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Discovery of six new genetic risk variants predisposing to CAD
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Much work has been put in to discovering genetic variants predisposing to CAD since the first, 9p21, was discovered in 2007. The CAD phenotype in the original study and subsequent association studies did not differentiate MI and CAD. These two phenotypes are interchangeable since MI is almost always due to rupture of an atherosclerotic plaque with a superimposed thrombus. The 9p21 variant was associated with three important features; it occurs commonly (75% of European population), carries only a small increase in risk for CAD and is independent of conventional risk factors for CAD.
In view of the minimal increased risk associated with each genetic risk variant for CAD, it would require even larger sample sizes than expected to discover these genetic risk variants, so we formed one of the largest international collaborations in the history of cardiology. This collaboration brought together the necessary large sample size, expertise and resources of academic research centers from the United States, Canada, United Kingdom, Germany and Iceland, referred to as the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM). The initial sample size consisted of more than 200,000 cases and controls, which has since been greatly expanded. This international consortium was dedicated to performing genome-wide association studies to discover genetic variants predisposing to CAD.
Discovery of genetic variants
In a series of publications, the consortium has identified multiple genetic risk variants for CAD. In an article by the consortium published in February in the Journal of the American College of Cardiology, six novel genetic variants were discovered that predisposed to CAD.
The investigators’ discovery cohort consisted of 42,335 cases and 78,240 control subjects. This cohort was genotyped with 29,393 single nucleotide polymorphisms, and results were replicated in 30,533 cases and 42,530 control subjects. Meta-analysis identified six genetic variants predisposing to CAD that were of genome-wide significance (P = 5 x 10–8). Each genetic risk variant occurs very commonly, with a frequency in the general population varying from 15% to 86%. In keeping with previous results, each genetic risk variant predisposing to CAD exhibited only minimal risk. The RR for CAD was increased by only 4% to 9%.
The finding of an additional six genetic risk variants predisposing to CAD results in 62 genetic risk variants predisposing to CAD. All 62 of these genetic risk variants have been shown to be of genome-wide significance and confirmed through replication in an independent population.
These genetic risk variants exhibit several features of clinical significance. The genetic risk for CAD is proportional to the number of genetic risk variants inherited by the individual rather than the risk intensity of any one genetic variant. These genetic risk variants occur commonly in the population, and each is associated with only minimal to moderate risk. Of the 62 genetic risk variants, only 24 mediate their risk for CAD through the traditional risk factors for CAD (eg, cholesterol; see Table). This has major implications for both pathogenesis and treatment of CAD. The genetic risk variants acting through unknown mechanisms imply there are other factors contributing to the pathogenesis of CAD. In addition, elucidation of the molecular pathway through which the risk is meditated will provide novel targets for development of specific therapies.
Furthermore, in this study, an analysis was performed to determine whether any of the genetic risk variants predisposing to CAD would also predisposed to other traits. Interestingly, about one-half of the CAD genetic risk variants also were associated with another disease or trait. These findings will undoubtedly add to our understanding of the genetic basis for CAD and the mechanisms where by therapeutic interventions can be achieved.
Calculation of genetic risk
The genetic risk burden can be calculated and expressed in a single genetic risk score (GRS) by summing the product of the number of high-risk variants inherited by each individual for each susceptibility variant and the log of the OR previously determined.
Several studies have now documented that, utilizing this GRS, one can stratify for CAD risk independently of traditional risk factors and more accurately than risk stratification based on traditional risk factors. Furthermore, in a recent study utilizing GRS for CAD risk stratification, it was shown that a healthy lifestyle was associated with 46% reduction in cardiac events compared with those with an unfavorable lifestyle. This confirms, as already known, that the treatment and prevention of genetic risk is the same as the treatment and prevention of acquired risk factors.
A transformative approach
The use of genetic risk factors to stratify risk for CAD is likely to transform primary prevention of this pandemic disease. Current methods to stratify risk such as the Framingham Risk Score are dependent on age and the changes in acquired risk factors. The GRS can be obtained at birth or any time throughout one’s lifetime. Thus, the GRS can be determined in asymptomatic individuals before developing coronary obstructive disease. This approach will be particularly meaningful in the primary prevention of CAD in premenopausal women.
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- For more information:
- Arlene Campillo, BS, is an MPH student at the University of Arizona College of Medicine. Robert Roberts, MD, MACC, FRSC, FRCPC, LLD (Hon.), is professor of medicine and International Society of Cardiovascular Translational Research Chair at University of Arizona College of Medicine. He is also a member of the Cardiology Today Editorial Board. The authors can be reached at 550 E. Van Buren St., Phoenix, AZ 85004; email: rroberts2@email.arizona.edu.
Disclosure: Campillo and Roberts report no relevant financial disclosures.