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Association between serum level of C-reactive protein and risk of cardiovascular events based on cohort studies

Abstract

Although the association between serum level of C-reactive protein (CRP) and risk of cardiovascular events (CVEs) has been reported, the comprehensive assessment of the quantitative association of CRP level with risk of CVEs has not been reported. Our meta-analysis aims to quantitatively evaluate the association of CRP level and risk of CVEs. We searched PubMed and Embase databases for articles published up to December 6, 2019. Studies with data on men and women, different types of CVEs and multiple cohorts within a study were treated as independent studies. Generalized least-squares regression models were used to assess the quantitative association between CRP level and risk of CVEs. Restricted cubic splines were used to model the possible linear association between CRP and CVEs. We included 36 articles (60 studies; 227,715 participants) in the analysis. The pooled relative risks (RRs) of high versus low CRP level for cardiovascular disease (CVD), stroke and coronary heart disease (CHD) were 1.64 (95% confidence interval [CI], 1.49–1.82), 1.46 (95% CI, 1.35–1.58), and 1.55 (95% CI, 1.47–1.63), respectively. A linear association was found between CRP level and CVD (P = 0.429), stroke (P = 0.940), and CHD (P = 0.931); with each 1-mg/L increase in CRP level, the pooled RRs for CVD, stroke, and CHD were 1.18 (95% CI, 1.12–1.24), 1.07 (95% CI, 1.04–1.09), and 1.12 (95% CI, 1.08–1.16), respectively. This meta-analysis suggests that risk of CVEs increases with increasing serum CRP level.

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Fig. 1
Fig. 2: Forest plot of relative risk statistics for cardiovascular disease per 1-mg/L increase in serum level of C-reactive protein.
Fig. 3: Forest plot of relative risk statistics for stroke per 1-mg/L increase in serum level of C-reactive protein.
Fig. 4: Forest plot of relative risk statistics for coronary heart disease per 1-mg/L increase in serum level of C-reactive protein.
Fig. 5: Linear association between serum level of C-reactive protein and risk of cardiovascular events modeled by using restricted cubic splines.

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References

  1. Ritchey MD, Wall HK, Owens PL, Wright JS. Vital signs: state-level variation in nonfatal and fatal cardiovascular events targeted for prevention by million hearts 2022. Mmwr Morbidity Mortal Wkly Rep. 2018;67:974–82.

    Article  Google Scholar 

  2. Roth GA, Mensah GA, Johnson CO, Addolorato G, Ammirati E, Baddour LM, et al. Global burden of cardiovascular diseases and risk factors, 1990-2019: update from the GBD 2019 study. J Am Coll Cardiol. 2020;76:2982–3021.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest. 2003;111:1805–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N. Engl J Med. 2002;347:1557–65.

    Article  CAS  PubMed  Google Scholar 

  5. Nisa H, Hirata A, Kohno M, Kiyohara C, Ohnaka K. High-sensitivity C-reactive protein and risks of all-cause and cause-specific mortality in a Japanese population. Asian Pac J cancer Prev. 2016;17:2643–8.

    PubMed  Google Scholar 

  6. Li Y, Zhong X, Cheng G, Zhao C, Zhang L, Hong Y, et al. Hs-CRP and all-cause, cardiovascular, and cancer mortality risk: a meta-analysis. Atherosclerosis. 2017;259:75–82.

    Article  CAS  PubMed  Google Scholar 

  7. Ross R. Atherosclerosis-an inflammatory disease. N. Engl J Med. 1999;340:115–26.

    Article  CAS  PubMed  Google Scholar 

  8. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N. Engl J Med. 2000;342:836–43.

    Article  CAS  PubMed  Google Scholar 

  9. Kuo HK, Yen CJ, Chang CH, Kuo CK, Chen JH, Sorond F. Relation of C-reactive protein to stroke, cognitive disorders, and depression in the general population: systematic review and meta-analysis. Lancet Neurol. 2005;4:371–80.

    Article  CAS  PubMed  Google Scholar 

  10. McBride JD, Cooper MA. A high sensitivity assay for the inflammatory marker C-reactive protein employing acoustic biosensing. J Nanobiotechnol. 2008;6:5.

    Article  CAS  Google Scholar 

  11. Kelley-Hedgepeth A, Lloyd-Jones DM, Colvin A, Matthews KA, Johnston J, Sowers MR, et al. Ethnic differences in C-reactive protein concentrations. Clin Chem. 2008;54:1027–37.

