학술논문
Lymphocyte activation gene-3-associated protein networks are associated with HDL-cholesterol and mortality in the Trans-omics for Precision Medicine program
Document Type
article
Author
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
Source
Communications Biology. 5(1)
Subject
Language
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.