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The Association of C-Reactive Protein and CRP Genotype with Coronary Heart Disease: Findings from Five Studies with 4,610 Cases amongst 18,637 Participants

Lawlor, DA; Harbord, RM; Timpson, NJ; Lowe, GDO; Rumley, A; Gaunt, TR; Baker, I; ... Smith, GD; + view all (2008) The Association of C-Reactive Protein and CRP Genotype with Coronary Heart Disease: Findings from Five Studies with 4,610 Cases amongst 18,637 Participants. PLOS ONE , 3 (8) , Article e3011. 10.1371/journal.pone.0003011. Green open access

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Abstract

Background: It is unclear whether C-reactive protein (CRP) is causally related to coronary heart disease (CHD). Genetic variants that are known to be associated with CRP levels can be used to provide causal inference of the effect of CRP on CHD. Our objective was to examine the association between CRP genetic variant +1444C>T (rs1130864) and CHD risk in the largest study to date of this association.Methods and Results: We estimated the association of CRP genetic variant +1444C>T (rs1130864) with CRP levels and with CHD in five studies and then pooled these analyses (N= 18,637 participants amongst whom there were 4,610 cases). CRP was associated with potential confounding factors (socioeconomic position, physical activity, smoking and body mass) whereas genotype (rs1130864) was not associated with these confounders. The pooled odds ratio of CHD per doubling of circulating CRP level after adjustment for age and sex was 1.13 (95% CI: 1.06, 1.21), and after further adjustment for confounding factors it was 1.07 (95% CI: 1.02, 1.13). Genotype (rs1130864) was associated with circulating CRP; the pooled ratio of geometric means of CRP level among individuals with the TT genotype compared to those with the CT/CC genotype was 1.21 (95% CI: 1.15, 1.28) and the pooled ratio of geometric means of CRP level per additional T allele was 1.14 (95% CI: 1.11, 1.18), with no strong evidence in either analyses of between study heterogeneity (I-2 = 0%, p>0.9 for both analyses). There was no association of genotype (rs1130864) with CHD: pooled odds ratio 1.01 (95% CI: 0.88, 1.16) comparing individuals with TT genotype to those with CT/CC genotype and 0.96 (95% CI: 0.90, 1.03) per additional T allele (I-2<7.5%, p. 0.6 for both meta-analyses). An instrumental variables analysis (in which the proportion of CRP levels explained by rs1130864 was related to CHD) suggested that circulating CRP was not associated with CHD: the odds ratio for a doubling of CRP level was 1.04 (95% CI: 0.61, 1.80).Conclusions: We found no association of a genetic variant, which is known to be related to CRP levels, (rs1130864) and having CHD. These findings do not support a causal association between circulating CRP and CHD risk, but very large, extended, genetic association studies would be required to rule this out.

Type: Article
Title: The Association of C-Reactive Protein and CRP Genotype with Coronary Heart Disease: Findings from Five Studies with 4,610 Cases amongst 18,637 Participants
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0003011
Publisher version: http://dx.doi.org/10.1371/journal.pone.0003011
Language: English
Additional information: © 2008 Lawlor et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The British Women's Heart and Health Study is funded by the (UK) Department of Health (DOH) and the DNA extraction, genotyping and the CRP assay were funded by British Heart Foundation (BHF) grants. The Caerphilly study was funded by the Medical Research Council (MRC) of the United Kingdom. Funding for the Caerphilly DNA Bank was from an MRC grant (G9824960). The Whitehall II study has been supported by grants from the MRC; BHF; Health and Safety Executive; DOH; National Heart Lung and Blood Institute (HL36310), US, NIH: National Institute on Aging (AG13196), US, NIH; Agency for Health Care Policy Research (HS06516); and the John D and Catherine T MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health. The Health in Men Study has received funding from the National Health and Medical Research Council of Australia (279408/379600). DA Lawlor, G Davey Smith and INM Day work in the MRC CAiTE Centre and N Timspon is funded in full by the grant for this center (G0601625). DA Lawlor funded in part by a UK DOH career scientist award ((PHCSA03). R M Harbord is funded in part by an MRC grant (G0601625). T Gaunt is a BHF Intermediate Fellow (FS/05/065). M.Kivimaki is supported by the Academy of Finland (Projects no. 117604, 124327 and 124332). MG Marmot is an MRC Research Professor. PE Norman is supported by a National Health and Medical Research Council of Australia Practitioner Fellowship (458505). The views expressed in this paper are those of the authors and not necessarily those of any funding body or others whose support is acknowledged. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Epidemiology and Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Epidemiology and Health > Epidemiology and Public Health
URI: https://discovery.ucl.ac.uk/id/eprint/142646
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