PMID- 35501457
OWN - NLM
STAT- MEDLINE
DCOM- 20220504
LR  - 20230513
IS  - 2399-3642 (Electronic)
IS  - 2399-3642 (Linking)
VI  - 5
IP  - 1
DP  - 2022 May 2
TI  - Lymphocyte activation gene-3-associated protein networks are associated with 
      HDL-cholesterol and mortality in the Trans-omics for Precision Medicine program.
PG  - 362
LID - 10.1038/s42003-022-03304-0 [doi]
LID - 362
AB  - 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.
CI  - (c) 2022. The Author(s).
FAU - Manichaikul, Ani
AU  - Manichaikul A
AUID- ORCID: 0000-0002-5998-795X
AD  - Center for Public Heath Genomics, University of Virginia, Charlottesville, VA, 
      USA.
FAU - Lin, Honghuang
AU  - Lin H
AUID- ORCID: 0000-0003-3043-3942
AD  - Department of Medicine, University of Massachusetts Medical School, Worcester, 
      MA, USA.
FAU - Kang, Chansuk
AU  - Kang C
AD  - Center for Public Heath Genomics, University of Virginia, Charlottesville, VA, 
      USA.
FAU - Yang, Chaojie
AU  - Yang C
AUID- ORCID: 0000-0001-6782-1389
AD  - Center for Public Heath Genomics, University of Virginia, Charlottesville, VA, 
      USA.
FAU - Rich, Stephen S
AU  - Rich SS
AUID- ORCID: 0000-0003-3872-7793
AD  - Center for Public Heath Genomics, University of Virginia, Charlottesville, VA, 
      USA.
FAU - Taylor, Kent D
AU  - Taylor KD
AD  - The Institute for Translational Genomics and Population Sciences, Department of 
      Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA 
      Medical Center, Torrance, CA, USA.
FAU - Guo, Xiuqing
AU  - Guo X
AUID- ORCID: 0000-0002-5264-5068
AD  - The Institute for Translational Genomics and Population Sciences, Department of 
      Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA 
      Medical Center, Torrance, CA, USA.
FAU - Rotter, Jerome I
AU  - Rotter JI
AD  - The Institute for Translational Genomics and Population Sciences, Department of 
      Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA 
      Medical Center, Torrance, CA, USA.
FAU - Craig Johnson, W
AU  - Craig Johnson W
AD  - University of Washington, Seattle, WA, USA.
FAU - Cornell, Elaine
AU  - Cornell E
AD  - University of Vermont, Burlington, VT, USA.
FAU - Tracy, Russell P
AU  - Tracy RP
AUID- ORCID: 0000-0002-0080-2420
AD  - University of Vermont, Burlington, VT, USA.
FAU - Peter Durda, J
AU  - Peter Durda J
AD  - University of Vermont, Burlington, VT, USA.
FAU - Liu, Yongmei
AU  - Liu Y
AD  - Duke University, Chapel Hill, NC, USA.
FAU - Vasan, Ramachandran S
AU  - Vasan RS
AUID- ORCID: 0000-0001-7357-5970
AD  - Department of Medicine, University of Massachusetts Medical School, Worcester, 
      MA, USA.
FAU - Adrienne Cupples, L
AU  - Adrienne Cupples L
AUID- ORCID: 0000-0003-0273-7965
AD  - Department of Biostatistics, Boston University School of Public Health, Boston, 
      MA, USA.
FAU - Gerszten, Robert E
AU  - Gerszten RE
AUID- ORCID: 0000-0002-6767-7687
AD  - Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
FAU - Clish, Clary B
AU  - Clish CB
AUID- ORCID: 0000-0001-8259-9245
AD  - Metabolite Profiling, Broad Institute, Cambridge, MA, USA.
FAU - Jain, Deepti
AU  - Jain D
AD  - University of Washington, Seattle, WA, USA.
FAU - Conomos, Matthew P
AU  - Conomos MP
AUID- ORCID: 0000-0001-9744-0851
AD  - University of Washington, Seattle, WA, USA.
FAU - Blackwell, Thomas
AU  - Blackwell T
AD  - University of Michigan, Ann Arbor, MI, USA.
FAU - Papanicolaou, George J
AU  - Papanicolaou GJ
AD  - National Institutes of Health, Bethesda, MD, USA.
FAU - Rodriguez, Annabelle
AU  - Rodriguez A
AUID- ORCID: 0000-0002-3917-8565
AD  - Center for Vascular Biology, University of Connecticut Health, Farmington, CT, 
      USA. rodriguezoquendo@uchc.edu.
