Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data

Frances Wensley; Pei Gao; Stephen Burgess; Stephen Kaptoge; Emanuele Di Angelantonio; Tina Shah; James C Engert; Robert Clarke; George Davey-Smith; Børge G Nordestgaard; Danish Saleheen; Nilesh J Samani; Manjinder Sandhu; Sonia Anand; Mark B Pepys; Liam Smeeth; John Whittaker; Juan Pablo Casas; Simon G Thompson; Aroon D Hingorani; John Danesh; C Reactive Protein Coronary Heart Disease Genetics Collaboration (CCGC); Anne Tybjærg-Hansen

Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data

Frances Wensley, Pei Gao, Stephen Burgess, Stephen Kaptoge, Emanuele Di Angelantonio, Tina Shah, James C Engert, Robert Clarke, George Davey-Smith, Børge G Nordestgaard, Danish Saleheen, Nilesh J Samani, Manjinder Sandhu, Sonia Anand, Mark B Pepys, Liam Smeeth, John Whittaker, Juan Pablo Casas, Simon G Thompson, Aroon D HingoraniJohn Danesh, C Reactive Protein Coronary Heart Disease Genetics Collaboration (CCGC), Anne Tybjærg-Hansen

172 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	B M J
Vol/bind	342
Sider (fra-til)	d548
ISSN	0959-8146
Status	Udgivet - 19 feb. 2011

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Wensley, F., Gao, P., Burgess, S., Kaptoge, S., Di Angelantonio, E., Shah, T., Engert, J. C., Clarke, R., Davey-Smith, G., Nordestgaard, B. G., Saleheen, D., Samani, N. J., Sandhu, M., Anand, S., Pepys, M. B., Smeeth, L., Whittaker, J., Casas, J. P., Thompson, S. G., ... Tybjærg-Hansen, A. (2011). Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data. B M J, 342, d548.

Wensley, F, Gao, P, Burgess, S, Kaptoge, S, Di Angelantonio, E, Shah, T, Engert, JC, Clarke, R, Davey-Smith, G, Nordestgaard, BG, Saleheen, D, Samani, NJ, Sandhu, M, Anand, S, Pepys, MB, Smeeth, L, Whittaker, J, Casas, JP, Thompson, SG, Hingorani, AD, Danesh, J, C Reactive Protein Coronary Heart Disease Genetics Collaboration (CCGC) & Tybjærg-Hansen, A 2011, 'Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data', B M J, bind 342, s. d548.

@article{faf497d2ef0d40efa7f577a33479dbef,

title = "Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data",

abstract = "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.",

author = "Frances Wensley and Pei Gao and Stephen Burgess and Stephen Kaptoge and {Di Angelantonio}, Emanuele and Tina Shah and Engert, {James C} and Robert Clarke and George Davey-Smith and Nordestgaard, {B{\o}rge G} and Danish Saleheen and Samani, {Nilesh J} and Manjinder Sandhu and Sonia Anand and Pepys, {Mark B} and Liam Smeeth and John Whittaker and Casas, {Juan Pablo} and Thompson, {Simon G} and Hingorani, {Aroon D} and John Danesh and Anne Tybj{\ae}rg-Hansen and Anne Tybj{\ae}rg-Hansen",

year = "2011",

month = feb,

day = "19",

language = "English",

volume = "342",

pages = "d548",

journal = "The BMJ",

issn = "0959-8146",

publisher = "BMJ Publishing Group",

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TY - JOUR

T1 - Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data

AU - Wensley, Frances

AU - Gao, Pei

AU - Burgess, Stephen

AU - Kaptoge, Stephen

AU - Di Angelantonio, Emanuele

AU - Shah, Tina

AU - Engert, James C

AU - Clarke, Robert

AU - Davey-Smith, George

AU - Nordestgaard, Børge G

AU - Saleheen, Danish

AU - Samani, Nilesh J

AU - Sandhu, Manjinder

AU - Anand, Sonia

AU - Pepys, Mark B

AU - Smeeth, Liam

AU - Whittaker, John

AU - Casas, Juan Pablo

AU - Thompson, Simon G

AU - Hingorani, Aroon D

AU - Danesh, John

AU - C Reactive Protein Coronary Heart Disease Genetics Collaboration (CCGC)

AU - Tybjærg-Hansen, Anne

PY - 2011/2/19

Y1 - 2011/2/19

N2 - 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.

AB - 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.

M3 - Journal article

SN - 0959-8146

VL - 342

SP - d548

JO - The BMJ

JF - The BMJ

ER -

Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data

Abstract

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