- Manichaikul, Ani;
- Lin, Honghuang;
- Kang, Chansuk;
- Yang, Chaojie;
- Rich, Stephen S;
- Taylor, Kent D;
- Guo, Xiuqing;
- Rotter, Jerome I;
- Craig Johnson, W;
- Cornell, Elaine;
- Tracy, Russell P;
- Peter Durda, J;
- Liu, Yongmei;
- Vasan, Ramachandran S;
- Adrienne Cupples, L;
- Gerszten, Robert E;
- Clish, Clary B;
- Jain, Deepti;
- Conomos, Matthew P;
- Blackwell, Thomas;
- Papanicolaou, George J;
- Rodriguez, Annabelle
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.