C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis

Emerging Risk Factors Collaboration, Stephen Kaptoge, Emanuele Di Angelantonio, Gordon Lowe, Mark B Pepys, Simon G Thompson, Rory Collins, John Danesh, R W Tipping, C E Ford, S L Pressel, G Walldius, I Jungner, A R Folsom, L Chambless, C M Ballantyne, D Panagiotakos, C Pitsavos, C Chrysohoou, C Stefanadis, M W Knuiman, U Goldbourt, M Benderly, D Tanne, P Whincup, S G Wannamethee, R W Morris, S Kiechl, J Willeit, A Mayr, G Schett, N Wald, S Ebrahim, D Lawlor, J Yarnell, J Gallacher, E Casiglia, V Tikhonoff, P J Nietert, S E Sutherland, D L Bachman, J E Keil, M Cushman, B M Psaty, R Tracy, A Tybjaerg-Hansen, B G Nordestgaard, J Zacho, R Frikke-Schmidt, S Giampaoli, L Palmieri, S Panico, D Vanuzzo, L Pilotto, A Gómez de la Cámara, J A Gómez Gerique, L Simons, J McCallum, Y Friedlander, F G R Fowkes, A Lee, J Taylor, J M Guralnik, C L Phillips, R B Wallace, J M Guralnik, C L Phillips, D G Blazer, J M Guralnik, C L Phillips, C L Phillips, J M Guralnik, K-T Khaw, H Brenner, E Raum, H Müller, D Rothenbacher, J-H Jansson, P Wennberg, A Nissinen, C Donfrancesco, S Giampaoli, V Salomaa, K Harald, P Jousilahti, E Vartiainen, M Woodward, R B D'Agostino, P A Wolf, R S Vasan, E J Benjamin, E-M Bladbjerg, T Jørgensen, L Møller, J Jespersen, R Dankner, A Chetrit, F Lubin, A Rosengren, L Wilhelmsen, G Lappas, H Eriksson, C Björkelund, L Lissner, C Bengtsson, P Cremer, D Nagel, R S Tilvis, T E Strandberg, Y Kiyohara, H Arima, Y Doi, T Ninomiya, B Rodriguez, J Dekker, G Nijpels, C D A Stehouwer, E Rimm, J K Pai, S Sato, H Iso, A Kitamura, H Noda, U Goldbourt, J T Salonen, K Nyyssönen, T-P Tuomainen, J A Laukkanen, D J H Deeg, M A Bremmer, T W Meade, J A Cooper, B Hedblad, G Berglund, G Engström, W M M Verschuren, A Blokstra, M Cushman, A R Folsom, B M Psaty, S Shea, A Döring, W Koenig, C Meisinger, W M M Verschuren, A Blokstra, H B Bueno-de-Mesquita, L Wilhelmsen, A Rosengren, G Lappas, L H Kuller, G Grandits, R Selmer, A Tverdal, W Nystad, R F Gillum, M Mussolino, E Rimm, S Hankinson, J E Manson, J K Pai, V Salomaa, K Harald, P Jousilahti, E Vartiainen, T W Meade, J A Cooper, C Knottenbelt, J A Cooper, K A Bauer, K Davidson, S Kirkland, J Shaffer, M R Korin, S Sato, A Kitamura, Y Naito, H Iso, I Holme, R Selmer, A Tverdal, W Nystad, H Nakagawa, K Miura, P Ducimetiere, X Jouven, G Luc, C J Crespo, M R Garcia-Palmieri, P Amouyel, D Arveiler, A Evans, J Ferrieres, H Schulte, G Assmann, C J Packard, N Sattar, R G Westendorp, B M Buckley, B Cantin, B Lamarche, J-P Després, G R Dagenais, E Barrett-Connor, D L Wingard, R R Bettencourt, V Gudnason, T Aspelund, G Sigurdsson, B Thorsson, M Trevisan, J Witteman, I Kardys, M M B Breteler, A Hofman, H Tunstall-Pedoe, R Tavendale, G Lowe, M Woodward, B V Howard, Y Zhang, L Best, J Umans, Y Ben-Shlomo, G Davey-Smith, A Onat, T W Meade, I Njølstad, E B Mathiesen, M-L Løchen, T Wilsgaard, E Ingelsson, S Basu, T Cederholm, L Byberg, J M Gaziano, M Stampfer, P M Ridker, J M Gaziano, P M Ridker, H Ulmer, G Diem, H Concin, A Tosetto, F Rodeghiero, S Wassertheil-Smoller, J E Manson, I M Marmot, R Clarke, R Collins, A Fletcher, E Brunner, M Shipley, P M Ridker, J Buring, J Shepherd, S Cobbe, I Ford, M Robertson, Y He, A Marin Ibañez, E J M Feskens, M Walker, S Watson, R Collins, E Di Angelantonio, S Erqou, S Kaptoge, S Lewington, L Pennells, P L Perry, K K Ray, N Sarwar, M Alexander, A Thompson, S G Thompson, M Walker, S Watson, I R White, A M Wood, J Danesh, Emerging Risk Factors Collaboration, Stephen Kaptoge, Emanuele Di Angelantonio, Gordon Lowe, Mark B Pepys, Simon G Thompson, Rory