Carriers of rare damaging

Journal

medRxiv : the preprint server for health sciences
Titre abrégé: medRxiv
Pays: United States
ID NLM: 101767986

Informations de publication

Date de publication:
16 Aug 2023
Historique:
pubmed: 30 8 2023
medline: 30 8 2023
entrez: 30 8 2023
Statut: epublish

Résumé

The CCL2/CCR2 axis governs monocyte trafficking and recruitment to atherosclerotic lesions. Human genetic analyses and population-based studies support an association between circulating CCL2 levels and atherosclerosis. Still, it remains unknown whether pharmacological targeting of CCR2, the main CCL2 receptor, would provide protection against human atherosclerotic disease. In whole-exome sequencing data from 454,775 UK Biobank participants (40-69 years), we identified predicted loss-of-function (LoF) or damaging missense (REVEL score >0.5) variants within the A total of 45 predicted LoF or damaging missense variants were identified in the Heterozygous carriers of damaging

Sections du résumé

Background UNASSIGNED
The CCL2/CCR2 axis governs monocyte trafficking and recruitment to atherosclerotic lesions. Human genetic analyses and population-based studies support an association between circulating CCL2 levels and atherosclerosis. Still, it remains unknown whether pharmacological targeting of CCR2, the main CCL2 receptor, would provide protection against human atherosclerotic disease.
Methods UNASSIGNED
In whole-exome sequencing data from 454,775 UK Biobank participants (40-69 years), we identified predicted loss-of-function (LoF) or damaging missense (REVEL score >0.5) variants within the
Results UNASSIGNED
A total of 45 predicted LoF or damaging missense variants were identified in the
Conclusions UNASSIGNED
Heterozygous carriers of damaging

Identifiants

DOI: 10.1101/2023.08.14.23294063 PMID: 37645892 PMC: PMC10462211
pubmed: 37645892
doi: 10.1101/2023.08.14.23294063
pmc: PMC10462211
pii:
doi:

Types de publication

Preprint

Langues

eng

Subventions

Organisme : NHLBI NIH HHS
ID : R01 HL105756
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH129337
Pays : United States

Déclaration de conflit d'intérêts

Conflicts of Interest: SMD receives research support from RenalytixAI and personal fees from Calico Labs, both outside the current work. MEM receives funding from Regeneron Pharmaceutical Inc. unrelated to this work. RD has received research support from AstraZeneca and Goldfinch Bio, not related to this work. BMP serves on the Steering Committee of the Yale Open Data Access Program funded by Johnson & Johnson. LMR is a consultant for the TOPMed Administrative Coordinating Center (through WeStat). The other authors have nothing to declare.

Auteurs

Marios K Georgakis (MK)

Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University (LMU), Munich, Germany.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

Rainer Malik (R)

Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University (LMU), Munich, Germany.

Natalie R Hasbani (NR)

Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.

Gabrielle Shakt (G)

Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, USA.

Alanna C Morrison (AC)

Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.

Noah L Tsao (NL)

Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, USA.

Renae Judy (R)

Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, USA.

Braxton D Mitchell (BD)

Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.
Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD.

Huichun Xu (H)

Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.

May E Montasser (ME)

Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.

Ron Do (R)

The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Eimear E Kenny (EE)

The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
The Center for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Ruth J F Loos (RJF)

The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

James G Terry (JG)

Department of Radiology, Vanderbilt University Medical Center, Nashville, TN, USA.

John Jeffrey Carr (JJ)

Department of Radiology, Vanderbilt University Medical Center, Nashville, TN, USA.

Joshua C Bis (JC)

Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.

Bruce M Psaty (BM)

Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
Department of Health Systems and Population Health, University of Washington, Seattle, WA, USA.
Department of Epidemiology, University of Washington, Seattle, WA, USA.

W T Longstreth (WT)

Department of Epidemiology, University of Washington, Seattle, WA, USA.
Department of Neurology, University of Washington, Seattle, WA, USA.

Kendra A Young (KA)

Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora CO, USA.

Sharon M Lutz (SM)

Department of Population Medicine, PRecisiOn Medicine Translational Research (PROMoTeR) Center, Harvard Pilgrim Health Care and Harvard Medical School, Boston, MA, USA.
Department of Biostatistics, T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.

Michael H Cho (MH)

Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Jai Broome (J)

Department of Biostatistics, University of Washington, Seattle, WA, USA.

Alyna T Khan (AT)

Department of Biostatistics, University of Washington, Seattle, WA, USA.

Fei Fei Wang (FF)

Department of Biostatistics, University of Washington, Seattle, WA, USA.

Nancy Heard-Costa (N)

Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
Boston University and National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA.

Sudha Seshadri (S)

Bigg's Institute for Alzheimer's Disease and neurodegenerative disorders, University of Texas Health Science Center, San Antonio, TX, USA.

Ramachandran S Vasan (RS)

Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
Boston University and National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA.
Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.

Nicholette D Palmer (ND)

Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Barry I Freedman (BI)

Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Donald W Bowden (DW)

Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Lisa R Yanek (LR)

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Brian G Kral (BG)

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Lewis C Becker (LC)

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Patricia A Peyser (PA)

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.

Lawrence F Bielak (LF)

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.

Farah Ammous (F)

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.

April P Carson (AP)

Department of Medicine, University of Mississippi Medical Center, Jackson, MS.

Michael E Hall (ME)

Department of Medicine, University of Mississippi Medical Center, Jackson, MS.

Laura M Raffield (LM)

Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC.

Stephen S Rich (SS)

Center for Public Health Genomics, University of Virginia, Charlottesville, VA USA.

Wendy S Post (WS)

Johns Hopkins Bloomberg School of Public Health, Johns Hopkins School of Medicine, Baltimore, MD USA.

Russel P Tracy (RP)

Departments of Pathology & Laboratory Medicine, and Biochemistry, Larner College of Medicine, University of Vermont, Burlington, VT USA.

Kent D Taylor (KD)

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.

Xiuqing Guo (X)

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.

Michael C Mahaney (MC)

Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville TX USA.

Joanne E Curran (JE)

Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville TX USA.

John Blangero (J)

Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville TX USA.

Shoa L Clarke (SL)

Department of Medicine (Division of Cardiovascular Medicine), Stanford University School of Medicine, Stanford, CA, USA.
Stanford Cardiovascular Institute, Stanford, CA, USA.
VA Palo Alto Health Care System, Palo Alto, CA, USA.

Jeffrey W Haessler (JW)

Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle WA 98109 USA.

Yao Hu (Y)

Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle WA 98109 USA.

Themistocles L Assimes (TL)

Department of Medicine (Division of Cardiovascular Medicine), Stanford University School of Medicine, Stanford, CA, USA.
Stanford Cardiovascular Institute, Stanford, CA, USA.
VA Palo Alto Health Care System, Palo Alto, CA, USA.

Charles Kooperberg (C)

Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle WA 98109 USA.

Scott M Damrauer (SM)

Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, USA.
Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Jerome I Rotter (JI)

Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville TX USA.

Paul S de Vries (PS)

Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.

Martin Dichgans (M)

Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University (LMU), Munich, Germany.
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
German Centre for Neurodegenerative Diseases (DZNE), Munich, Germany.

Classifications MeSH