Genetic Risk Stratification and Prevention of CAD: An Idea Whose Time Is Now

The latter part of the 20th century was the golden age for genetics, as it focused on linkage analysis in families and discovered genes responsible for >4000 single gene disorders (1). Cardiovascular success included familial hypertrophic cardiomyopathy and atrial fibrillation, as well as Wolff–Parkinson–White, the long QT, and Brugada syndromes (1). A notable feature of the 21st century will be the breakthrough in genetics of polygenic disorders. In the year 2007, we and the Icelandic group simultaneously and independently discovered the first genetic risk variant (9p21) for coronary artery disease (CAD).2 This was followed closely by successes of the Wellcome Trust Group and many other investigators (2). An international collaboration was established to analyze and perform genome-wide association studies for CAD with a sample size of over 200000 cases and controls, referred to as the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. This collaboration provided the necessary expertise, resources, and sample size to identify over 60 genetic variants predisposing to CAD with more to come (2). All these variants are genome-wide significant (P < 5 × 10−8) and have been replicated in independent populations. This information provided proof of concept for the observations made by epidemiologists decades ago, namely, 40% to 60% of risk for CAD is inherited. Genetic risk variants for CAD, as for all polygenic disorders, have several features in common: they occur commonly, each variant imparts only minimal risk, they occur primarily in nonprotein coding regions of the genome, and the total risk burden for CAD is proportional to the number of independent genetic risk variants rather than the intensity of any one variant. CAD, a pandemic disease, is the number one killer in men and women in the US and throughout the world (2). Someone born today in the US has a 47% chance of experiencing a cardiac event during his or her life span (2). The good news is that CAD and its clinical manifestations, such as myocardial infarction or sudden death, have been shown to be preventable. Clinical trials have consistently shown reduction of known conventional risk factors for CAD, such as plasma LDL cholesterol (LDL-C), is associated with a 30% to 40% reduction in cardiac morbidity and mortality. A single value for a genetic risk score (GRS) can be obtained by summing the product of the number of risk variants inherited by each individual and the log of the odds ratio. Mega et al. (3) employed 27 proven genetic risk variants for CAD in a retrospective study of 4 randomized, controlled clinical trials of both primary [Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvestatin (JUPITER) and Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)] and secondary prevention [Cholesterol and Recurrent Events (CARE) and Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22)] by using statin therapy. The sample size of 48421 individuals with 3477 cardiac events was stratified into low, intermediate, and high GRS for CAD. The primary prevention trial JUPITER required treatment of 25 individuals to prevent 1 cardiac event in individuals with high GRS, 42 with intermediate, and 66 with low GRS. A more recent study (4), which included the West of Scotland Coronary Prevention Study (WOSCOPS), genotyped 57 genetic risk variants in a sample size of 10456 individuals; this study showed that the high genetic risk group exhibited a risk reduction of 44% versus a relative risk reduction of 24% in others. The number to treat to prevent 1 coronary event with statin therapy in the high genetic risk group was 13 versus 38 among all others. These results confirm the greater discriminatory power of GRS over that of conventional risk factors in determining who is at high risk for CAD and also who will benefit most from statin therapy. The preceding statement may be considered controversial, but the scientific evidence supporting it is not controversial. Investigators have shown significant statistical net reclassification improvement and improved c-index of GRS for risk stratification over that of conventional risk factors (5–8). The genetic high risk group requires treatment with statins of only 13 to 36 individuals to prevent one cardiac event as opposed to the hundreds with use of conventional risk factors (3, 4). Estimates of 10-year risk for CAD using conventional risk factors are highly dependent on age; in contrast, the GRS is independent of age and remains the same throughout one's lifetime. The GRS is primarily independent of conventional risk factors. Lastly, subclinical CAD correlates closely with GRS but not with conventional risk factors (4, 9, 