Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant dataBMJ 2011; 342 doi: https://doi.org/10.1136/bmj.d548 (Published 15 February 2011) Cite this as: BMJ 2011;342:d548
- C Reactive Protein Coronary Heart Disease Genetics Collaboration (CCGC)
- Correspondence to:
- Accepted 9 November 2010
Objective To use genetic variants as unconfounded proxies of C reactive protein concentration to study its causal role in coronary heart disease.
Design Mendelian randomisation meta-analysis of individual participant data from 47 epidemiological studies in 15 countries.
Participants 194 418 participants, including 46 557 patients with prevalent or incident coronary heart disease. Information was available on four CRP gene tagging single nucleotide polymorphisms (rs3093077, rs1205, rs1130864, rs1800947), concentration of C reactive protein, and levels of other risk factors.
Main outcome measures Risk ratios for coronary heart disease associated with genetically raised C reactive protein versus risk ratios with equivalent differences in C reactive protein concentration itself, adjusted for conventional risk factors and variability in risk factor levels within individuals.
Results CRP variants were each associated with up to 30% per allele difference in concentration of C reactive protein (P<10−34) and were unrelated to other risk factors. Risk ratios for coronary heart disease per additional copy of an allele associated with raised C reactive protein were 0.93 (95% confidence interval 0.87 to 1.00) for rs3093077; 1.00 (0.98 to 1.02) for rs1205; 0.98 (0.96 to 1.00) for rs1130864; and 0.99 (0.94 to 1.03) for rs1800947. In a combined analysis, the risk ratio for coronary heart disease was 1.00 (0.90 to 1.13) per 1 SD higher genetically raised natural log (ln) concentration of C reactive protein. The genetic findings were discordant with the risk ratio observed for coronary heart disease of 1.33 (1.23 to 1.43) per 1 SD higher circulating ln concentration of C reactive protein in prospective studies (P=0.001 for difference).
Conclusion Human genetic data indicate that C reactive protein concentration itself is unlikely to be even a modest causal factor in coronary heart disease.
Frances Wensley, Pei Gao (University of Cambridge); Stephen Burgess (MRC Biostatistics Unit, Cambridge,); Stephen Kaptoge, Emanuele Di Angelantonio (University of Cambridge); Tina Shah (University College London); James C Engert (McGill University, Canada); Robert Clarke (University of Oxford); George Davey-Smith (University of Bristol); Børge G Nordestgaard (University of Copenhagen, Denmark); Danish Saleheen (University of Cambridge); Nilesh J Samani (University of Leicester); Manjinder Sandhu (University of Cambridge); Sonia Anand (McMaster University, Canada); Mark B Pepys (University College London); Liam Smeeth, John Whittaker, Juan Pablo Casas (London School of Hygiene and Tropical Medicine, UK); Simon G Thompson (MRC Biostatistics Unit, Cambridge); Aroon D Hingorani (University College London); John Danesh (University of Cambridge).
