Rare damaging CCR2 variants are associated with lower lifetime cardiovascular risk

Marios K Georgakis; Rainer Malik; Omar El Bounkari; Natalie R Hasbani; Jiang Li; Jennifer E Huffman; Gabrielle Shakt; Reinier W P Tack; Tamara N Kimball; Yaw Asare; Alanna C Morrison; Noah L Tsao; Renae Judy; Braxton D Mitchell; Huichun Xu; May E Montasser; Ron Do; Eimear E Kenny; Ruth J F Loos; James G Terry; John Jeffrey Carr; Joshua C Bis; Bruce M Psaty; W T Longstreth; Kendra A Young; Sharon M Lutz; Michael H Cho; Jai Broome; Alyna T Khan; Fei Fei Wang; Nancy Heard-Costa; Sudha Seshadri; Ramachandran S Vasan; Nicholette D Palmer; Barry I Freedman; Donald W Bowden; Lisa R Yanek; Brian G Kral; Lewis C Becker; Patricia A Peyser; Lawrence F Bielak; Farah Ammous; April P Carson; Michael E Hall; Laura M Raffield; Stephen S Rich; Wendy S Post; Russel P Tracy; Kent D Taylor; Xiuqing Guo; Michael C Mahaney; Joanne E Curran; John Blangero; Shoa L Clarke; Jeffrey W Haessler; Yao Hu; Themistocles L Assimes; Charles Kooperberg; Jürgen Bernhagen; Christopher D Anderson; Scott M Damrauer; Ramin Zand; Jerome I Rotter; Paul S de Vries; Martin Dichgans

doi:10.1101/2023.08.14.23294063

Rare damaging CCR2 variants are associated with lower lifetime cardiovascular risk

medRxiv [Preprint]. 2024 Jun 26:2023.08.14.23294063. doi: 10.1101/2023.08.14.23294063.

Authors

Marios K Georgakis^{1

2

3}, Rainer Malik¹, Omar El Bounkari¹, Natalie R Hasbani⁴, Jiang Li⁵, Jennifer E Huffman⁶, Gabrielle Shakt^{7

8}, Reinier W P Tack^{2

9}, Tamara N Kimball^{2

10}, Yaw Asare¹, Alanna C Morrison⁴, Noah L Tsao^{7

8}, Renae Judy^{7

8}, Braxton D Mitchell^{11

12}, Huichun Xu¹¹, May E Montasser¹¹, Ron Do^{13

14}, Eimear E Kenny^{13

15

16

17}, Ruth J F Loos¹³, James G Terry¹⁸, John Jeffrey Carr¹⁸, Joshua C Bis¹⁹, Bruce M Psaty^{19

20

21}, W T Longstreth^{21

22}, Kendra A Young²³, Sharon M Lutz^{24

25}, Michael H Cho²⁶, Jai Broome²⁷, Alyna T Khan²⁷, Fei Fei Wang²⁷, Nancy Heard-Costa^{28

29}, Sudha Seshadri³⁰, Ramachandran S Vasan^{28

29

31}, Nicholette D Palmer³², Barry I Freedman³³, Donald W Bowden³², Lisa R Yanek³⁴, Brian G Kral³⁴, Lewis C Becker³⁴, Patricia A Peyser³⁵, Lawrence F Bielak³⁵, Farah Ammous³⁵, April P Carson³⁶, Michael E Hall³⁶, Laura M Raffield³⁷, Stephen S Rich³⁸, Wendy S Post³⁹, Russel P Tracy⁴⁰, Kent D Taylor⁴¹, Xiuqing Guo⁴¹, Michael C Mahaney⁴², Joanne E Curran⁴², John Blangero⁴², Shoa L Clarke^{43