10). Thus, the time has come for comprehensive risk stratification using both the GRS and conventional risk factors. Khera et al. (11) used a GRS to prospectively stratify for CAD risk in a sample size of 55685 participants. Participants exhibiting a high GRS for CAD (20%) had a 91% higher risk of cardiac events than those with low GRS. Individuals with a healthy lifestyle (no current smoking, no obesity, regular physical activity, and a healthy diet) had a 46% lower risk of cardiac events than an unfavorable lifestyle independent of genetic risk category. This study confirms genetic risk stratification is highly discriminatory and refutes the myth that genetic risk cannot be treated by lifestyle modification. Currently, a 40-year-old woman having a plasma LDL-C of 180 mg/dl (10 mmol/L) and no other risk factors according to the Cardiology Clinical Practice Guidelines would not receive therapy until she develops another risk factor or a cardiac event. The mean plasma LDL-C concentration in women at that age is 121 mg/dl (6.7 mmol/L). Thus, such individuals stratified into the genetic high-risk group would receive statin therapy to reduce LDL-C to the recommended plasma concentrations of 70 to 80 mg/dl (3.9–4.5 mmol/L). Detection of asymptomatic individuals at a high risk for CAD would transform primary prevention. Two-thirds of genetic risk variants mediate their risk through unknown pathways independent of conventional risk factors, thus individuals stratified into high genetic risk may have no conventional risk factors. For these individuals, we currently have no therapy, and at this time, we have no idea what percentage of the population would fit into this category. It is hoped these unknown pathways will be discovered and used as targets to develop new therapies. Primary prevention in young adult males or premenopausal females has the potential to prevent the disease before it occurs. Incorporation of the GRS as an independent risk factor into the guidelines can markedly attenuate CAD, a pandemic disease. The discovery of genetic risk variants predisposing to CAD offer further hope in our quest to conquer this disease. Novel genetic risk variants will serve as targets for the development of new therapies such as PCSK9 inhibitors. Utilization of genetic variants in the technique of Mendelian randomization (MR) will help determine whether the drug target is causative. Potential drug targets such as uric acid, secretory phospholipase A2 (sPLA2), and lipoprotein-associated PL A2 (Lp-PLA2) have been excluded because they were shown by MR not to be causative (12, 13) MR is being embraced by industry to assure the targets selected for drug development are indeed causative. Application of genetic risk variants for CAD in MR studies, which are relatively free of confounding factors, showed plasma HDL-C concentrations are not associated with protection from CAD (2). It debunked the myth that plasma HDL-C is the cause of the protection. It has been observed for some time that the hematological cancer referred to as clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of myocardial infarction. The mechanism remains a mystery. The recent application of genetics screened individuals with CHIP for 4 known mutations (DNMT3A, TET2, ASXL1, JAK2). Individuals having one or more of these mutations exhibited a 4-fold increased risk of myocardial infarction, whereas patients with CHIP having none of these mutations showed no increased risk of myocardial infarction. One of these mutations, TET2, has been shown to induce atherosclerosis in mice due to enhanced macrophage secretion of cytokines of the CXC chemokine family (14). Statins are extremely effective, reducing the cardiac mortality in the US by 50%. Prevention based on GRS for CAD in young adult males and premenopausal females would be to prevent the first cardiac event. Knowing about 50% of the population will have a cardiac event in their lifetime, it is reasonable to assume 20% to 30% will be in the high genetic risk category from birth. When will we embrace these genetic risk variants to prevent CAD, the most common cause of death in today's world? The microarray chip to genotype for 60 genetic variants and stratify for CAD risk is available. Will hospital laboratories standardize the tests? There are now over 3000 genetic risk variants for more than 200 diseases. The cost to detect and analyze these genetic markers is in line with other biomarkers and can be determined any time throughout one's life span. coronary artery disease LDL cholesterol genetic risk score Mendelian randomization clonal hematopoiesis of indeterminate potential. The author would like to acknowledge Miss Arlene Guadalupe Campillo, MPH, for her support in preparation of the manuscript.