LA  - eng
GR  - N01HC95169/HL/NHLBI NIH HHS/United States
GR  - R01 HL071251/HL/NHLBI NIH HHS/United States
GR  - 75N92020D00005/HL/NHLBI NIH HHS/United States
GR  - N01HC95165/HL/NHLBI NIH HHS/United States
GR  - N01HC95159/HL/NHLBI NIH HHS/United States
GR  - N01HC95163/HL/NHLBI NIH HHS/United States
GR  - 75N92020D00002/HL/NHLBI NIH HHS/United States
GR  - UL1 RR033176/RR/NCRR NIH HHS/United States
GR  - R01 HL131862/HL/NHLBI NIH HHS/United States
GR  - UL1 TR000040/TR/NCATS NIH HHS/United States
GR  - R01 HL117626/HL/NHLBI NIH HHS/United States
GR  - P30 DK040561/DK/NIDDK NIH HHS/United States
GR  - 75N92020D00007/HL/NHLBI NIH HHS/United States
GR  - N01HC95161/HL/NHLBI NIH HHS/United States
GR  - 75N92020D00001/HL/NHLBI NIH HHS/United States
GR  - UL1 TR001881/TR/NCATS NIH HHS/United States
GR  - 75N92019D00031/HL/NHLBI NIH HHS/United States
GR  - R01 HL120393/HL/NHLBI NIH HHS/United States
GR  - R01 HL071259/HL/NHLBI NIH HHS/United States
GR  - N01HC95168/HL/NHLBI NIH HHS/United States
GR  - HHSN268201500014C/HL/NHLBI NIH HHS/United States
GR  - N01HC95162/HL/NHLBI NIH HHS/United States
GR  - R01 HL071051/HL/NHLBI NIH HHS/United States
GR  - 75N92020D00004/HL/NHLBI NIH HHS/United States
GR  - UL1 TR001420/TR/NCATS NIH HHS/United States
GR  - HHSN268201500001I/HL/NHLBI NIH HHS/United States
GR  - R01 HL105756/HL/NHLBI NIH HHS/United States
GR  - R01 HL071205/HL/NHLBI NIH HHS/United States
GR  - R01 HL071258/HL/NHLBI NIH HHS/United States
GR  - N01HC95167/HL/NHLBI NIH HHS/United States
GR  - 75N92020D00003/HL/NHLBI NIH HHS/United States
GR  - N01HC25195/HL/NHLBI NIH HHS/United States
GR  - U54 HG003067/HG/NHGRI NIH HHS/United States
GR  - HHSN268201500003I/HL/NHLBI NIH HHS/United States
GR  - N01HC95164/HL/NHLBI NIH HHS/United States
GR  - R01 HL092577/HL/NHLBI NIH HHS/United States
GR  - 75N92020D00006/HL/NHLBI NIH HHS/United States
GR  - UL1 TR001079/TR/NCATS NIH HHS/United States
GR  - N01HC95166/HL/NHLBI NIH HHS/United States
GR  - R01 HL071250/HL/NHLBI NIH HHS/United States
GR  - N01HC95160/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220502
PL  - England
TA  - Commun Biol
JT  - Communications biology
JID - 101719179
RN  - 0 (Cholesterol, HDL)
RN  - 0 (Chromatin)
RN  - 0 (LRIG3 protein, human)
RN  - 0 (Membrane Proteins)
SB  - IM
MH  - *Atherosclerosis
MH  - Cholesterol, HDL
MH  - Chromatin
MH  - Humans
MH  - Lymphocyte Activation
MH  - Membrane Proteins
MH  - *Precision Medicine
PMC - PMC9061762
COIS- A.R. reports inventorship rights to patents held by University of Connecticut 
      Health and Lipid Genomics. A.R. is the founder of Lipid Genomics. The remaining 
      authors declare no competing interests.
EDAT- 2022/05/03 06:00
MHDA- 2022/05/06 06:00
PMCR- 2022/05/02
CRDT- 2022/05/02 23:21
PHST- 2021/08/04 00:00 [received]
PHST- 2022/03/21 00:00 [accepted]
PHST- 2022/05/02 23:21 [entrez]
PHST- 2022/05/03 06:00 [pubmed]
PHST- 2022/05/06 06:00 [medline]
PHST- 2022/05/02 00:00 [pmc-release]
AID - 10.1038/s42003-022-03304-0 [pii]
AID - 3304 [pii]
AID - 10.1038/s42003-022-03304-0 [doi]
PST - epublish
SO  - Commun Biol. 2022 May 2;5(1):362. doi: 10.1038/s42003-022-03304-0.