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

C Reactive Protein Coronary Heart Disease Genetics Collaboration (CCGC) and Warrington, N. (2011) Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data. BMJ, 342 7794: d548.1-d548.8. doi:10.1136/bmj.d548


Author C Reactive Protein Coronary Heart Disease Genetics Collaboration (CCGC)
Warrington, N.
Title Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data
Journal name BMJ
ISSN 1756-1833
0959-535X
Publication date 2011-02-19
Year available 2011
Sub-type Article (original research)
DOI 10.1136/bmj.d548
Open Access Status DOI
Volume 342
Issue 7794
Start page d548.1
End page d548.8
Total pages 8
Place of publication London, United Kingdom
Publisher B M J Group
Language eng
Subject 2700 Medicine
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) 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.
Formatted 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 
Keyword Medicine, General & Internal
General & Internal Medicine
MEDICINE, GENERAL & INTERNAL
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID G0802432
916.12.154
NHLBI: HL36310
AG13196
2001 D 032
20041151
2007-5942
HHSN268200900009C
G1000718
IN 00023001
ES/I025561/2
PG/2008/008
MC_UU_12019/1
NIAAA: AA021223-01
F32DA024920
HL075451
RG/10/12/28456
MC_UU_12013/1
P20MD006899
092731
HHSN268201100005C
U01HG004402
HHSN268200625226C
PG/09/022
0090049
HHSN268200960009C
N01-HC-48047
HL46380
AG023629
41/5PE
PENEK 05/04
AG1764406S1
LSHM-CT-2006-037197
IGE05012
01 EA 9401
SOC 95201408 05F02
70-2488-Ha I
SOC 98200769 05F02
0312750B
SP716/1-1
KFO192/1
GK1208
064947/Z/01/Z
712058
1R01 AG23522
00023001
279408
HL35464
QLG1-CT-2002-00896
562183
110413
32
2010 B 131
R01 42733
R01 NS39987
078557
NHLBI 33014
E033
90.700.441
LSHM-CT-2007-037273
090532/Z/09/Z
050-060-810
175.010.2005.011
014-93-015
050-060-810
184.021.007
2001.064
T6-101
HL36310
HHSN268201100046C
R01HL087641
R01HL59367
R01HL086694
U01 DK062418
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: UQ Diamantina Institute Publications
 
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Created: Wed, 11 Jun 2014, 01:35:33 EST by Kylie Hengst on behalf of UQ Diamantina Institute