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Genetic Risk Stratification

Tipping Point for Global Primary Prevention of Coronary Artery Disease
Originally publishedhttps://doi.org/10.1161/CIRCULATIONAHA.118.034732Circulation. 2018;137:2554–2556

    In 2003, Wald and Law1 predicted that coronary artery disease (CAD) would be markedly attenuated if not eliminated. CAD is a preventable disease based on randomized, placebo-controlled clinical trials that consistently showed 30% to 40% reduction in cardiac events with decreased plasma cholesterol.1 Epidemiologists claimed for decades that 40% to 50% of predisposition for CAD is genetic. Discovery of the first genetic risk variant in 2007 has led to an avalanche of >90 genetic risk variants predisposing to CAD, each of genome-wide significance and replicated in independent populations,2 but each with relatively low individual effect sizes. The total individual genetic risk burden for CAD is proportional to the number of genetic risk variants inherited. These variants account for ≈25% of genetic predisposition to CAD, which is less than the predicted 40%, signaling that more genetic risk variants are yet to be discovered. It is interesting to note that only one third of the genetic risk variants for CAD mediate their risk through known conventional risk factors. Exploration of the unknown pathways mediating the risk conferred by these genetic variants is already enabling new insights into the pathogenesis of coronary atherosclerosis (eg, inflammation, lack of protection of high-density lipoprotein cholesterol) and novel targets for the development of specific drugs.

    Genetic Risk Score, a Proven Predictor of CAD Independent of Conventional Risk Factors

    A major impetus for our pursuit of genetic risk variants was to better predict those at higher risk for CAD who would benefit most from preventive measures, particularly primary prevention. The genetic risk for CAD can be expressed as a single number referred to as a genetic risk score (GRS) by summing the product of the number of high-risk variants inherited by each individual and the natural log of the previously determined odds ratio. The power of genetic risk stratification for CAD was assessed (reviewed in Assimes & Roberts2), primarily retrospectively, in several large clinical trials with a collective sample size of >50 000. Participants were stratified into low-, intermediate-, and high-risk GRS groups, and higher GRS was found to provide prognostic information independent of conventional risk factors and equally effective in primary and secondary prevention. Furthermore, the GRS high-risk group in the JUPITER trial (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvestatin) had a larger relative risk reduction from statin therapy requiring treatment of only 25 to prevent 1 cardiac event. GRS stratification in the WOSCOPS (West of Scotland Coronary Prevention Study) showed that only 13 in the high-risk group were required to be treated to prevent 1 cardiac event.

    In a recent prospective study by Khera et al,3 the high-risk GRS group had an almost 2-fold higher risk of cardiac events than those classified as low risk. About 20% of the population was classified as high risk and 60% as intermediate. Individuals in the high-risk GRS group with a healthy lifestyle had a 46% lower risk of cardiac events than those with an unfavorable lifestyle. This prospective study confirmed that stratification by the GRS is highly discriminatory and independent of conventional risk factors. It also refutes the myth that genetic risk cannot be modified by lifestyle modification. In a recent study4 of individuals with early onset coronary artery disease (≤40 years of age for men, ≤45 years of age for women), the risk for CAD was predominantly genetic, with high GRS associated with a 2-fold increased risk. The same study estimated that the top 2% of the population by GRS have risk for early onset CAD equivalent to individuals with familial hypercholesterolemia, who are rarer in the population.

    Advantages of Assessing the GRS Compared With Conventional Risk Factors for Primary Prevention

    The risk for CAD determined by the GRS does not change throughout one’s lifetime, and thus it can be determined at birth or anytime thereafter. Unlike the Framingham Score, Pooled Cohort Equations, and others, it is not dependent on age and other confounding factors. However, the potential influence of the environment, such as through epigenetic modification, is unknown. Coronary atherosclerosis, the main cause for CAD, develops slowly over decades, enabling GRS to determine those at greatest risk even while in the preclinical stage. The sampling may be from blood or saliva and the DNA, genotyped in bulk can be performed at a cost in keeping with most biomarkers. Thus, it behooves us to initiate comprehensive risk stratification using both the GRS and conventional risk factors.

    GRS May Enable More Cost-Effective and Safer Primary Prevention of CAD on a Global Scale

    CAD has now become pandemic, being the number 1 killer in the developed and underdeveloped worlds. An American has a 50% chance of experiencing a cardiac event during a normal lifespan. The marked reduction in death from CAD because of decreasing cholesterol led Heller et al5 to analyze the cost-effectiveness and safety of administrating statin therapy to everyone ≥40 years of age. In the United States, this would result in 28.9 million more statin users than the guidelines recommend at a cost of billions of dollars, but they claim it would save lives and be cost-effective. There is the concern, as indicated by the accompanying Editorial, of the high cost, potential side effects, and lack of benefit of statin administration to individuals at very low risk. It is important to note that the authors did not consider genetic risk stratification. In contrast to treating everyone, GRS risk stratification, as illustrated in the Figure, would be expected to categorize 20% to 30% at high risk for CAD and 30% to 50% at intermediate risk, thereby identifying those likely to benefit most from statin therapy. It could therefore decrease unwanted side effects and be cost-effective depending on the risk cutoff point.

    Figure.

    Figure. A saliva sample taken by a swab from the mouth to extract the DNA. DNA is genotyped for variants that are known to predispose to CAD. The genetic risk score (GRS) is calculated as a single number on which the group will be divided into 3 categories: high risk, intermediate risk, and low risk. The percentage expected (indicated for each category) is based on previous published studies.

    Adoption of Genetic Risk Stratification by Cardiology Clinical Practice Guidelines Would Transform Prevention and Management of CAD

    Primary prevention of CAD is somewhat prohibited by the current practice guidelines because treatment is essentially for those individuals with ≥2 risk factors. For example, a 40-year-old female with the only 1 risk factor of low-density lipoprotein cholesterol of 180 mg/dL (10 mmol/L) would not receive statin therapy. GRS could help better stratify such individuals to determine the utility of statins to reduce low-density lipoprotein cholesterol to the recommended plasma concentrations of 70 to 80 mg/dL (3.9–4.5 mmol/L). It is also known that asymptomatic middle-age premenopausal women have a low-density lipoprotein cholesterol averaging 121 mg/dL (6.7 mmol/L), whereas their CAD is preclinical. GRS stratification to identify those likely to benefit the most from primary prevention in the preclinical phase should be the ideal goal. Early GRS screening of asymptomatic individuals to identify those at high risk for CAD would transform the prevention of this pandemic disease.

    Acknowledgments

    The author acknowledges Arlene Guadalupe Campillo, MPH, for her support in preparation of the article.

    Footnotes

    http://circ.ahajournals.org

    The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

    Robert Roberts, MD, Department of Medicine, University of Arizona College of Medicine–Phoenix, International Society of Cardiovascular Translational Research, 550 E Van Buren Street, Phoenix, AZ 85004. E-mail

    References

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