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

被引：76

作者：

Schunk, Stefan J. ^{[1
]}

Kleber, Marcus E. ^{[2
,3
]}

Maerz, Winfried ^{[2
,4
,5
]}

Pang, Shichao ^{[6
]}

Zewinger, Stephen ^{[1
]}

Triem, Sarah ^{[1
]}

Ege, Philipp ^{[1
]}

Reichert, Matthias C. ^{[7
]}

Krawczyk, Marcin ^{[7
,8
]}

Weber, Susanne N. ^{[7
]}

Jaumann, Isabella ^{[1
]}

Schmit, David ^{[1
]}

Sarakpi, Tamim ^{[1
]}

Wagenpfeil, Stefan ^{[9
]}

Kramann, Rafael ^{[10
,11
]}

Boerwinkle, Eric ^{[12
,13
]}

Ballantyne, Christie M. ^{[14
,15
]}

Grove, Megan L. ^{[12
]}

Tragante, Vinicius ^{[16
]}

Pilbrow, Anna P. ^{[17
]}

Richards, A. Mark ^{[17
]}

Cameron, Vicky A. ^{[17
]}

Doughty, Robert N. ^{[18
]}

Dube, Marie-Pierre ^{[19
,20
]}

Tardif, Jean-Claude ^{[19
,20
]}

Feroz-Zada, Yassamin ^{[19
]}

Sun, Maxine ^{[20
]}

Liu, Chang ^{[21
]}

Ko, Yi-An ^{[22
]}

Quyyumi, Arshed A. ^{[21
]}

Hartiala, Jaana A. ^{[23
]}

Tang, W. H. Wilson ^{[24
,25
]}

Hazen, Stanley L. ^{[24
,25
]}

Allayee, Hooman ^{[23
]}

McDonough, Caitrin W. ^{[26
]}

Gong, Yan ^{[26
]}

Cooper-DeHoff, Rhonda M. ^{[26
,27
]}

Johnson, Julie A. ^{[26
,27
]}

Scholz, Markus ^{[28
,29
]}

Teren, Andrej ^{[29
,30
]}

Burkhardt, Ralph ^{[29
,31
]}

Martinsson, Andreas ^{[32
]}

Smith, J. Gustav ^{[33
,34
]}

Wallentin, Lars ^{[35
,36
]}

James, Stefan K. ^{[35
,36
]}

Eriksson, Niclas ^{[35
,36
]}

White, Harvey ^{[37
]}

Held, Claes ^{[35
,36
]}

Waterworth, Dawn ^{[38
]}

Trompet, Stella ^{[39
]}

机构：

[1] Saarland Univ Hosp, Dept Internal Med Nephrol & Hypertens 4, Kirrberger Str,Bldg 41, D-66424 Homburg, Germany

[2] Heidelberg Univ, Mannheim Med Fac, Dept Med 5, Theodor Kutzer Ufer 1-3, D-68167 Mannheim, Germany

[3] SYNLAB MVZ Humangenet Mannheim, Harrlachweg 1, D-68163 Mannheim, Germany

[4] Med Univ Graz, Clin Inst Med & Lab Diagnost, Auenbruggerpl 2, A-8036 Graz, Austria

[5] Synlab Holding GmbH, Synlab Acad, Harrlachweg 1, D-68163 Mannheim, Germany

[6] Tech Univ Munich, Deutsch Herzzentrum Munchen, Kardiol, Lazarettstr 36, D-80636 Munich, Germany

[7] Saarland Univ, Dept Med 2, Med Ctr, Kirrberger Str, D-66424 Homburg, Germany

[8] Med Univ Warsaw, Ctr Preclin Res, Dept Gen Transplant & Liver Surg, Lab Metab Liver Dis,CePT, Ul Banacha 1B, PL-02097 Warsaw, Poland

[9] Saarland Univ, Inst Med Biometry Epidemiol & Med Informat, Campus Homburg Saar,Kirrberger Str, D-66424 Homburg, Germany

[10] Rhein Westfal TH Aachen, Div Nephrol & Clin Immunol, Pauwelsstr 30, D-52074 Aachen, Germany

[11] Rhein Westfal TH Aachen, Inst Expt Med & Syst Biol, Pauwelsstr 30, D-52074 Aachen, Germany

[12] Univ Texas Hlth Sci Ctr Houston, Dept Epidemiol Human Genet & Environm Sci, Sch Publ Hlth, Human Genet Ctr, 1200 Pressler St, Houston, TX 77030 USA

[13] Baylor Coll Med, Human Genome Sequencing Ctr, BCM226, Houston, TX 77030 USA

[14] Baylor Coll Med, Dept Med, Sect Cardiovasc Res, One Baylor Plaza, Houston, TX 77030 USA

[15] Methodist DeBakey Heart & Vasc Ctr, Ctr Cardiovasc Dis Prevent, 6565 Fannin St, Houston, TX 77030 USA

[16] UMC Utrecht, Heart & Lungs Div, Dept Cardiol, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands

[17] Univ Otago Christchurch, Christchurch Heart Inst, 2 Riccarton Ave, Christchurch 8011, New Zealand

[18] Univ Auckland, Heart Hlth Res Grp, Level 2,22-30 Pk Ave, Auckland, New Zealand

