title: Lymphocyte activation gene 3 and coronary artery disease.
abstract: BACKGROUND:The lipoprotein scavenger receptor BI (SCARB1) rs10846744 noncoding variant is significantly associated with atherosclerotic disease independently of traditional cardiovascular risk factors. We identified a potentially novel connection between rs10846744, the immune checkpoint inhibitor lymphocyte activation gene 3 (LAG3), and atherosclerosis.METHODS:In vitro approaches included flow cytometry, lipid raft isolation, phosphosignaling, cytokine measurements, and overexpressing and silencing LAG3 protein. Fasting plasma LAG3 protein was measured in hyperalphalipoproteinemic (HALP) and Multi-Ethnic Study of Atherosclerosis (MESA) participants.RESULTS:In comparison with rs10846744 reference (GG homozygous) cells, LAG3 protein levels by flow cytometry (P< 0.001), in lipid rafts stimulated and unstimulated (P= 0.03), and phosphosignaling downstream of B cell receptor engagement of CD79A (P= 0.04), CD19 (P= 0.04), and LYN (P= 0.001) were lower in rs10846744 risk (CC homozygous) cells. Overexpressing LAG3 protein in risk cells and silencing LAG3 in reference cells confirmed its importance in phosphosignaling. Secretion of TNF-α was higher (P= 0.04) and IL-10 was lower (P= 0.04) in risk cells. Plasma LAG3 levels were lower in HALP carriers of the CC allele (P< 0.0001) and by race (P= 0.004). In MESA, race (P= 0.0005), age (P= 0.003), lipid medications (P= 0.03), smoking history (P< 0.0001), and rs10846744 genotype (P= 0.002) were independent predictors of plasma LAG3. In multivariable regression models, plasma LAG3 was significantly associated with HDL-cholesterol (HDL-C) (P= 0.007), plasma IL-10 (P< 0.0001), and provided additional predictive value above the Framingham risk score (P= 0.04). In MESA, when stratified by high HDL-C, plasma LAG3 was associated with coronary heart disease (CHD) (odds ratio 1.45,P= 0.004).CONCLUSION:Plasma LAG3 is a potentially novel independent predictor of HDL-C levels and CHD risk.FUNDING:This work was supported by an NIH RO1 grant (HL075646), the endowed Linda and David Roth Chair for Cardiovascular Research, and the Harold S. Geneen Charitable Trust Coronary Heart Disease Research award to Annabelle Rodriguez. MESA is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-001079, UL1-TR-000040, and DK063491. Cardiometabochip genotyping data for the MESA samples was supported in part by grants and contracts R01HL98077, N02-HL-64278, HL071205, UL1TR000124, DK063491, RD831697, and P50 ES015915.
authors: Center for Vascular Biology and.
authors: Diana
authors: D
authors: Golden
authors: Center for Vascular Biology and.
authors: Antonina
authors: A
authors: Kolmakova
authors: Center for Vascular Biology and.
authors: Sunitha
authors: S
authors: Sura
authors: Department of Immunology, University of Connecticut Health Center, Farmington, Connecticut, USA.
authors: Anthony T
authors: AT
authors: Vella
authors: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia.|Biostatistics Section, Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia, USA.
authors: Ani
authors: A
authors: Manichaikul
authors: Biostatistics Section, Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia, USA.
authors: Xin-Qun
authors: XQ
authors: Wang
authors: Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA.
authors: Suzette J
authors: SJ
authors: Bielinski
authors: Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Los Angeles, California, USA.
authors: Kent D
authors: KD
authors: Taylor
authors: Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Los Angeles, California, USA.
authors: Yii-Der Ida
authors: YI
authors: Chen
authors: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia.
authors: Stephen S
authors: SS
authors: Rich
authors: Center for Vascular Biology and.
authors: Annabelle
authors: A
authors: Rodriguez
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000097:blood / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics*; D008076:Cholesterol, HDL / Q000097:blood; D003324:Coronary Artery Disease / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D021962:Membrane Microdomains; D008875:Middle Aged; D051122:Scavenger Receptors, Class B / Q000235:genetics; D055815:Young Adult; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D008076:Cholesterol, HDL; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D000093322:Lymphocyte Activation Gene 3 Protein; C000720326:Lag3 protein, human