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No link between CHD risk and variants in CRP locus
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Researchers found no causal link between the effects on coronary heart disease from C-reactive protein genotypes and C-reactive protein levels.
Researchers first conducted both a genome-wide association study (n=17,967) and a replication study (n=13,615) to identify the genetic loci associated with plasma CRP concentrations. The researchers also conducted a Mendelian randomization study of the relationship between the most strongly-associated single-nucleotide polymorphism (SNP) in the CRP locus for an association between CRP variants and CHD risk. comparing the results to published data on 28,112 cases and 100,823 controls, according to the study.
The researchers reported that SNP rs6700896 in LEPR, rs4537545 in IL6R, rs7553007 in the CRP locus, rs1183910 in HNF1A and rs4420638 in APOE-CI-CII were associated with CRP levels. Of these five polymorphisms, SNP rs7553007 in the CRP locus was associated with CHD (OR=0.98; 95% CI, 0.94-1.01) per 20% lower CRP level. Following a Mendelian randomization study of variants in the CRP locus, there was no association with CHD (1.00; 95% CI, 0.97-1.02 vs. 0.94; 95% CI, 0.94-0.95) per 20% lower CRP level. The researchers also reported that SNP rs6700896 in LEPR (OR=1.06; 95% CI, 1.02-1.09 per minor allele), rs4420638 in APOE-CI-CII (OR=1.16; 95% CI, 1.12-1.21) and rs4537545 in IL6R (OR=0.94; CI 95%, 0.91-0.97) were all associated with risk for CHD.
“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,” the researchers concluded. “Moreover, this study suggests that development of therapeutic strategies targeting specific reductions in plasma levels of CRP are unlikely to be fruitful.” – by Eric Raible
Elliott P. JAMA. 2009;302:37-48.
Along with a New England Journal of Medicine paper looking at the same question last year, this article nearly puts the nail in the coffin for the hypothesis that CRP plays a significant causal role for the development of CHD events over the next decade in a given individual. C-reactive protein is likely a marker reflecting some other pathophysiological processes such as insulin resistance.
An elevated high-sensitivity CRP (hsCRP) is generally associated with an odds ratio of 1.5-2.0, depending on the study population looked at, for a future CHD event. High-sensitivity CRP seems to predict the development of acute ischemic events better than the development of stable angina requiring revascularization. Other research groups are looking at similar mendelian randomization research techniques (that were employed in this particular study) to see if certain polymorphisms of lipid factors or other emerging risk factors accurately predict the development of future CVD events.
It will be very interesting what the upcoming National Heart Lung and Blood Institute prevention and lipid guidelines that Drs. Sid Smith, Neil Stone, Alice Lichtenstein and others are working on will say about emerging risk factors such as hsCRP. The JUPITER trial did prove that persons in their 60's with a normal LDL (but elevated apolipoprotein B and non-HDL-cholesterol) benefit from statin therapy. The number needed to treat (NNT) is likely significantly lower when the hsCRP is >2 than if it is <2. We await the JUPITER data on the NNT in various subgroups such as women. We also want to know if the NNT is lower in those with an hsCRP that was higher at baseline.
An hsCRP of two may be above average for most white men, but it is clearly below average for most African American and Hispanic women. Dr. Susan Lakoski's excellent work from MESA on this topic should be mandatory reading for Drs. Smith, Stone, Lichtenstein, Nabel, Lauer and others that are involved in ATP 4 and the prevention guidelines.
Cardiology Today Section Editor