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

Juan P. Casas, Tina Shah, Jackie Cooper, Emma Hawe, Alex D. McMahon, Dairena Gaffney, Christopher J. Packard, Denis S. O'Reily, Irene Juhan-Vague, John S. Yudkin, Elena Tremoli, Maurizio Margaglione, Giovanni Di Minno, Anders Hamsten, Teake Kooistra, Jeffrey W. Stephens, Steven J. Hurel, Shona Livingstone, Helen M. Colhoun, George J. MillerLeonelo E. Bautista, Tom Meade, Naveed Sattar, Steve E. Humphries, Aroon D. Hingorani

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)922-931
Number of pages10
JournalInternational Journal of Epidemiology
Volume35
Issue number4
DOIs
Publication statusPublished - Aug 2006

Fingerprint

Random Allocation
C-Reactive Protein
Observational Studies
Myocardial Infarction
Odds Ratio
Genotype
Confidence Intervals
Alleles
Genes
Genetic Association Studies
Germ Cells
Causality
Haplotypes
Phenotype

Keywords

  • C-reactive protein
  • Cardiovascular disease
  • Genetics
  • Meta-analysis
  • Polymorphism

ASJC Scopus subject areas

  • Epidemiology

Cite this

Casas, J. P., Shah, T., Cooper, J., Hawe, E., McMahon, A. D., Gaffney, D., ... Hingorani, A. D. (2006). Insight into the nature of the CRP-coronary event association using Mendelian randomization. International Journal of Epidemiology, 35(4), 922-931. https://doi.org/10.1093/ije/dyl041

Insight into the nature of the CRP-coronary event association using Mendelian randomization. / Casas, Juan P.; Shah, Tina; Cooper, Jackie; Hawe, Emma; McMahon, Alex D.; Gaffney, Dairena; Packard, Christopher J.; O'Reily, Denis S.; Juhan-Vague, Irene; Yudkin, John S.; Tremoli, Elena; Margaglione, Maurizio; Di Minno, Giovanni; Hamsten, Anders; Kooistra, Teake; Stephens, Jeffrey W.; Hurel, Steven J.; Livingstone, Shona; Colhoun, Helen M.; Miller, George J.; Bautista, Leonelo E.; Meade, Tom; Sattar, Naveed; Humphries, Steve E.; Hingorani, Aroon D.

In: International Journal of Epidemiology, Vol. 35, No. 4, 08.2006, p. 922-931.

Research output: Contribution to journalArticle

Casas, JP, Shah, T, Cooper, J, Hawe, E, McMahon, AD, Gaffney, D, Packard, CJ, O'Reily, DS, Juhan-Vague, I, Yudkin, JS, Tremoli, E, Margaglione, M, Di Minno, G, Hamsten, A, Kooistra, T, Stephens, JW, Hurel, SJ, Livingstone, S, Colhoun, HM, Miller, GJ, Bautista, LE, Meade, T, Sattar, N, Humphries, SE & Hingorani, AD 2006, 'Insight into the nature of the CRP-coronary event association using Mendelian randomization', International Journal of Epidemiology, vol. 35, no. 4, pp. 922-931. https://doi.org/10.1093/ije/dyl041
Casas, Juan P. ; Shah, Tina ; Cooper, Jackie ; Hawe, Emma ; McMahon, Alex D. ; Gaffney, Dairena ; Packard, Christopher J. ; O'Reily, Denis S. ; Juhan-Vague, Irene ; Yudkin, John S. ; Tremoli, Elena ; Margaglione, Maurizio ; Di Minno, Giovanni ; Hamsten, Anders ; Kooistra, Teake ; Stephens, Jeffrey W. ; Hurel, Steven J. ; Livingstone, Shona ; Colhoun, Helen M. ; Miller, George J. ; Bautista, Leonelo E. ; Meade, Tom ; Sattar, Naveed ; Humphries, Steve E. ; Hingorani, Aroon D. / Insight into the nature of the CRP-coronary event association using Mendelian randomization. In: International Journal of Epidemiology. 2006 ; Vol. 35, No. 4. pp. 922-931.
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keywords = "C-reactive protein, Cardiovascular disease, Genetics, Meta-analysis, Polymorphism",
author = "Casas, {Juan P.} and Tina Shah and Jackie Cooper and Emma Hawe and McMahon, {Alex D.} and Dairena Gaffney and Packard, {Christopher J.} and O'Reily, {Denis S.} and Irene Juhan-Vague and Yudkin, {John S.} and Elena Tremoli and Maurizio Margaglione and {Di Minno}, Giovanni and Anders Hamsten and Teake Kooistra and Stephens, {Jeffrey W.} and Hurel, {Steven J.} and Shona Livingstone and Colhoun, {Helen M.} and Miller, {George J.} and Bautista, {Leonelo E.} and Tom Meade and Naveed Sattar and Humphries, {Steve E.} and Hingorani, {Aroon D.}",
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T1 - Insight into the nature of the CRP-coronary event association using Mendelian randomization

AU - Casas, Juan P.

AU - Shah, Tina

AU - Cooper, Jackie

AU - Hawe, Emma

AU - McMahon, Alex D.

AU - Gaffney, Dairena

AU - Packard, Christopher J.

AU - O'Reily, Denis S.

AU - Juhan-Vague, Irene

AU - Yudkin, John S.

AU - Tremoli, Elena

AU - Margaglione, Maurizio

AU - Di Minno, Giovanni

AU - Hamsten, Anders

AU - Kooistra, Teake

AU - Stephens, Jeffrey W.

AU - Hurel, Steven J.

AU - Livingstone, Shona

AU - Colhoun, Helen M.

AU - Miller, George J.

AU - Bautista, Leonelo E.

AU - Meade, Tom

AU - Sattar, Naveed

AU - Humphries, Steve E.

AU - Hingorani, Aroon D.

PY - 2006/8

Y1 - 2006/8

N2 - 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.

AB - 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.

KW - C-reactive protein

KW - Cardiovascular disease

KW - Genetics

KW - Meta-analysis

KW - Polymorphism

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