Study Does Not Support Causal Association of C-reactive Protein With CHD
An analysis of the association between genetic variations of the inflammation biomarker C-reactive protein (CRP) with coronary heart disease failed to support a causal association, according to a study in the July 1 issue of JAMA.
Coronary heart disease (CHD) is the leading cause of death worldwide. Inflammation plays a key role in the development of CHD at every stage, from initiation to progression and rupture of plaque. CRP is currently the most widely used biomarker of inflammation, according to background information in the article. “There is considerable interest in establishing whether CRP has a causal role in CHD or whether CRP is merely a marker of underlying atherosclerosis,” the authors write.
Paul Elliott, F.R.C.P., of Imperial College London, and colleagues conducted a genetic association study to identify common genetic loci (the specific site of a particular gene on its chromosome) that influence CRP levels and used the concept of mendelian randomization (the randomized allocation of alleles””an alternative form of a gene at a locus””at conception) to examine the possible causal relationship of CRP levels with CHD. First a genome-wide association (n = 17,967) and replication study (n = 13,615) were conducted to identify genetic loci associated with plasma CRP concentrations. Data collection took place between 1989 and 2008 and genotyping between 2003 and 2008. The researchers then carried out a mendelian randomization study of the most closely associated single-nucleotide polymorphism (SNP) in the CRP locus and published data on other CRP variants involving a total of 28,112 cases and 100,823 controls, to investigate the association of CRP variants with coronary heart disease. These findings were compared with findings predicted from meta-analysis of observational studies of CRP levels and risk of coronary heart disease.
The researchers found: “The present genome-wide association study confirms the associations of common genetic variants in the LEPR, IL6R, CRP, and HNF1A loci and APOE-CI-CII cluster with CRP levels. However, the minor allele of SNP rs7553007 and other variants in the CRP locus included in our mendelian randomization study were not associated with CHD risk.”
The authors write that the variants included in their mendelian randomization study are associated with approximately 20 percent lower CRP levels, corresponding to a 6 percent reduction in CHD risk predicted by the meta-analysis of observational studies of CHD risk. “The lack of association with CHD of genetic variants in the CRP locus suggests that the observational data linking CRP levels and CHD may be confounded [factors that can influence outcomes] by association with other CHD risk factors, or reflect a secondary inflammatory response associated with atherosclerosis (reverse causation), rather than indicate a causal relationship.”
“In summary, our mendelian randomization study of more than 28,000 cases and 100,000 controls found no association of variants in the CRP locus and CHD, arguing against a causal role for CRP in atherosclerosis. Moreover, this study suggests that development of therapeutic strategies targeting specific reductions in plasma levels of CRP are unlikely to be fruitful,” the researchers conclude.
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