Genetic Risk Stratification for Primary Prevention of CAD in Men and Pre & Post-menopausal Women

Coronary artery disease (CAD) is an epidemic, being the most common cause of death in the world. CAD is preventable as shown by clinical trials that reduce conventional risk factors such as hypercholesterolemia. Epidemiologists have claimed 40-60% of pre-disposition to CAD is genetic. In 2007, the investigators and the Icelandic group independently identified the first genetic risk variant for CAD, 9p21. Through the formation of an international consortium, the investigators have now identified over 200 genetic risk variants predisposing to CAD. Utilizing a genetic risk score (GRS) based on these variants for CAD, several studies have retrospectively documented the risk stratification for primary or secondary prevention of CAD to be superior and relatively independent of, conventional risk factors. Studies in over 1 million individuals show those with the highest genetic risk exhibit up to a 4-fold increased risk of CAD. More importantly, those with a high GRS and a more favorable lifestyle experienced 50% reduction in cardiac events. In the high risk group one needs to treat only 13 individuals with statin therapy to prevent one cardiac event. The GRS detects those at high risk who will benefit most from primary prevention. The myth that one cannot treat genetic predisposition has been dispelled. While secondary prevention of CAD has been successful, application of primary prevention has until now lacked a risk marker to detect those who would benefit most. Given only 47% of the population will experience a cardiac event, administering preventive therapy, such as statin, to everyone would be unnecessarily expensive and inappropriate. Since the GRS is determined at birth, and does not change during one lifetime it is close to ideal for primary prevention. GRS detects among asymptomatic individuals at any age those at high-risk for CAD, who will benefit most from preventive therapy.

The investigators propose to genotype males and females at age 40 years and older, who are asymptomatic and without known heart disease (N=2000). DNA from a blood sample will be genotyped for millions of genetic risk variants for CAD by Baylor College of Medicine Human Genome Sequencing Center Clinical Laboratory (HGSC-CL) in CLIA-approved laboratories.

The derived GRS will be added to the conventional risk score using the American College of Cardiology/American Heart Association's (AHA) Pooled Cohort Atherosclerotic Cardiovascular Disease (ASCVD) Risk Equation. In the female cohort, investigators will also be screening for female-specific risk factors that have been added to the ACC/AHA 2018 Blood Cholesterol Guidelines to be used as risk enhancers. Everyone at high risk, will be referred to their physician for further management and given the opportunity for genetic counseling by a member of the research team. Completion of the 2 year recruitment will meet the objectives, however, an annual follow-up will be obtained by electronic survey via REDCap, letter or phone call over a 10 year period as it may provide information on long term genetic prediction.

The overall objective after 2 years is to determine if genetic screening for risk of CAD in asymptomatic men and women has the discriminatory power to detect those at highest risk who would potentially benefit most from appropriate primary prevention. It will also determine whether the GRS is appropriate for different ethnic and race groups such as Hispanics, African Americans and Whites, and to what extent those individuals knowing that they are at higher risk, are more likely to seek further advice on management of the risks (either through changes in lifestyle or therapy). The investigators expect to complete recruitment in two years and prove that the GRS is appropriate for clinical application and can detect individuals that have a 50% or more increase in risk for CAD.