich, S.S (Author), Rodriguez, A. (Author), Rotter, J.I (Author), Taylor, K.D (Author), Tracy, R.P (Author), Vasan, R.S (Author), Yang, C. (Author)
• Format: Article
• Language: English
• Published: Nature Research 2022
• Online Access: View Fulltext in Publisher
• ISBN: 23993642 (ISSN)
• DOI: 10.1038/s42003-022-03304-0

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. © 2022, The Author(s).