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IJE Advance Access published online on March 24, 2006
International Journal of Epidemiology, doi:10.1093/ije/dyl041
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Published by Oxford University Press on behalf of the International Epidemiological Association © The Author 2006; all rights reserved.
Accepted February 15, 2006

Original paper

Insight into the nature of the CRP-coronary event association using Mendelian randomization

Juan P. Casas 1 {dagger}, Tina Shah 2 {dagger}, Jackie Cooper 3, Emma Hawe 3, Alex D. McMahon 4, Dairena Gaffney 5, Christopher J. Packard 5, Denis S. O'Reilly 5, Irene Juhan-Vague 6, John S. Yudkin 7, Elena Tremoli 8, Maurizio Margaglione 9, Giovanni Di Minno 9, Anders Hamsten 10, Teake Kooistra 11, Jeffrey W. Stephens 3, Steven J. Hurel 12, Shona Livingstone 13, Helen M. Colhoun 13, George J. Miller 14, Leonelo E. Bautista 15, Tom Meade 16, Naveed Sattar 5, Steve E. Humphries 3, and Aroon D. Hingorani 17 *

1 Centre for Clinical Pharmacology, Department of Medicine, BHF Laboratories at University College London (UCL), London, UK; Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK
2 Centre for Clinical Pharmacology, Department of Medicine, BHF Laboratories at University College London (UCL), London, UK; Centre for Cardiovascular Genetics, Department of Medicine, BHF Laboratories at UCL, London, UK
3 Centre for Cardiovascular Genetics, Department of Medicine, BHF Laboratories at UCL, London, UK
4 Robertson Centre for Biostatistics, University of Glasgow, Glasgow, Scotland, UK
5 Department of Pathological Biochemistry, Glasgow Royal Infirmary, Glasgow, Scotland, UK
6 Laboratoire d'Hématologie, CHU Timone, Inserm Unit 626, Marseille, France
7 Diabetes and Cardiovascular Disease Academic Unit, Archway Campus, Royal Free and UCL Medical School, London, UK
8 Department of Pharmacological Sciences, University of Milan, Milan, Italy; Monzino Cardiologic Center, Milan, Italy
9 Instituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
10 King Gustaf V Research Institute Department of Medicine, Karolinska Hospital, Karolinska Institute, Stockholm, Sweden
11 The Gaubius Laboratory, The Netherlands Organization for Applied Scientific Research-Prevention and Health, Leiden, The Netherlands
12 Department of Diabetes, Endocrinology and Metabolism, Middlesex Hospital, London, UK
13 Department of Epidemiology at UCL, London, UK
14 Wolfson Institute of Preventive Medicine at the Medical College of St Bartholomew's Hospital, London, UK
15 Department of Population Health Sciences, University of Wisconsin Medical School, Madison, WI, USA
16 Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK
17 Centre for Clinical Pharmacology, Department of Medicine, BHF Laboratories at University College London (UCL), London, UK

* To whom correspondence should be addressed.
Aroon D. Hingorani, E-mail: a.hingorani{at}ucl.ac.uk


  Abstract

Background It is unclear wheather the association between C-reactive protein (CRP) and incident coronary events is free from bias and confounding. Individuals homozygous for a +1444C>T polymorphism in the CRP gene have higher circulating concentrations of CRP. Since the distribution of this polymorphism occurs at random during gamete formation, its association with coronary events should not be biased or confounded.

Methods We calculated the weighted mean difference in CRP between individuals with variants of the +1444C>T polymorphism in the CRP gene among 4659 European men from six studies (genotype-intermediate phenotype studies). We used this difference together with data from previous observational studies to compute an expected odds ratio (OR) for non-fatal myocardial infarction (MI) among individuals homozygous for the T allele. We then performed four new genetic association studies (6201 European men) to obtain a summary OR for the association between the +1444C>T polymorphism and non-fatal MI (genotype-disease studies).

Results CRP was 0.68 mg/l [95% confidence interval (95% CI) 0.31-1.10; P = 0.0001] higher among subjects homozygous for the +1444-T allele, with no confounding by a range of covariates. The expected ORs among TT subjects for non-fatal MI corresponding to this difference in CRP was 1.20 (95% CI 1.07-1.38) using the Reykjavik Heart study data and 1.25 (1.09-1.43) for all observational studies to 2004. The estimate for the observed adjusted-OR for non-fatal MI among TT subjects was 1.01 (95% CI 0.74-1.38), lower than both expected ORs.

Conclusions A common CRP gene polymorphism is associated with important differences in CRP concentrations, free from confounding. The null association of this variant with coronary events suggests possible residual confounding (or reverse causation) in the CRP-coronary event association in observational studies, though the confidence limits are still compatible with a modest causal effect. Additional studies of genotype (or haplotype) and coronary events would help clarify whether or not the link between CRP and coronary events in observational studies is causal.

Keywords: C-reactive protein; cardiovascular disease; genetics; polymorphism; meta-analysis.
{dagger} Both authors contributed equally to this article.

A Commentary has been commissioned to accompany this article and will appear with this paper in the printed issue.


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