Collins, John Danesh, R W Tipping, C E Ford, S L Pressel, G Walldius, I Jungner, A R Folsom, L Chambless, C M Ballantyne, D Panagiotakos, C Pitsavos, C Chrysohoou, C Stefanadis, M W Knuiman, U Goldbourt, M Benderly, D Tanne, P Whincup, S G Wannamethee, R W Morris, S Kiechl, J Willeit, A Mayr, G Schett, N Wald, S Ebrahim, D Lawlor, J Yarnell, J Gallacher, E Casiglia, V Tikhonoff, P J Nietert, S E Sutherland, D L Bachman, J E Keil, M Cushman, B M Psaty, R Tracy, A Tybjaerg-Hansen, B G Nordestgaard, J Zacho, R Frikke-Schmidt, S Giampaoli, L Palmieri, S Panico, D Vanuzzo, L Pilotto, A Gómez de la Cámara, J A Gómez Gerique, L Simons, J McCallum, Y Friedlander, F G R Fowkes, A Lee, J Taylor, J M Guralnik, C L Phillips, R B Wallace, J M Guralnik, C L Phillips, D G Blazer, J M Guralnik, C L Phillips, C L Phillips, J M Guralnik, K-T Khaw, H Brenner, E Raum, H Müller, D Rothenbacher, J-H Jansson, P Wennberg, A Nissinen, C Donfrancesco, S Giampaoli, V Salomaa, K Harald, P Jousilahti, E Vartiainen, M Woodward, R B D'Agostino, P A Wolf, R S Vasan, E J Benjamin, E-M Bladbjerg, T Jørgensen, L Møller, J Jespersen, R Dankner, A Chetrit, F Lubin, A Rosengren, L Wilhelmsen, G Lappas, H Eriksson, C Björkelund, L Lissner, C Bengtsson, P Cremer, D Nagel, R S Tilvis, T E Strandberg, Y Kiyohara, H Arima, Y Doi, T Ninomiya, B Rodriguez, J Dekker, G Nijpels, C D A Stehouwer, E Rimm, J K Pai, S Sato, H Iso, A Kitamura, H Noda, U Goldbourt, J T Salonen, K Nyyssönen, T-P Tuomainen, J A Laukkanen, D J H Deeg, M A Bremmer, T W Meade, J A Cooper, B Hedblad, G Berglund, G Engström, W M M Verschuren, A Blokstra, M Cushman, A R Folsom, B M Psaty, S Shea, A Döring, W Koenig, C Meisinger, W M M Verschuren, A Blokstra, H B Bueno-de-Mesquita, L Wilhelmsen, A Rosengren, G Lappas, L H Kuller, G Grandits, R Selmer, A Tverdal, W Nystad, R F Gillum, M Mussolino, E Rimm, S Hankinson, J E Manson, J K Pai, V Salomaa, K Harald, P Jousilahti, E Vartiainen, T W Meade, J A Cooper, C Knottenbelt, J A Cooper, K A Bauer, K Davidson, S Kirkland, J Shaffer, M R Korin, S Sato, A Kitamura, Y Naito, H Iso, I Holme, R Selmer, A Tverdal, W Nystad, H Nakagawa, K Miura, P Ducimetiere, X Jouven, G Luc, C J Crespo, M R Garcia-Palmieri, P Amouyel, D Arveiler, A Evans, J Ferrieres, H Schulte, G Assmann, C J Packard, N Sattar, R G Westendorp, B M Buckley, B Cantin, B Lamarche, J-P Després, G R Dagenais, E Barrett-Connor, D L Wingard, R R Bettencourt, V Gudnason, T Aspelund, G Sigurdsson, B Thorsson, M Trevisan, J Witteman, I Kardys, M M B Breteler, A Hofman, H Tunstall-Pedoe, R Tavendale, G Lowe, M Woodward, B V Howard, Y Zhang, L Best, J Umans, Y Ben-Shlomo, G Davey-Smith, A Onat, T W Meade, I Njølstad, E B Mathiesen, M-L Løchen, T Wilsgaard, E Ingelsson, S Basu, T Cederholm, L Byberg, J M Gaziano, M Stampfer, P M Ridker, J M Gaziano, P M Ridker, H Ulmer, G Diem, H Concin, A Tosetto, F Rodeghiero, S Wassertheil-Smoller, J E Manson, I M Marmot, R Clarke, R Collins, A Fletcher, E Brunner, M Shipley, P M Ridker, J Buring, J Shepherd, S Cobbe, I Ford, M Robertson, Y He, A Marin Ibañez, E J M Feskens, M Walker, S Watson, R Collins, E Di Angelantonio, S Erqou, S Kaptoge, S Lewington, L Pennells, P L Perry, K K Ray, N Sarwar, M Alexander, A Thompson, S G Thompson, M Walker, S Watson, I R White, A M Wood, J Danesh

Abstract

Background: Associations of C-reactive protein (CRP) concentration with risk of major diseases can best be assessed by long-term prospective follow-up of large numbers of people. We assessed the associations of CRP concentration with risk of vascular and non-vascular outcomes under different circumstances.

