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Meta-analysis of Genome-Wide Association Studies in >80,000 Subjects Identifies Multiple Loci for C-Reactive Protein Levels
Dehghan A, Dupuis J, Barbalic M, et al
Circulation. 2011;123:731-738
Summary
A recent large meta-analysis of genome-wide association studies from 15 cohort studies comprising 66,185 subjects and a replication sample of 16,540 subjects identified 18 gene loci associated with C-reactive protein (CRP) levels. These 18 gene loci were mostly associated with immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation.
The authors developed a genetic risk score that explains about 5% of the variation in CRP levels, showing that genetic factors are important in determining CRP levels. In comparison, body mass index, the main nongenetic determinant of CRP studied, was reported to explain 5%-15% of the variation in CRP levels.
However, neither the individual genes nor the combined genetic risk score showed consistent or genome-wide significant associations with risk for clinical coronary events.
Viewpoint
A consensus is building that high-sensitivity CRP (hs-CRP) is a great pathophysiologic integrator of factors associated with coronary heart disease (CHD). Indeed, there is no controversy regarding the fact that hs-CRP is a strong independent risk for CHD. The JUPITER trial demonstrated that rosuvastatin treatment significantly reduced major cardiovascular events in men over age 50 and women over age 60 who had hs-CRP > 2.0 mg/dL with 1 additional CV risk factor but low LDL cholesterol (< 130 mg/dL).
The current trial, however, does not appear to implicate CRP as having a causal role in the atherosclerotic process. Rather, it seems to indicate that genetic predisposition to metabolic disorders such as diabetes or chronic inflammation is linked to both higher levels of CRP and higher rates of CHD. Therefore, the genetic factors that predispose the patient to a higher risk for cardiovascular disease are only manifested if environmental factors are triggered, such as weight gain leading to obesity.
More specifically, this study seems to indicate that levels of hs-CRP are determined by both genetic and environmental factors, and that it is this interaction, but not the individual components, that predict increased risk for cardiovascular disease.
Regardless of whether CRP plays a direct causal role in atherosclerotic disease, it is clearly a clinically useful biomarker. It satisfies each of the following stipulations put forth by the American Heart Association for a clinically useful risk marker: (1) demonstrates consistent independence of effect in multiple prospective cohort studies; (2) demonstrates incremental information on utility beyond that of usual risk factors; (3) demonstrates that assessment leads to clinical impact on patient management and outcomes; and (4) is readily assessed with standardized assays.
One of the most appealing aspects of hs-CRP as a biomarker is that therapeutic approaches that lower hs-CRP also decrease cardiovascular events, and that the lower the hs-CRP on treatment, the lower the risk. However, to become a target for therapy, there needs to be clinical trial evidence that lowering hs-CRP without affecting other causative factors, such as apo-B lipoproteins, is associated with a reduction in major atherosclerotic disease. These hypotheses are now being tested with anti-inflammatory agents that lower hs-CRP but do not beneficially modify the lipoprotein profile. These trials will hopefully answer the next important question: whether reducing inflammation independent of modifying the substrate of that inflammation results in improved patient outcomes.
Abstract
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