    Article  CAS  PubMed  Google Scholar 

  12. DI B, R F, M F, K R, M H. C-Reactive protein as a risk factor for coronary heart disease: a systematic review and meta-analyses for the U.S. Prev Serv Task Force Ann Intern Med. 2009;151:483–95.

    Google Scholar 

  13. Saito I, Maruyama K, Eguchi E. C-reactive protein and cardiovascular disease in east asians: a systematic review. Clin Med Insights Cardiol. 2014;2014:35–42.

    Google Scholar 

  14. Xu T, Ke K. C-reactive protein and ischemic stroke risk in general population: a dose-response meta-analysis of prospective studies. Int J Cardiol. 2015;190:264–7.

    Article  PubMed  Google Scholar 

  15. E B, J L, M W, JC M. Blood-borne biomarkers of mortality risk: systematic review of cohort studies. PLoS ONE. 2015;10:0127550.

    Article  CAS  Google Scholar 

  16. Zhou Y, Han W, Gong D, Man C, Fan Y. Hs-CRP in stroke: a meta-analysis. Clin Chim Acta. 2016;453:21–7.

    Article  CAS  PubMed  Google Scholar 

  17. Wells GASB, O’Connell D, Peterson J, Welch V, Losos M, Tugwell P The Newcastle–Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analysis. Ottawa (Canada): Ottawa Health Research Institute; 2019.

  18. Orsini N, Li R, Wolk A, Khudyakov P, Spiegelman D. Meta-analysis for linear and nonlinear dose-response relations: examples, an evaluation of approximations, and software. Am J Epidemiol. 2012;175:66–73.

    Article  PubMed  Google Scholar 

  19. Bekkering GE, Harris RJ, Thomas S, Mayer AM, Beynon R, Ness AR, et al. How much of the data published in observational studies of the association between diet and prostate or bladder cancer is usable for meta-analysis? Am J Epidemiol. 2008;167:1017–26.

    Article  PubMed  Google Scholar 

  20. Orsini N. Generalized least squares for trend estimation of summarized dose–response data. Stata J. 2006;6:40–57.

    Article  Google Scholar 

  21. Bagnardi V, Zambon A, Quatto P, Corrao G. Flexible meta-regression functions for modeling aggregate dose-response data, with an application to alcohol and mortality. Am J Epidemiol. 2004;159:1077–86.

    Article  PubMed  Google Scholar 

  22. DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clin Trials. 1986;7:177–88.

    Article  CAS  PubMed  Google Scholar 

  23. Greenland S. Dose-response and trend analysis in epidemiology: alternatives to categorical analysis. Epidemiology. 1995;6:356–65.

    Article  CAS  PubMed  Google Scholar 

  24. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60.

    PubMed  PubMed Central  Google Scholar 

  25. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088–101.

    Article  CAS  PubMed  Google Scholar 

  26. Li ZH, Zhong WF, Lv YB, Kraus VB, Gao X, Chen PL et al. Associations of plasma high-sensitivity C-reactive protein concentrations with all-cause and cause-specific mortality among middle-aged and elderly individuals. Immunit Ageing. 2019;16:28.

  27. Dong Y, Wang X, Zhang L, Chen Z, Zheng C, Wang J, et al. High-sensitivity C reactive protein and risk of cardiovascular disease in China-CVD study. J Epidemiol Community Health. 2019;73:188–92.

    Article  PubMed  Google Scholar 

  28. Lin YH, Glei D, Weinstein M, Wu SI, Chien KL. Additive value of interleukin-6 and C-reactive protein in risk prediction for all-cause and cardiovascular mortality among a representative adult cohort in Taiwan. J Formos Med Assoc. 2017;116:982–92.

    Article  CAS  PubMed  Google Scholar 

  29. Sung KC, Ryu S, Chang Y, Byrne CD, Kim SH. C-reactive protein and risk of cardiovascular and all-cause mortality in 268 803 East Asians. Eur Heart J. 2014;35:1809–16.

    Article  CAS  PubMed  Google Scholar 

  30. Patterson C, Smith AE, Yarnell JWG, Rumley A, Ben-Shlomo Y, Lowe GDO. The associations of interleukin-6 (IL-6) and downstream inflammatory markers with risk of cardiovascular disease: The Caerphilly Study. Atherosclerosis. 2010;209:551–7.

    Article  CAS  PubMed  Google Scholar 

  31. M H, Y C, E S. Association of very highly elevated C-reactive protein concentration with cardiovascular events and all-cause mortality. Clin Chem. 2010;56:132–5.

    Article  Google Scholar 

  32. S J, Y B, X H, Q F, C W, J P, et al. Serum C-reactive protein and risk of cardiovascular events in middle-aged and older Chinese population. Am J Cardiol. 2009;103:1727–31.