C reactive Protein Coronary Heart Disease Genetics Collaboration (CCGC) Investigators
AGES: G Eiriksdottir, T B Harris, L J Launer, V Gudnason; ARIC: A R Folsom, G Andrews, C M Ballantyne; BHF-FHS: N J Samani, A S Hall, P S Braund, A J Balmforth; BRHS: P H Whincup, R Morris; BWHHS: D A Lawlor, G D O Lowe, N Timpson, S Ebrahim; CAPS: Y Ben-Shlomo, G Davey-Smith, N Timpson; CCHS, CGPS, and CIHDS: B G Nordestgaard, A Tybjærg-Hansen, J Zacho; CHAOS: M Brown, M Sandhu, S L Ricketts, S Ashford; CHS: L Lange, A Reiner, M Cushman, R Tracy (see www.chs-nhlbi.org for acknowledgments); CRPHANS: C Wu, J Ge, Y Zou, A Sun; CUDAS and CUPID: J Hung, B McQuillan, P Thompson, J Beilby, N Warrington, L J Palmer; 4D: C Wanner, C Drechsler, M M Hoffmann; EAS: F G R Fowkes, G D O Lowe, I Tzoulaki; ELSA: M Kumari, M Miller, M Marmot; EPICNL: C Onland-Moret, Y T van der Schouw, J M Boer, C Wijmenga; EPICNOR: S L Ricketts, S Ashford, M Sandhu, K-T Khaw; FRAMOFF: R S Vasan, R B Schnabel, J F Yamamoto, E J Benjamin; GERMIFS: H Schunkert, J Erdmann, I R König, C Hengstenberg; GISSI-P: B Chiodini, M G Franzosi, S Pietri, F Gori; HEALTHABC: M Rudock; Y Liu, K Lohman, T B Harris; HIFMECH: S E Humphries, A Hamsten; HIMS: P E Norman, G J Hankey, K Jamrozik, L J Palmer; HPFS: E B Rimm, J K Pai; HVHS: B M Psaty, S R Heckbert, J C Bis; INTERHEART: S Yusuf, S Anand, J C Engert, C Xie; ISIS: R Collins, R Clarke, D Bennett; LOLIPOP: J Kooner, J Chambers, P Elliott; LURIC: W März, M E Kleber, B O Böhm, B R Winkelmann; MALMO: O Melander, G Berglund; MONICAKORA: W Koenig, B Thorand, J Baumert, A Peters; NHS: E B Rimm, J Manson, J K Pai; NPHSII: S E Humphries, J A Cooper, P J Talmud; NSC: P Ladenvall, L Johansson, J-H Jansson, G Hallmans; PENNCATH: M P Reilly, L Qu, M Li, D J Rader; PROCARDIS: H Watkins, R Clarke, J Hopewell; PROMIS: D Saleheen, J Danesh, P Frossard; PROSPER: N Sattar, M Robertson, J Shepherd, E Schaefer; ROTTERDAM: A Hofman, J C M Witteman, I Kardys, A Dehghan; SHEEP: U de Faire, A Bennet, B Gigante, K Leander; SPEED: Y Ben-Shlomo, G Davey-Smith, N Timpson; UCP: B Peters, A H Maitland-van der Zee, A de Boer, O Klungel; WHIOS: A Reiner, J Manson, P Greenland, J Dai, S Liu; WHITEII: M Kumari, E Brunner, M Kivimaki, M Marmot; WOSCOPS: N Sattar, D O’Reilly, I Ford, C J Packard.
We thank C Hennekens for helpful comments.
Contributors: Statistical team: S G Thompson (co-chair), J Whittaker (co-chair), S Burgess, P Gao, S Kaptoge, C Verzilli, and F Wensley (coordinator). Data management: M Walker and S Watson. Coordinating centre: F Wensley (coordinator), S Anand, S Burgess, J P Casas, E Di Angelantonio, J Engert, P Gao, S Kaptoge, MB Pepys, T Shah, L Smeeth, SG Thompson, C Verzilli, M Walker, S Watson, J Whittaker, S Yusuf, A D Hingorani (co-principal investigator), and J Danesh (co-principal investigator). P Gao, S Burgess, S Kaptoge, and E Di Angelantonio contributed equally to this work, as did AD Hingorani and J Danesh. J Danesh is guarantor.
Funding: The coordinating centre is supported by grant SP/08/007 from the British Heart Foundation. Various sources have supported recruitment, follow-up, and laboratory measurements in the contributing studies. Investigators of several of these studies have contributed to a list naming some of these funding sources, which can be found at http://ceu.phpc.cam.ac.uk/research/ccgc/studies/. AD Hingorani acknowledges support from the Rosetrees Foundation and the British Heart Foundation (FS05/125).
Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Ethical approval: This study was approved by the Cambridgeshire ethics review committee, and was conducted independently from its funders.
Data sharing: No additional data available.
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