Methods: We meta-analysed individual records of 160 309 people without a history of vascular disease (ie, 1.31 million person-years at risk, 27 769 fatal or non-fatal disease outcomes) from 54 long-term prospective studies. Within-study regression analyses were adjusted for within-person variation in risk factor levels.

Results: Log(e) CRP concentration was linearly associated with several conventional risk factors and inflammatory markers, and nearly log-linearly with the risk of ischaemic vascular disease and non-vascular mortality. Risk ratios (RRs) for coronary heart disease per 1-SD higher log(e) CRP concentration (three-fold higher) were 1.63 (95% CI 1.51-1.76) when initially adjusted for age and sex only, and 1.37 (1.27-1.48) when adjusted further for conventional risk factors; 1.44 (1.32-1.57) and 1.27 (1.15-1.40) for ischaemic stroke; 1.71 (1.53-1.91) and 1.55 (1.37-1.76) for vascular mortality; and 1.55 (1.41-1.69) and 1.54 (1.40-1.68) for non-vascular mortality. RRs were largely unchanged after exclusion of smokers or initial follow-up. After further adjustment for fibrinogen, the corresponding RRs were 1.23 (1.07-1.42) for coronary heart disease; 1.32 (1.18-1.49) for ischaemic stroke; 1.34 (1.18-1.52) for vascular mortality; and 1.34 (1.20-1.50) for non-vascular mortality.

Interpretation: CRP concentration has continuous associations with the risk of coronary heart disease, ischaemic stroke, vascular mortality, and death from several cancers and lung disease that are each of broadly similar size. The relevance of CRP to such a range of disorders is unclear. Associations with ischaemic vascular disease depend considerably on conventional risk factors and other markers of inflammation.

Funding: British Heart Foundation, UK Medical Research Council, BUPA Foundation, and GlaxoSmithKline.

Copyright 2010 Elsevier Ltd. All rights reserved.

Figures

Figure 1
Figure 1
Geometric mean C-reactive protein (CRP) concentration in men and women according to cohort and assay source (A) and within 5-year bands adjusted for cohort (B) Data from the third National Health and Nutrition Examination Survey (NHANESIII) and Population Study of Women in Göteborg (GOTOW) are not represented in the graph because they did not use high sensitivity CRP assays. NS=not stated. Error bars represent the 95% CIs.
Figure 2
Figure 2
Cross-sectional associations between geometric mean C-reactive protein (CRP) concentration and some conventional risk factors and other characteristics Mean CRP concentration was adjusted to age 50 years. Error bars represent the 95% CIs. BP=blood pressure. r=Pearson's correlation coefficient (95% CI) for association between the risk marker and loge CRP concentration in men and women combined.
Figure 3
Figure 3
Risk ratios for major vascular and non-vascular outcomes by quantiles of C-reactive protein (CRP) concentration, with different degree of adjustment for potential confounders Adjusted study-specific loge risk ratios were combined by use of multivariate random-effects meta-analysis. The adjustments were age, sex, and study only (A); age, sex, study, systolic blood pressure, smoking, history of diabetes, body-mass index, concentrations of loge triglycerides, non-HDL cholesterol, and HDL cholesterol, and alcohol consumption (B); and (A) plus (B) plus fibrinogen (C). Studies with fewer than ten cases of any outcome were excluded from the analysis of that outcome. Error bars represent the 95% CIs, calculated using floating absolute risk technique. The sizes of the boxes are proportional to the inverse of the variance of the risk ratios.
Figure 4
Figure 4
Age-adjusted and sex-adjusted risk ratios for mortality from vascular and non-vascular diseases per three-fold higher usual C-reactive protein (CRP) concentration Data are numbers, unless otherwise indicated. Risk ratios (boxes) were adjusted only for age, and stratified (when appropriate), by sex and trial group. Studies with fewer than ten cases of any outcome were excluded from the analysis of that outcome. The risk ratios are presented per 1·11 higher loge CRP (ie, 1-SD), corresponding to a three-fold higher CRP concentration. Horizontal lines represent the 95% CIs. The sizes of the boxes are proportional to the inverse of the variance of the risk ratios.

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