    Article  CAS  Google Scholar 

  33. Elkind MSV, Luna JM, Moon YP, Liu KM, Spitalnik SL, Paik MC, et al. High-sensitivity C-reactive protein predicts mortality but not stroke: The Northern Manhattan Study. Neurology. 2009;73:1300–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wilson PW, Pencina M, Jacques P, Selhub J, D’Agostino Sr R, O’Donnell CJ. C-reactive protein and reclassification of cardiovascular risk in the Framingham Heart Study. Circulation. 2008;1:92–7.

    PubMed  Google Scholar 

  35. Jeppesen J, Hansen TW, Olsen MH, Rasmussen S, Ibsen H, Torp-Pedersen C, et al. C-reactive protein, insulin resistance and risk of cardiovascular disease: a population-based study. Eur J Cardiovasc Prev Rehab. 2008;15:594–8.

    Article  Google Scholar 

  36. Arima H, Kubo M, Yonemoto K, Doi Y, Ninomiya T, Tanizaki Y, et al. High-sensitivity c-reactive protein and coronary heart disease in a general population of Japanese: The Hisayama study. Arterioscler Thromb Vasc Biol. 2008;28:1385–91.

    Article  CAS  PubMed  Google Scholar 

  37. Koenig W, Khuseyinova N, Baumert J, Meisinger C. Prospective study of high-sensitivity C-reactive protein as a determinant of mortality: Results from the MONICA/KORA Augsburg cohort study, 1984-1998. Clin Chem. 2008;54:335–42.

    Article  CAS  PubMed  Google Scholar 

  38. R D, P G, BH N, D’ Agostino RBS, PW W, EJ B, et al. C-reactive protein, inflammatory conditions, and cardiovascular disease risk. Am J Med. 2007;120:1054–62.

    Article  CAS  Google Scholar 

  39. Tzoulaki I, Murray GD, Lee AJ, Rumley A, Lowe GDO, Fowkes FGR. Relative value of inflammatory, hemostatic, and rheological factors for incident myocardial infarction and stroke: The Edinburgh artery study. Circulation. 2007;115:2119–27.

    Article  PubMed  Google Scholar 

  40. Evans CR, Long DL, Howard G, McClure LA, Zakai NA, Jenny NS, et al. C-reactive protein and stroke risk in blacks and whites: The REasons for Geographic And Racial Differences in Stroke cohort. Am Heart J. 2019;217:94–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wang GL, Zhang R, Zhou YT, Wang AL, Xu T, Zhang MZ, et al. Combined effects of a body shape index and serum C-reactive protein on ischemic stroke incidence among Mongolians in China. Biomed Environ Sci. 2019;32:169–76.

    PubMed  Google Scholar 

  42. Eltoft A, Arntzen KA, Wilsgaard T, Hansen JB, Mathiesen EB, Johnsen SH. Joint effect of carotid plaque and C-reactive protein on first-ever ischemic stroke and myocardial infarction? J Am Heart Assoc. 2018;7:e008951.

  43. Parrinello CM, Lutsey PL, Ballantyne CM, Folsom AR, Pankow JS, Selvin E. Six-year change in high-sensitivity C-reactive protein and risk of diabetes, cardiovascular disease, and mortality. Am Heart J. 2015;170:380–9.e4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Liu Y, Wang J, Zhang L, Wang C, Wu J, Zhou Y, et al. Relationship between C-reactive protein and stroke: a large prospective community based study. PLoS ONE. 2014;9:e107017.

  45. Van Wijk DF, Boekholdt SM, Wareham NJ, Ahmadi-Abhari S, Kastelein JJP, Stroes ESG, et al. C-reactive protein, fatal and nonfatal coronary artery disease, stroke, and peripheral artery disease in the prospective EPIC-norfolk cohort study. Arterioscler Thromb Vasc Biol. 2013;33:2888–94.

    Article  PubMed  CAS  Google Scholar 

  46. Makita S, Nakamura M, Satoh K, Tanaka F, Onoda T, Kawamura K, et al. Serum C-reactive protein levels can be used to predict future ischemic stroke and mortality in Japanese men from the general population. Atherosclerosis. 2009;204:234–8.

    Article  CAS  PubMed  Google Scholar 

  47. Wakugawa Y, Kiyohara Y, Tanizaki Y, Kubo M, Ninomiya T, Hata J, et al. C-reactive protein and risk of first-ever ischemic and hemorrhagic stroke in a general Japanese population: The Hisayama study. Stroke. 2006;37:27–32.

