Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality-Reference-Cited by-同舟云学术

Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality

Published:2021-03-22 Issue:18 Volume:42 Page:1742-1756
ISSN:0195-668X
Container-title:European Heart Journal
language:en
Short-container-title:

Author:

Schunk Stefan J¹,Kleber Marcus E²³^ORCID,März Winfried²⁴⁵,Pang Shichao⁶^ORCID,Zewinger Stephen¹,Triem Sarah¹,Ege Philipp¹,Reichert Matthias C⁷^ORCID,Krawczyk Marcin⁷⁸,Weber Susanne N⁷,Jaumann Isabella¹,Schmit David¹,Sarakpi Tamim¹,Wagenpfeil Stefan⁹^ORCID,Kramann Rafael¹⁰¹¹^ORCID,Boerwinkle Eric¹²¹³,Ballantyne Christie M¹⁴¹⁵,Grove Megan L¹²,Tragante Vinicius¹⁶^ORCID,Pilbrow Anna P¹⁷^ORCID,Richards A Mark¹⁷^ORCID,Cameron Vicky A¹⁷^ORCID,Doughty Robert N¹⁸,Dubé Marie-Pierre¹⁹²⁰,Tardif Jean-Claude¹⁹²⁰^ORCID,Feroz-Zada Yassamin¹⁹,Sun Maxine²⁰,Liu Chang²¹^ORCID,Ko Yi-An²²^ORCID,Quyyumi Arshed A²¹,Hartiala Jaana A²³^ORCID,Tang W H Wilson²⁴²⁵^ORCID,Hazen Stanley L²⁴²⁵^ORCID,Allayee Hooman²³^ORCID,McDonough Caitrin W²⁶^ORCID,Gong Yan²⁶^ORCID,Cooper-DeHoff Rhonda M²⁶²⁷,Johnson Julie A²⁶²⁷,Scholz Markus²⁸²⁹^ORCID,Teren Andrej²⁹³⁰,Burkhardt Ralph²⁹³¹^ORCID,Martinsson Andreas³²,Smith J Gustav³³,Wallentin Lars³⁴³⁵^ORCID,James Stefan K³⁴³⁵,Eriksson Niclas³⁴³⁵^ORCID,White Harvey³⁶^ORCID,Held Claes³⁴³⁵^ORCID,Waterworth Dawn³⁷^ORCID,Trompet Stella³⁸,Jukema J Wouter³⁹⁴⁰^ORCID,Ford Ian⁴¹^ORCID,Stott David J⁴²^ORCID,Sattar Naveed⁴³^ORCID,Cresci Sharon⁴⁴⁴⁵^ORCID,Spertus John A⁴⁶^ORCID,Campbell Hannah⁴⁴⁴⁵,Tierling Sascha⁴⁷,Walter Jörn⁴⁷^ORCID,Ampofo Emmanuel⁴⁸,Niemeyer Barbara A⁴⁹^ORCID,Lipp Peter⁵⁰^ORCID,Schunkert Heribert⁶⁵¹,Böhm Michael⁵²,Koenig Wolfgang⁶⁵¹⁵³^ORCID,Fliser Danilo¹,Laufs Ulrich⁵⁴^ORCID,Speer Thimoteus¹⁵⁵^ORCID, ,

Affiliation:

1. Department of Internal Medicine IV, Nephrology and Hypertension, Saarland University Hospital, Kirrberger Strasse, Building 41, 66424 Homburg/Saar, Germany

2. Vth Department of Medicine, University Heidelberg, Mannheim Medical Faculty, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany

3. SYNLAB MVZ Humangenetik Mannheim, Harrlachweg 1, 68163 Mannheim, Germany

4. Clinical Institute of Medical and Laboratory Diagnostics, Medical University Graz, Auenbruggerpl. 2, 8036 Graz, Austria

5. Synlab Academy, Synlab Holding GmbH, Harrlachweg 1, 68163 Mannheim, Germany

6. Kardiologie, Deutsches Herzzentrum München, Technische Universität München, Lazarettstraße 36, 80636 Munich, Germany

7. Department of Medicine II, Saarland University Medical Center, Kirrberger Straße, 66424 Homburg, Germany

8. Laboratory of Metabolic Liver Diseases, Centre for Preclinical Research, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, ul. Banacha 1B, CePT, 02-097 Warsaw, Poland

9. Institute of Medical Biometry, Epidemiology & Medical Informatics, Saarland University Campus Homburg/Saar, Kirrberger Straße, 66424 Homburg/Saar, Germany

10. Division of Nephrology and Clinical Immunology, RWTH Aachen University, Pauwelsstrasse 30 52074 Aachen, Germany

11. Institute of Experimental Medicine and Systems Biology, RWTH, Pauwelsstraße 30, 52074 Aachen, Germany

12. Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, 1200 Pressler Street, Houston, TX 77030, USA

13. Human Genome Sequencing Center, Baylor College of Medicine, BCM226, Houston, TX 77030, USA

14. Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA

15. Center of Cardiovascular Disease Prevention, Methodist DeBakey Heart and Vascular Center, 6565 Fannin St, Houston, TX 77030, USA

