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

Casas, Juan P.; Shah, Tina; Cooper, Jackie A.; Hawe, Emma; McMahon, Alex D.; Gaffney, Dairena; Packard, Christopher J.; O’Reilly, Denis St. J.; Juhan‐Vague, I.; Yudkin, John; Tremoli, Elena; Margaglione, Maurizio; Minno, G. Di; Hamsten, Anders; Kooistra, Teake; Stephens, Jeffrey W.; Hurel, Steven J.; Livingstone, Shona; Colhoun, Helen M.; Miller, George; Bautista, Leonelo E.; Meade, T W; Sattar, Naveed; Humphries, Steve E.; Hingorani, Aroon D.

doi:10.1093/ije/dyl041

Cited by 158 publications

(138 citation statements)

References 69 publications

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“…The results of the present study suggest that IL-6-mediated inflammatory reactions are potential confounders of the associations of fibrinogen and CRP with risk of CHD. Some reports on the lack of association of functional genotypes for fibrinogen [24] and possibly CRP [25] with risk of CHD are consistent with the hypothesis that the associations of circulating inflammatory markers (including fibrinogen and CRP) with risk of CHD (and mortality) may result from effects of multiple adverse environmental influences [12], some of which may be mediated by IL-6 and other proinflammatory cytokines. However, a significant association between CRP genotypes and cardiovascular events has recently been reported in a large study [26] and further studies of genotypes for inflammatory markers and CVD risk are required.…”

Section: Discussionsupporting

confidence: 57%

A comparison of the associations between seven hemostatic or inflammatory variables and coronary heart disease

Woodward

Rumley

Welsh

et al. 2007

Journal of Thrombosis and Haemostasis

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Summary. Background: While meta-analyses of prospective studies have established that plasma levels of several hemostatic variables are associated with the risk of coronary heart disease (CHD), these have been suggested to be acute-phase reactant proteins. This study examines their associations with inflammatory markers [C-reactive protein (CRP) and interleukin-6 (IL-6)] and the effect of adjustment on their associations with CHD risk. Methods and results: In a nested case-control study, 247 CHD cases and 473 controls were matched for age and sex from 10 529 men and women in the Fletcher Challenge cohort. Plasma levels of all hemostatic variables except von Willebrand factor (VWF) and lipoprotein (a) [Lp(a)] showed significant associations with CRP and IL-6. Fibrinogen, VWF, tissue plasminogen activator antigen (t-PA), D-dimer, Lp(a), CRP and IL-6 levels were significantly associated with risk of CHD. After adjustment for conventional risk factors, CRP, D-dimer and IL-6 levels were significantly associated with risk of CHD. On further adjustments for the other six hemostatic and inflammatory variables these associations were reduced, but remained significant for D-dimer and IL-6; odds ratios (95% CI), comparing the highest to lowest third, were 3.10 (1.25-7.67) and 2.79 (1.11-6.99), respectively. Conclusion: The associations of plasma levels of some hemostatic variables (fibrinogen, VWF, t-PA and Lp(a); but not fibrin D-dimer) with CHD risk are attenuated when inflammatory markers (CRP and IL-6) as well as conventional risk factors are included in multivariable analyses. D-dimer and IL-6 each have the potential to increase the prediction of CHD, in addition to conventional risk factors.

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Section: Discussionsupporting

confidence: 57%

A comparison of the associations between seven hemostatic or inflammatory variables and coronary heart disease

Woodward

Rumley

Welsh

et al. 2007

Journal of Thrombosis and Haemostasis

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“…This finding is similar to that reported in the West of Scotland Coronary Prevention Study. 21 Casas et al 4 found that subjects with the variant genotype (TT) of the CRP þ 1444 C/T polymorphism had a higher BMI than the wildtype allele carriers. However, their study was restricted to male Caucasians.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3] Polymorphisms in the CRP gene have been associated with anthropometric characteristics (such as BMI) in humans. 4 Interleukin-6 (IL-6) is a pleiotropic cytokine with an important role in both immunoregulation and non-immune events in most cell types and tissues outside of the immune system. 5 IL-6 binds its receptor (IL-6R), and thereby activates an intracellular signaling cascade leading to the inflammatory response.…”

Section: Introductionmentioning

confidence: 99%

Combined effect of C-reactive protein gene SNP +2147 A/G and interleukin-6 receptor gene SNP rs2229238 C/T on anthropometric characteristics among school children in Taiwan

Lin

Chu

et al. 2010

Int J Obes

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“…But animal studies are not able readily to answer questions about cardiovascular disease. Human studies of organ-specific gene knockouts or upregulation present different obstacles, although the concept of 'Mendelian randomisation' has been used, particularly in cardiovascular risk, to explore the role of several putative mechanisms [71]. Human intervention studies are generally pharmacological.…”

Section: Demonstrating Causation-the Need For Experimentsmentioning

confidence: 99%

Insulin resistance and the metabolic syndrome—or the pitfalls of epidemiology

Yudkin

2007

Diabetologia

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The clustering of dyslipidaemia, hypertension and glucose intolerance, predominantly in overweight individuals, has been ascribed many names, including syndrome X and the metabolic syndrome. In Reaven's original description of syndrome X, a central aetiological role was attributed to insulin resistance, and this assumption has remained as the dominant paradigm for the metabolic syndrome. There are a number of conceptual problems in such a model, particularly those arising from observations that several novel markers, including measures of endothelial dysfunction and of low-grade inflammation, are as closely related to insulin resistance as are the classic components of the syndrome. Because it is difficult to envisage how these traits might develop as a consequence of insulin resistance, such observations indicate the need for a new paradigm to explain the mechanisms of association better. It has been proposed that a state of low-grade inflammation, consequent upon the production of adipocytokines, particularly from truncal fat, explains the observed relationships between insulin resistance and endothelial dysfunction better than does a model revolving around insulin resistance. Furthermore, the inflammatory cytokines generated from adipose tissue may influence vessel endothelial function without elevations in circulating concentrations. This review alludes to several problems inherent in the epidemiological method in understanding disease mechanisms. These include crude biological measures, the use of venous systemic fasting samples, imprecision of assays, naive physiological models, simplistic statistical approaches and, without clinical trials, an inability to test causation. Integrated systems biology needs more complex approaches to investigate disease mechanisms, involving cell, organ, whole organism and population studies.

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

Cited by 158 publications

References 69 publications

A comparison of the associations between seven hemostatic or inflammatory variables and coronary heart disease

A comparison of the associations between seven hemostatic or inflammatory variables and coronary heart disease

Combined effect of C-reactive protein gene SNP +2147 A/G and interleukin-6 receptor gene SNP rs2229238 C/T on anthropometric characteristics among school children in Taiwan

Insulin resistance and the metabolic syndrome—or the pitfalls of epidemiology

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