    Article  CAS  PubMed  Google Scholar 

  48. Bos MJ, Schipper CMA, Koudstaal PJ, Witteman JCM, Hofman A, Breteler MMB. High serum C-reactive protein level is not an independent predictor for stroke: The Rotterdam Study. Circulation. 2006;114:1591–8.

    Article  CAS  PubMed  Google Scholar 

  49. Cesari M, Penninx BWJH, Newman AB, Kritchevsky SB, Nicklas BJ, Sutton-Tyrrell K, et al. Inflammatory markers and onset of cardiovascular events: results from the Health ABC Study. Circulation. 2003;108:2317–22.

  50. Cao JJ, Thach C, Manolio TA, Psaty BM, Kuller LH, Chaves PH, et al. C-reactive protein, carotid intima-media thickness, and incidence of ischemic stroke in the elderly: the Cardiovascular Health Study. Circulation. 2003;108:166–70.

    Article  CAS  PubMed  Google Scholar 

  51. Rost NS, Wolf PA, Kase CS, Kelly-Hayes M, Silbershatz H, Massaro JM, et al. Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: The Framingham Study. Stroke. 2001;32:2575–9.

    Article  CAS  PubMed  Google Scholar 

  52. Wu Z, Huang Z, Jin W, Rimm EB, Lichtenstein AH, Kris-Etherton PM, et al. Peripheral inflammatory biomarkers for myocardial infarction risk: A prospective community-based study. Clin Chem. 2017;63:663–72.

    Article  CAS  PubMed  Google Scholar 

  53. Sugiyama T, Ishikawa S, Kotani K, Gotoh T, Itoh Y, Kayaba K, et al. Relationship between serum high-sensitivity C-reactive protein and myocardial infarction in a general Japanese population. J Clin Lab Anal. 2016;30:999–1002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Horvei LD, Braekkan SK, Mathiesen E, Njolstad I, Wilsgaard T, Brox J, et al. Obesity measures, CRP and risk of venous thromboembolism and myocardial infarction. J Thromb Haemost. 2015;2:17.

    Google Scholar 

  55. Veeranna V, Zalawadiya SK, Panaich S, Patel KV, Afonso L. Comparative analysis of red cell distribution width and high sensitivity C-reactive protein for coronary heart disease mortality prediction in multi-ethnic population: findings from the 1999–2004 NHANES. Int J Cardiol. 2013;168:5156–61.

  56. Straczek C, Ducimetiere P, Barberger-Gateau P, Helmer C, Ritchie K, Jouven X, et al. Higher level of systemic C-Reactive protein is independently predictive of coronary heart disease in older community-dwelling adults: The three-city study. J Am Geriatrics Soc. 2010;58:129–35.

    Article  Google Scholar 

  57. Kardys I, Knetsch AM, Bleumink GS, Deckers JW, Hofman A, Stricker BHC, et al. C-reactive protein and risk of heart failure. The Rotterdam Study. Am Heart J. 2006;152:514–20.

    Article  CAS  PubMed  Google Scholar 

  58. M C, AM A, BM P, TA M, LH K, GL B, et al. C-reactive protein and the 10-year incidence of coronary heart disease in older men and women The Cardiovascular Health Study. Circulation. 2005;112:25–31.

    Article  CAS  Google Scholar 

  59. Lowe GD, Sweetnam PM, Yarnell JW, Rumley A, Rumley C, Bainton D, et al. C-reactive protein, fibrin D-dimer, and risk of ischemic heart disease: the Caerphilly and Speedwell studies. Arterioscler Thromb Vasc Biol. 2004;24:1957–62.

    Article  CAS  PubMed  Google Scholar 

  60. Mendall MA, Strachan DP, Butland BK, Ballam L, Morris J, Sweetnam PM, et al. C-reactive protein: relation to total mortality, cardiovascular mortality and cardiovascular risk factors in men. Eur Heart J. 2000;21:1584–90.

    Article  CAS  PubMed  Google Scholar 

  61. Benzaquen LR, Yu H, Rifai N. High sensitivity C-reactive protein: an emerging role in cardiovascular risk assessment. Crit Rev Clin Lab Sci. 2002;39:459–97.

    Article  CAS  PubMed  Google Scholar 

  62. Fonseca FA, Izar MC. High-sensitivity C-reactive protein and cardiovascular disease across countries and ethnicities. Clinics (Sao Paulo, Braz). 2016;71:235–42.

