Diana Golden1, Antonina Kolmakova1, Sunitha Sura1, Anthony T Vella2, Ani Manichaikul3,4, Xin-Qun Wang4, Suzette J Bielinski5, Kent D Taylor6, Yii-Der Ida Chen6, Stephen S Rich3, Annabelle Rodriguez1. 1. Center for Vascular Biology and. 2. Department of Immunology, University of Connecticut Health Center, Farmington, Connecticut, USA. 3. Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia. 4. Biostatistics Section, Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia, USA. 5. Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA. 6. Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Los Angeles, California, USA.
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.
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: Alkes L Price; Nick J Patterson; Robert M Plenge; Michael E Weinblatt; Nancy A Shadick; David Reich Journal: Nat Genet Date: 2006-07-23 Impact factor: 38.330
Authors: Nicola Gagliani; Chiara F Magnani; Samuel Huber; Monica E Gianolini; Mauro Pala; Paula Licona-Limon; Binggege Guo; De'Broski R Herbert; Alessandro Bulfone; Filippo Trentini; Clelia Di Serio; Rosa Bacchetta; Marco Andreani; Leonie Brockmann; Silvia Gregori; Richard A Flavell; Maria-Grazia Roncarolo Journal: Nat Med Date: 2013-04-28 Impact factor: 53.440
Authors: William E Boden; Jeffrey L Probstfield; Todd Anderson; Bernard R Chaitman; Patrice Desvignes-Nickens; Kent Koprowicz; Ruth McBride; Koon Teo; William Weintraub Journal: N Engl J Med Date: 2011-11-15 Impact factor: 91.245
Authors: Paolo Zanoni; Sumeet A Khetarpal; Daniel B Larach; William F Hancock-Cerutti; John S Millar; Marina Cuchel; Stephanie DerOhannessian; Anatol Kontush; Praveen Surendran; Danish Saleheen; Stella Trompet; J Wouter Jukema; Anton De Craen; Panos Deloukas; Naveed Sattar; Ian Ford; Chris Packard; Abdullah al Shafi Majumder; Dewan S Alam; Emanuele Di Angelantonio; Goncalo Abecasis; Rajiv Chowdhury; Jeanette Erdmann; Børge G Nordestgaard; Sune F Nielsen; Anne Tybjærg-Hansen; Ruth Frikke Schmidt; Kari Kuulasmaa; Dajiang J Liu; Markus Perola; Stefan Blankenberg; Veikko Salomaa; Satu Männistö; Philippe Amouyel; Dominique Arveiler; Jean Ferrieres; Martina Müller-Nurasyid; Marco Ferrario; Frank Kee; Cristen J Willer; Nilesh Samani; Heribert Schunkert; Adam S Butterworth; Joanna M M Howson; Gina M Peloso; Nathan O Stitziel; John Danesh; Sekar Kathiresan; Daniel J Rader Journal: Science Date: 2016-03-11 Impact factor: 47.728
Authors: Caroline Robert; Antoni Ribas; Jedd D Wolchok; F Stephen Hodi; Omid Hamid; Richard Kefford; Jeffrey S Weber; Anthony M Joshua; Wen-Jen Hwu; Tara C Gangadhar; Amita Patnaik; Roxana Dronca; Hassane Zarour; Richard W Joseph; Peter Boasberg; Bartosz Chmielowski; Christine Mateus; Michael A Postow; Kevin Gergich; Jeroen Elassaiss-Schaap; Xiaoyun Nicole Li; Robert Iannone; Scot W Ebbinghaus; S Peter Kang; Adil Daud Journal: Lancet Date: 2014-07-15 Impact factor: 79.321
Authors: Christian Lienhardt; Annalisa Azzurri; Amedeo Amedei; Katherine Fielding; Jackson Sillah; Oumou Y Sow; Boubacar Bah; Marisa Benagiano; Alimou Diallo; Roberto Manetti; Kebba Manneh; Per Gustafson; Steve Bennett; Mario M D'Elios; Keith McAdam; Gianfranco Del Prete Journal: Eur J Immunol Date: 2002-06 Impact factor: 5.532
Authors: Paul C Tumeh; Christina L Harview; Jennifer H Yearley; I Peter Shintaku; Emma J M Taylor; Lidia Robert; Bartosz Chmielowski; Marko Spasic; Gina Henry; Voicu Ciobanu; Alisha N West; Manuel Carmona; Christine Kivork; Elizabeth Seja; Grace Cherry; Antonio J Gutierrez; Tristan R Grogan; Christine Mateus; Gorana Tomasic; John A Glaspy; Ryan O Emerson; Harlan Robins; Robert H Pierce; David A Elashoff; Caroline Robert; Antoni Ribas Journal: Nature Date: 2014-11-27 Impact factor: 49.962
Authors: Jacqueline T Vuong; Ashley F Stein-Merlob; Arash Nayeri; Tamer Sallam; Tomas G Neilan; Eric H Yang Journal: J Am Coll Cardiol Date: 2022-02-15 Impact factor: 24.094
Authors: Annabelle Rodriguez; Bernardo L Trigatti; Chieko Mineo; Darcy Knaack; John T Wilkins; Daisy Sahoo; Bela F Asztalos; Samia Mora; Marina Cuchel; Henry J Pownall; Corina Rosales; Pascal Bernatchez; Amanda Ribeiro Martins da Silva; Godfrey S Getz; Jacob L Barber; Gregory C Shearer; Angela M Zivkovic; Uwe J F Tietge; Frank M Sacks; Margery A Connelly; Michael N Oda; W Sean Davidson; Mary G Sorci-Thomas; Tomas Vaisar; Giacomo Ruotolo; Kasey C Vickers; Catherine Martel Journal: Arterioscler Thromb Vasc Biol Date: 2019-10-10 Impact factor: 8.311
Authors: Sudipa Sarkar; Sabina Haberlen; Wendy S Post; Theodoros Kelesidis; Dorothy Wiley; Lawrence Kingsley; Eun-Young Kim; Frank J Palella; Mallory D Witt; Matthew J Budoff; Annabelle Rodriguez; Todd T Brown Journal: AIDS Res Hum Retroviruses Date: 2021-09-20 Impact factor: 2.205