44

45}, Jeffrey W Haessler⁴⁶, Yao Hu⁴⁶, Themistocles L Assimes^{43

44

45}, Charles Kooperberg⁴⁶, Jürgen Bernhagen^{1

3

47}, Christopher D Anderson^{2

9

10}, Scott M Damrauer^{7

8

48}, Ramin Zand^{49

50}, Jerome I Rotter⁴¹, Paul S de Vries⁴, Martin Dichgans^{1

3

51

47}

Affiliations

¹ Institute for Stroke and Dementia Research (ISD), University Hospital, Ludwig-Maximilians-University (LMU), Munich, Germany.
² Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
⁴ 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.
⁵ Department of Molecular and Functional Genomics, Geisinger Health System, Danville, Pennsylvania, USA.
⁶ Veterans Affairs Healthcare System, Boston, MA, USA.
⁷ Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
⁸ Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, USA.
⁹ Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹⁰ Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
¹¹ Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.
¹² Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, MD.
¹³ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁴ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁵ The Center for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁶ Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁷ Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁸ Department of Radiology, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁹ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
²⁰ Department of Health Systems and Population Health, University of Washington, Seattle, WA, USA.
²¹ Department of Epidemiology, University of Washington, Seattle, WA, USA.
²² Department of Neurology, University of Washington, Seattle, WA, USA.
²³ Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora CO, USA.
²⁴ Department of Population Medicine, PRecisiOn Medicine Translational Research (PROMoTeR) Center, Harvard Pilgrim Health Care and Harvard Medical School, Boston, MA, USA.
²⁵ Department of Biostatistics, T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
²⁶ Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
²⁷ Department of Biostatistics, University of Washington, Seattle, WA, USA.
²⁸ Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
²⁹ Boston University and National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA.
³⁰ Bigg's Institute for Alzheimer's Disease and neurodegenerative disorders, University of Texas Health Science Center, San Antonio, TX, USA.
³¹ Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
³² Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
³³ Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
³⁴ Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³⁵ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
³⁶ Department of Medicine, University of Mississippi Medical Center, Jackson, MS.
³⁷ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC.
³⁸ Center for Public Health Genomics, University of Virginia, Charlottesville, VA USA.
³⁹ Johns Hopkins Bloomberg School of Public Health, Johns Hopkins School of Medicine, Baltimore, MD USA.
⁴⁰ Departments of Pathology & Laboratory Medicine, and Biochemistry, Larner College of Medicine, University of Vermont, Burlington, VT USA.
⁴¹ 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.
⁴² Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville TX USA.
⁴³ Department of Medicine (Division of Cardiovascular Medicine), Stanford University School of Medicine, Stanford, CA, USA.
⁴⁴ Stanford Cardiovascular Institute, Stanford, CA, USA.
⁴⁵ VA Palo Alto Health Care System, Palo Alto, CA, USA.
⁴⁶ Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle WA 98109 USA.
⁴⁷ German Centre for Cardiovascular Research (DZHK, Munich), partner site Munich Heart Alliance, Munich, Germany.
⁴⁸ Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
⁴⁹ Department of Neurology, Pennsylvania State University, Hershey, Pennsylvania, USA.
⁵⁰ Department of Neurology, Neuroscience Institute, Geisinger Health System, Danville, PA, USA.
⁵¹ German Centre for Neurodegenerative Diseases (DZNE), Munich, Germany.

Abstract

Background: Previous work has shown a role of CCL2, a key chemokine governing monocyte trafficking, in atherosclerosis. However, it remains unknown whether targeting CCR2, the cognate receptor of CCL2, provides protection against human atherosclerotic cardiovascular disease.

Methods: Computationally predicted damaging or loss-of-function (REVEL>0.5) variants within CCR2 were detected in whole-exome-sequencing data from 454,775 UK Biobank participants and tested for association with cardiovascular endpoints in gene-burden tests. Given the key role of CCR2 in monocyte mobilization, variants associated with lower monocyte count were prioritized for experimental validation. The response to CCL2 of human cells transfected with these variants was tested in migration and cAMP assays. Validated damaging variants were tested for association with cardiovascular endpoints, atherosclerosis burden, and vascular risk factors. Significant associations were replicated in six independent datasets (n=1,062,595).

Results: Carriers of 45 predicted damaging or loss-of-function CCR2 variants (n=787 individuals) were at lower risk of myocardial infarction and coronary artery disease. One of these variants (M249K, n=585, 0.15% of European ancestry individuals) was associated with lower monocyte count and with both decreased downstream signaling and chemoattraction in response to CCL2. While M249K showed no association with conventional vascular risk factors, it was consistently associated with a lower risk of myocardial infarction (Odds Ratio [OR]: 0.66 95% Confidence Interval [CI]: 0.54-0.81, p=6.1×10^-5) and coronary artery disease (OR: 0.74 95%CI: 0.63-0.87, p=2.9×10^-4) in the UK Biobank and in six replication cohorts. In a phenome-wide association study, there was no evidence of a higher risk of infections among M249K carriers.

Conclusions: Carriers of an experimentally confirmed damaging CCR2 variant are at a lower lifetime risk of myocardial infarction and coronary artery disease without carrying a higher risk of infections. Our findings provide genetic support for the translational potential of CCR2-targeting as an atheroprotective approach.

Keywords: CCR2; atherosclerosis; cardiovascular disease; genetics; inflammation.

Publication types

Preprint

Abstract

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