    Article  Google Scholar 

  63. Carlson CS, Aldred SF, Lee PK, Tracy RP, Schwartz SM, Rieder M, et al. Polymorphisms within the C-reactive protein (CRP) promoter region are associated with plasma CRP levels. Am J Hum Genet. 2005;77:64–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation. 2000;102:2165–8.

    Article  CAS  PubMed  Google Scholar 

  65. Pasceri V, Cheng JS, Willerson JT, Yeh ET. Modulation of C-reactive protein-mediated monocyte chemoattractant protein-1 induction in human endothelial cells by anti-atherosclerosis drugs. Circulation. 2001;103:2531–4.

    Article  CAS  PubMed  Google Scholar 

  66. Han Y, Wu S, Hu Q, Xiao JQ, Wei DM, Liu LL, et al. Thrombomodulin and high-sensitive C-reactive protein Levels in blood correlate with the development of cerebral infarction among Asians. Mol Neurobiol. 2016;53:2659–67.

    Article  CAS  PubMed  Google Scholar 

  67. Maekawa Y, Nagai T, Anzai A. Pentraxins: CRP and PTX3 and cardiovascular disease. Inflamm Allergy Drug targets. 2011;10:229–35.

    Article  CAS  PubMed  Google Scholar 

  68. Calabrò P, Golia E, Yeh ET. CRP and the risk of atherosclerotic events. Semin Immunopathol. 2009;31:79–94.

    Article  PubMed  CAS  Google Scholar 

  69. Montecucco F, Mach F. New evidences for C-reactive protein (CRP) deposits in the arterial intima as a cardiovascular risk factor. Clin Interv Aging. 2008;3:341–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Siegel D, Devaraj S, Mitra A, Raychaudhuri SP, Raychaudhuri SK, Jialal I. Inflammation, atherosclerosis, and psoriasis. Clin Rev Allergy Immunol. 2013;44:194–204.

    Article  CAS  PubMed  Google Scholar 

  71. Hage FG. C-reactive protein and hypertension. J Hum Hypertens. 2014;28:410–5.

    Article  CAS  PubMed  Google Scholar 

  72. Conen D, Zeller A, Pfisterer M, Martina B. Usefulness of B-type natriuretic peptide and C-reactive protein in predicting the presence or absence of left ventricular hypertrophy in patients with systemic hypertension. Am J Cardiol. 2006;97:249–52.

    Article  CAS  PubMed  Google Scholar 

  73. Iwashima Y, Horio T, Kamide K, Rakugi H, Ogihara T, Kawano Y. C-reactive protein, left ventricular mass index, and risk of cardiovascular disease in essential hypertension. Hypertens Res. 2007;30:1177–85.

    Article  CAS  PubMed  Google Scholar 

  74. Tsioufis C, Dimitriadis K, Andrikou E, Thomopoulos C, Tsiachris D, Stefanadi E, et al. ADMA, C-reactive protein, and albuminuria in untreated essential hypertension: a cross-sectional study. Am J Kidney Dis. 2010;55:1050–9.

    Article  CAS  PubMed  Google Scholar 

  75. Li XY, Xu M, Wang JG, Wang XJ, Huang Y, Cheng Q, et al. Serum C-reactive protein (CRP) and microalbuminuria in relation to fasting and 2-h postload plasma glucose in a Chinese population. Clin Endocrinol. 2009;70:691–7.

    Article  CAS  Google Scholar 

  76. Mugabo Y, Li L, Renier G. The connection between C-reactive protein (CRP) and diabetic vasculopathy. Focus on preclinical findings. Curr Diabetes Rev. 2010;6:27–34.

    Article  CAS  PubMed  Google Scholar 

  77. Nordestgaard BG, Zacho J. Lipids, atherosclerosis and CVD risk: is CRP an innocent bystander? Nutr Metab Cardiovasc Dis. 2009;19:521–4.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We acknowledge all the authors for methodological advice and help to modify the meta-analysis, and the following financial support.

Funding

This work was supported by the National Natural Science Foundation of China (grant nos. 81373074, 81402752, and 81673260); the Natural Science Foundation of Guangdong Province (grant no. 2017A030313452).

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XY conceived, designed, analyzed data, and performed the work; YF, YZhao, YL, MH, RQ, SH, CG, QL, QZ, GT, XW, YW, DL, YZhang, DZ, CC, DH, LS revised the manuscript.

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Correspondence to Dongsheng Hu or Liang Sun.

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Yang, X., Zhang, D., Zhao, Y. et al. Association between serum level of C-reactive protein and risk of cardiovascular events based on cohort studies. J Hum Hypertens 35, 1149–1158 (2021). https://doi.org/10.1038/s41371-021-00546-z

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