16. Department of Cardiology, Heart and Lungs Division, UMC Utrecht, Heidelberglaan 100 3584 CX Utrecht, Netherlands

17. The Christchurch Heart Institute, University of Otago Christchurch, 2 Riccarton Avenue, Christchurch Central City, Christchurch 8011, New Zealand

18. Heart Health Research Group, University of Auckland, Level 2 / 22-30 Park Ave, Grafton, Auckland, New Zealand

19. Montreal Heart Institute, 5000 Rue Bélanger, Montreal QC H1T 1C8, Canada

20. Faculty of Medicine, Université der Montréal, Pavillon Roger-Gaudry, 2900 Edouard Montpetit Blvd, Montreal, Quebec H3T 1J4, Canada

21. Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Emory University School of Medicine, 1462 Clifton Road NE, Atlanta, GA 30322, USA

22. Department of Biostatistics and Bioinformatics, Rollins School of Public Healthy, Emory University, 1518 Clifton Road NE, Atlanta, GA 30322, USA

23. Department of Preventive Medicine, University of Southern California, Keck School of Medicine, 2001 N. Soto St. Los Angeles, CA 90033, USA

24. Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, USA

25. Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave, NB 21, Cleveland, OH 44195, USA

26. Department of Pharmacotherapy and Translational Research, University of Florida, College of Pharmacy, 1225 Center Drive, HPNP Building, Gainesville, FL 32610-0486, USA

27. Division of Cardiovascular Medicine, Department of Medicine, University of Florida, 1600 SW Archer Rd, Gainesville, FL 32610, USA

28. Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Härtelstraße 16-18, 04107 Leipzig, Germany

29. LIFE Research Center for Civilization Diseases, University of Leipzig, Härtelstraße 16-18, 04107 Leipzig, Germany

30. Heart Center Leipzig, Strümpellstraße 39, 04289 Leipzig, Germany

31. Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg,Germany

32. Department of Cardiology, Sahlgrenska University Hospital, Blå stråket 5, 413 45 Göteborg, Sweden

33. Department of Cardiology, Clinical Sciences, Lund University and Skane University Hospital, BMC F12, 221 84 Lund, Sweden

34. Department of Medical Sciences, Cardiology, Uppsala University, Akademiska sjukhuset Entrance 40, 751 85 Uppsala, Sweden

35. Uppsala Clinical Research Center, Uppsala University, Dag Hammarskjölds Väg 38, 751 85 Uppsala, Sweden

36. Green Lane Cardiovascular Service, Auckland City Hospital, 2 Park Road, Grafton, Auckland 1023, New Zealand

37. Genetics, GlaxoSmithKline, 709 Swedeland Rd, King of Prussia, PA 19406, USA

38. Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands

39. Department of Cardiology, Leiden University Medical Cernter, Albinusdreef 2, 2333 ZA Leiden, The Netherlands

40. Netherlands Heart Institute, Moreelsepark 1, 3511 EP Utrecht, The Netherlands

41. Robertson Centre for Biostatistics, University of Glasgow, Boyd Orr Building University Avenue, Glasgow G12 8QQ, UK

42. Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK

43. BHF Glasgow Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA UK

44. Washington University School of Medicine, 2300 I St NW, Washington, DC 20052, USA

45. Department of Medicine & Genetics, Campus Box 8232, 4515 McKinley Ave., St. Louis, MO 63110, USA

46. Saint Luke's Mid America Heart Institute and University of Missouri-Kansas City, 4401 Wornall Rd, Kansas City, MO 64111, USA

47. Faculty of Natural Sciences and Technology, Department of Genetics/Epigenetics, Saarland University, Postfach 151150, 66041 Saarbrücken, Germany

48. Institute of Clinical & Experimental Surgery, Saarland University, Kirrberger Straße, 66424 Homburg/Saar, Germany

49. Molecular Biophysics, CIPMM, Saarland University, Kirrberger Straße, 66424 Homburg/Saar, Germany

50. Center for Molecular Signaling (PZMS), Institute for Molecular Cell Biology, Research Center for Molecular Imaging and Screening, Medical Faculty, Saarland University, Kirrberger Straße, 66424 Homburg, Germany

51. Partner Site Munich Heart Alliance, German Centre of Cardiovascular Research (DZHK), Ismaninger Straße 22, 81675 Munich, Germany

52. Department of Internal Medicine III, Cardiology, Angiology, and Intensive Care Medicine, Saarland University Hospital, Kirrberger Strasse, Building 41, 66424 Homburg/Saar, Germany

53. Institute of Epidemiology and Medical Biometry, University of Ulm, Helmholtzstr. 22, 89081 Ulm, Germany

54. Department of Cardiology, University Medical Center Leipzig, Liebigstraße 20, Leipzig, Germany

55. Translational Cardio-Renal Medicine, Saarland University, Kirrberger Straße, 66424 Homburg/Saar, Germany

Abstract

Abstract Aims Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1β can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown. Methods and results We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality. Conclusion The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target.

Funder

Deutsche Forschungsgemeinschaft

European commission

German Federal Ministry of Education and Research

National Heart, Lung, and Blood Institute

National Institutes of Health

Department of Health and Human Services

National Human Genome Research Institute

NIH Roadmap for Medical Research

GeneBank

National Institutes for Health

NIH