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

Department of Pharmacological Sciences, University of Milan, Milano, Lombardy, Italy
International Journal of Epidemiology (Impact Factor: 9.18). 08/2006; 35(4):922-31. DOI: 10.1093/ije/dyl041
Source: PubMed


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.
We calculated the weighted mean difference in CRP between individuals with variants of the +1444C>T polymorphism in the CRP gene among 4,659 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 (6,201 European men) to obtain a summary OR for the association between the +1444C>T polymorphism and non-fatal MI (genotype-disease studies).
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.
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.

Full-text preview

Available from:
  • Source
    • "Eiriksdottir et al. [30] reported a significant interaction between BMI and waist circumference with the AA genotype of SNP rs1205 on CRP levels, indicating that this effect could explain why obesity promotes a more stable mRNA through the G allele, and the strong linkage disequilibrium has been found in different blocks of the CRP gene, as well as in the 3′UTR region in the block formed by the SNPs rs1130864 and rs1205. Casas et al. [31] found significant differences in mean BMI among individuals with TT genotype compared with C allele carriers, meanwhile, Teng et al. [32] found association between the interaction of obesity with SNPs rs2794521 and rs1800947 (P = 0.034 and P = 0.020, resp.), with increased serum levels of CRP. The SNP rs1130864 TT genotype has been consistently associated with increased serum levels of CRP [17, 24] and has been associated with cardiovascular events [9, 33]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective: We evaluated the association between four polymorphisms in the CRP gene with circulating levels of C-reactive protein (CRP), type 2 diabetes (T2D), obesity, and risk score of coronary heart disease. Methods: We studied 402 individuals and classified them into four groups: healthy, obese, T2D obese, and T2D without obesity, from Guerrero, Southwestern Mexico. Blood levels of CRP, glucose, cholesterol, triglycerides, and leukocytes were measured. Genotyping was performed by PCR/RFLP, and the risk score for coronary heart disease was determined by the Framingham's methodology. Results: The TT genotype of SNP rs1130864 was associated with increased body mass index and T2D patients with obesity. We found that the haplotype 2 (TGAG) was associated with increased levels of CRP (β = 0.3; 95%CI: 0.1, 0.5; P = 0.005) and haplotype 7 (TGGG) with higher body mass index (BMI) (β = 0.2; 95%CI: 0.1, 0.3; P < 0.001). The risk score for coronary heart disease was associated with increased levels of CRP, but not with any polymorphism or haplotype. Conclusions: The association between the TT genotype of SNP rs1130864 with obesity and the haplotype 7 with BMI may explain how obesity and genetic predisposition increase the risk of diseases such as T2D in the population of Southwestern Mexico.
    Full-text · Article · Sep 2012 · Experimental Diabetes Research
  • Source
    • "CRP and IL-6 were selected as these inflammatory biomarkers are indicative of systemic inflammation. As it is unclear as to whether CRP per se is causally associated with cardiovascular or other diseases (Casas et al., 2006; Kaptoge et al., 2010), we do not assume that they are on the causal pathway between adversity and coronary heart disease (C Reactive Protein Coronary Heart Disease Genetics Collaboration, 2011) or metabolic syndrome (Timpson et al., 2005). Rather, we consider them as a potential early marker of disease risk, based on prior work demonstrating that elevated levels of CRP are consistently associated with greater atherosclerosis and incident coronary events (Pearson et al., 2003; Danesh et al., 2004). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Retrospective studies show that childhood adversity is associated with systemic inflammation in adulthood. Few prospective studies have examined whether childhood adversity influences inflammation in an observable manner during childhood or adolescence and if these effects are sustained over time. Methods: Using longitudinal data from the Avon Longitudinal Study of Parents and Children, we examined associations between acute adverse events at seven time points prior to age 8 and inflammation at ages 10 and 15. Inflammatory markers at age 10 included interleukin-6 (IL-6; N=4655) and C-reactive protein (CRP; N=4647), and CRP was measured again at age 15 (N=3286). We further evaluated whether body mass index (BMI), depression, or cigarette smoking mediated associations between adverse events and inflammation. Results: Adverse events in middle childhood (occurring between ages 6 to 8), as well as cumulative adversity from birth to 8 years, were associated with higher levels of IL-6 and CRP at age 10. Adverse events reported in early childhood (1.5years) or middle childhood, and cumulative adversity from birth through 8years predicted increased levels of CRP at age 15, and these associations persisted after adjustment for CRP at age 10. Some, but not all, of these associations were mediated by BMI. Conclusions: This study documents that exposure to adverse events prior to age 8 is associated with elevated inflammation at age 10 and in mid-adolescence. These findings provide prospective evidence for a biological mechanism by which early experiences may shape long-term health. Future studies with earlier assessments of inflammation are necessary in order to elucidate potential sensitive periods and mechanisms that link childhood adversity to later disease vulnerability.
    Full-text · Article · Jun 2012 · Psychoneuroendocrinology
  • Source
    • "Several applications of Mendelian randomization, typically considering a binary outcome Y , a continuous exposure X and a dichotomous genotype G, have used the following reasoning to obtain an IV estimator for a causal effect [10] [11] [16] [35] [40]. The na¨ıve odds ratio of Y given X, which we denote NOR, is suspected to be confounded. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Instrumental variable (IV) methods are becoming increasingly popular as they seem to offer the only viable way to overcome the problem of unobserved confounding in observational studies. However, some attention has to be paid to the details, as not all such methods target the same causal parameters and some rely on more restrictive parametric assumptions than others. We therefore discuss and contrast the most common IV approaches with relevance to typical applications in observational epidemiology. Further, we illustrate and compare the asymptotic bias of these IV estimators when underlying assumptions are violated in a numerical study. One of our conclusions is that all IV methods encounter problems in the presence of effect modification by unobserved confounders. Since this can never be ruled out for sure, we recommend that practical applications of IV estimators be accompanied routinely by a sensitivity analysis. Comment: Published in at the Statistical Science ( by the Institute of Mathematical Statistics (
    Full-text · Article · Nov 2010 · Statistical Science
Show more