Putting genome analysis to good use: Lessons from C-reactive protein and cardiovascular disease
ABSTRACTNew methods of studying the human genome offer novel ways to examine the relationship between biomarkers and common, chronic human diseases. As an example, we will review a large genomics study (Elliott et al, JAMA 2009; 302:37–48) that concluded that C-reactive protein (CRP) is likely not a cause of coronary heart disease, although it is a marker for it.
KEY POINTS
- Genome-wide association studies can uncover associations between genetic markers and medical conditions, but they fall short of establishing causality or even clear biologic interactions between a genetic variant and a disease state.
- Mendelian randomization is a method for addressing the relationship between genetic variants and disease, ie, whether a biomarker affected by the variant is a cause of the disease or merely a bystander.
- CRP, an acute-phase reactant produced by the liver in response to inflammation, is one of many inflammatory markers whose levels correlate with coronary disease and which has been suggested to play a role in its pathogenesis.
- The findings of Elliott et al suggest that therapies that specifically lower CRP levels are not likely to affect coronary artery disease.
No association between low-CRP variants and heart disease
The authors found significant associations between these SNPs and CRP levels and between CRP levels and coronary heart disease, but not between the SNPs and coronary disease when results for three SNPs were combined and standardized to a 20% lower CRP level (odds ratio 1.00, 95% confidence interval 0.97–1.02).1
In view of the lack of association between coronary heart disease and SNPs that affect CRP levels, the authors suggested that the observational data linking CRP levels and coronary disease may have been confounded by other risk factors, or that the trend is due to reverse causation (the inflammatory response associated with atherosclerosis elevates CRP) rather than CRP’s directly causing heart disease.
These findings have important implications for management of cardiovascular disease, as therapeutic strategies to reduce plasma CRP levels are less likely to be beneficial.
The authors also described other genetic variants that may affect coronary heart disease. Carriers of minor alleles of SNPs in the gene for the leptin receptor LEPR and the APOE-CI-CII cluster showed a significantly higher risk of coronary heart disease.1 However, both variants were associated with lower levels of CRP (and, for the SNP in LEPR, lower body weight and body mass index), suggesting that the links with coronary heart disease are not mediated by CRP. These findings illustrate the ability of genome-wide association studies to identify novel susceptibility loci for complex disease without limiting investigation to genes previously thought to take part in coronary heart disease.
In view of the evidence from this study, it seems that the benefits accruing to patients with high CRP from lipid-lowering therapy as demonstrated in the JUPITER trial are likely not the result of CRP-lowering per se, but rather are the result of action on the underlying pathology that leads to elevation of inflammatory markers, including CRP. As an editorial accompanying the study by Elliot et al pointed out, the work not only provides important information in the effort to identify genetic markers associated with complex disease, but it also helps discern the role of the genes and their products in the progress and treatment of common diseases.36
Subsequent studies of CRP and the “directionality” of its role in coronary disease,37 as well as in other conditions such as obesity and cancer,38,39 have carried on the strategy of Elliott et al, providing further evidence for the function of CRP as a bystander in the inflammatory response and complex disease progression.
IMPLICATIONS OF THESE FINDINGS
Tools now exist to leapfrog the randomized controlled trials that have been the primary way of examining the role of potential mediators of common diseases. Mendelian randomization aids in determining whether biomarkers are involved in disease pathogenesis, are simply bystanders, or are secondary markers caused by the disease itself. While randomized controlled trials will still be important, this new approach offers the power of evaluating much larger sample sizes and more equally stratifying confounding factors between study groups by relying on independent assortment of genetic traits.
In medical care today, the prevention of coronary heart disease entails aggressive treatment of hypertension and hyperlipidemia, along with lifestyle modifications such as balanced diet, routine exercise, and smoking cessation. Given the large numbers of patients at risk, even with low risk scores using currently identified risk factors, more specific and sensitive markers (or panels of such markers) of cardiovascular risk are needed.
In the personalized medicine of the future, we will rely on markers that not only identify people at higher risk, but also tell us who would benefit from certain therapies. From the JUPITER trial, we understand that patients with elevated CRP levels may be appropriate candidates for statin therapy even if they have normal levels of LDL-C.36 The study by Elliott et al steers us away from using CRP-affecting SNPs in predicting the course of disease and also from the belief that targeting CRP alone would be a worthwhile therapeutic strategy.
The inflammatory hypothesis of coronary heart disease remains a very important area of investigation, and CRP may turn out to be one of the best biomarkers we have to predict the progression of coronary diseases. But the study by Elliott et al demonstrates that CRP-lowering drugs are unlikely to be magic bullets.
Most importantly, geneticists will partner with clinical researchers to answer important questions about biomarkers and genes, capitalizing on large sets of population data.