[19] Montreal Heart Inst, 5000 Rue Belanger, Montreal, PQ H1T 1C8, Canada

[20] Univ Montreal, Fac Med, Pavillon Roger Gaudry,2900 Edouard Montpetit Blvd, Montreal, PQ H3T 1J4, Canada

[21] Emory Univ, Emory Clin Cardiovasc Res Inst, Div Cardiol, Sch Med, 1462 Clifton Rd NE, Atlanta, GA 30322 USA

[22] Emory Univ, Rollins Sch Publ Hlth, Dept Biostat & Bioinformat, 1518 Clifton Rd NE, Atlanta, GA 30322 USA

[23] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, 2001 N Soto St, Los Angeles, CA 90033 USA

[24] Cleveland Clin, Dept Cardiovasc Med, 9500 Euclid Ave, Cleveland, OH 44195 USA

[25] Cleveland Clin, Dept Cardiovasc & Metab Sci, Lerner Res Inst, 9500 Euclid Ave,NB 21, Cleveland, OH 44195 USA

[26] Univ Florida, Coll Pharm, Dept Pharmacotherapy & Translat Res, 1225 Ctr Dr,HPNP Bldg, Gainesville, FL 32610 USA

[27] Univ Florida, Dept Med, Div Cardiovasc Med, 1600 SW Archer Rd, Gainesville, FL 32610 USA

[28] Univ Leipzig, Inst Med Informat Stat & Epidemiol, Hartelstr 16-18, D-04107 Leipzig, Germany

[29] Univ Leipzig, LIFE Res Ctr Civilizat Dis, Hartelstr 16-18, D-04107 Leipzig, Germany

[30] Heart Ctr Leipzig, Strumpellstr 39, D-04289 Leipzig, Germany

[31] Univ Hosp Regensburg, Inst Clin Chem & Lab Med, Franz Josef Strauss Allee 11, D-93053 Regensburg, Germany

[32] Sahlgrens Univ Hosp, Dept Cardiol, Bla Straket 5, S-41345 Gothenburg, Sweden

[33] Lund Univ, Dept Cardiol, Clin Sci, BMC F12, S-22184 Lund, Sweden

[34] Skane Univ Hosp, BMC F12, S-22184 Lund, Sweden

[35] Uppsala Univ, Dept Med Sci, Cardiol, Akad Sjukhuset Entrance 40, S-75185 Uppsala, Sweden

[36] Uppsala Univ, Uppsala Clin Res Ctr, Dag Hammarskjolds Vag 38, S-75185 Uppsala, Sweden

[37] Auckland City Hosp, Green Lane Cardiovasc Serv, 2 Pk Rd, Auckland 1023, New Zealand

[38] GlaxoSmithKline, Genet, 709 Swedeland Rd, King Of Prussia, PA 19406 USA

[39] Leiden Univ, Dept Internal Med, Sect Gerontol & Geriatr, Med Ctr, Albinusdreef 2, NL-2333 ZA Leiden, Netherlands

[40] Leiden Univ, Dept Cardiol, Med Ctr, Albinusdreef 2, NL-2333 ZA Leiden, Netherlands

[41] Netherlands Heart Inst, Moreelsepk 1, NL-3511 EP Utrecht, Netherlands

[42] Univ Glasgow, Robertson Ctr Biostat, Boyd Orr Bldg,Univ Ave, Glasgow G12 8QQ, Lanark, Scotland

[43] Univ Glasgow, Coll Med Vet & Life Sci, Inst Cardiovasc & Med Sci, 126 Univ Pl, Glasgow G12 8TA, Lanark, Scotland

[44] Univ Glasgow, BHF Glasgow Res Ctr, Inst Cardiovasc & Med Sci, 126 Univ Pl, Glasgow G12 8TA, Lanark, Scotland

[45] Washington Univ, Sch Med, 2300 I St NW, Washington, DC 20052 USA

[46] Dept Med & Genet, Campus Box 8232,4515 McKinley Ave, St Louis, MO 63110 USA

[47] st Lukes Mid Amer Heart Inst, 4401 Wornall Rd, Kansas City, MO 64111 USA

[48] Univ Missouri, 4401 Wornall Rd, Kansas City, MO 64111 USA

[49] Saarland Univ, Fac Nat Sci & Technol, Dept Genet Epigenet, Postfach 151150, D-66041 Saarbrucken, Germany

[50] Saarland Univ, Inst Clin & Expt Surg, Kirrberger Str, D-66424 Homburg, Germany

来源：

EUROPEAN HEART JOURNAL | 2021年 / 42卷 / 18期

基金：

美国国家卫生研究院;

关键词：

Cardiovascular diseases; Coronary artery disease; Inflammation; Inflammasome; NLRP3; CORONARY-HEART-DISEASE; C-REACTIVE PROTEIN; BLOOD-PRESSURE; INTERLEUKIN-6; RECEPTOR; CLONAL HEMATOPOIESIS; ATHEROSCLEROSIS; RISK; AGE; HYPERTENSION; INHIBITOR;

D O I：

10.1093/eurheartj/ehab107

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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-1 beta 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 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. [GRAPHICS] .

引用

页码：1742 / 1756

页数：15

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