Cardiogenomics in the Age of Personalized Lifestyle Medicine
Jeffrey S. Bland, PhD, FACN, FACB
In 2019, the American Heart Association published an update of heart disease and stroke statistics for the United States. This report was compiled using data collected between 2013 and 2016 for the National Health and Nutrition Examination Survey. The prevalence of cardiovascular disease (CVD)—coronary heart disease, heart failure, stroke, and hypertension—in adults greater than 20 years of age is 48% overall (121.5 million in 2016) and increases with advancing age in both men and women. Globally, CVD is the number one cause of death and in fact has increased by 14.5% since 2006.1 Evidence has clearly demonstrated the importance of lifestyle factors in the development of CVDs.2 Even so, population-based public health criteria for lifestyle interventions have had mixed success in reducing CVD incidence.3 Personalized lifestyle medicine—a concept that takes into account an individual’s unique response to lifestyle, diet, physical activity, stress, environmental exposures, and medications—may represent a more effective approach to the management of CVDs.4 On a global scale, the prevalence of many noncommunicable diseases are on the rise, and this trend has led researchers to focus on the interaction between genetics and lifestyle, diet, social, and environmental factors.5
There is emerging evidence that implementation of individualized preventive health care could help bend the curve of health care costs downward.6 In preventive cardiology, advancements would include integration of genomic, biometric, dietary, and lifestyle data to improve precision in both diagnosis and therapy. In an editorial titled “Introducing ‘Genomics and Precision Health’,” which was published in the Journal of the American Medical Association in May 2017, Dr William Feero asserted: “This shift is inexorably moving medicine from an endeavor in which care for individual patients is driven by trial and error informed by studies designed to measure populations outcomes to one in which care is selected based on a deep understanding of health and disease attributes unique to each individual.”7 What forces are driving this shift in perspective? The Framingham Cardiovascular Risk Score is one of the best known and most widely used tools to emerge from a population-based study. It is calculated using data related to smoking history, elevated serum cholesterol (and specifically elevated low-density lipoprotein [LDL] cholesterol), obesity, hypertension, maleness, and age. Yet despite its iconic standing and its deep roots in clinical care, it has been reported that the Framingham Risk Score has less than a 50% probability of predicting CVD within 10 years in men 30 to 39 years of age.8
To better appreciate how the concept of personalization is shaping the future of cardiology, we can look to a well-known and significant study from the recent past: the JUPITER primary prevention trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). When the results of this study were published in 2008, a key finding was the demonstration that CVD risk is linked to more factors than just elevated serum lipids. The JUPITER researchers found that people with low serum LDL cholesterol and elevated serum high-sensitivity C-reactive protein (hsCRP), which is an inflammatory biomarker, had a reduction in both hsCRP and cardiovascular events when treated with the statin rosuvastatin.9 This observation contributed to the increased recognition that CVD results from the interaction of many variables and some of these variables are controlled by numerous genes.10 Cardiology is now moving toward new therapeutic frontiers based on an expanded understanding of the complexities of gene-environment interaction and its connection to health and disease.11
“Polygenic” is a word used to describe the interaction of multiple genes in a network for the regulation of physiological function.12 According to Boyle et al, authors of an important 2017 publication called “An Expanded View of Complex Traits: From Polygenic to Omnigenic,” this definition may be too limited; they write: “A central role of genetics is to understand the links between genetic variation and disease…. But
for complex traits, association signals tend to be spread across most of the genome-including many genes without an obvious connection to disease.”13 These authors suggest that these gene regulatory networks are so interconnected to the etiology of complex diseases that a more appropriate characterization would be to refer to them as “omnigenic.” The functional expression of omnigenic networks that are involved in the etiology of complex chronic diseases such as CVD are influenced by signals derived from lifestyle, diet, and environmental exposures, including pharmaceutical drugs that are used for treatment.
for complex traits, association signals tend to be spread across most of the genome-including many genes without an obvious connection to disease.”13 These authors suggest that these gene regulatory networks are so interconnected to the etiology of complex diseases that a more appropriate characterization would be to refer to them as “omnigenic.” The functional expression of omnigenic networks that are involved in the etiology of complex chronic diseases such as CVD are influenced by signals derived from lifestyle, diet, and environmental exposures, including pharmaceutical drugs that are used for treatment.
How do we develop a unified conceptual approach to managing the complex interaction of gene networks and lifestyle variables? In cardiac care, a systems biology approach to precision personalized cardiology must be developed, and we are now starting to witness translation of this emerging scientific understanding. In a 2017 article, Bland, Minich, and Eck assert the following: “Emerging groundbreaking research projects have given us a glimpse of how systems thinking and computational methods may lead to personalized health advice. It is important that all stakeholders work together to create the needed paradigm shift in healthcare before the rising epidemic of NCDs [non-communicable diseases] overwhelm the society, the economy, and the dated health system.”14
Genetic Regulation of Cardiovascular Function: An Omnigenic Network
Cardiogenomics is a relatively new term that is being used to describe the use of genomic profiling to assess risk for CVD. An example of the advancement in this field is the recognition that polymorphisms of specific genes such as LDLR, APOB, and PCSK9 have been found to be important in establishing individual risk to CVD.15 The functional impact of these genes is known to be influenced by lifestyle, dietary, and environmental factors. For example, PCSK9 was discovered through genetic studies documenting familial hypercholesterolemia, and PCSK9 protein, which is secreted by the liver, binds to the LDL receptor and targets it for degradation; this results in alteration in LDL signaling and ApoB degradation that contributes to CVD risk.16 Additional research has demonstrated that variations in both the PCSK9 and hydroxymethylglutaryl CoA Reductase (HMGCR) genes contribute to CVD risk.17 Multiple single nucleotide polymorphisms (SNPs) exist for these genes and impart varying degrees of individual risk to CVD; it is becoming recognized that SNPs with a more mild influence on the disease phenotype are more significantly influenced by lifestyle, diet, and environmental factors.18 Clinical intervention trials in patients with existing atherosclerotic CVD who were administered a biological drug that blocks the binding of PCSK9 with the LDL receptor when administered along with statins demonstrated significant reduction in LDL cholesterol—beyond results that high-dose statins alone can produce—and also a reduction in the risk of subsequent cardiovascular events.19
These trials support the important understanding that variations in the PCSK9 gene can impact vascular biology and cardiovascular risk. A complete understanding of how PCSK9 fits into the omnigenic cardiovascular risk story is yet to be developed, but this work clearly indicates that multiple genes influence cardiovascular function and that single nucleotide variations in these genes can result in risk that is highly personalized to the individual. Recently, a controlled animal trial demonstrated that PCSK9 activity can be inhibited by the alkaloid berberine.20 Berberine is found in a variety of traditional medicinal plants historically used by a number of cultures, including barberry, tree turmeric, Oregon grape, goldenseal, yellow root, and California poppy. The results of this study indicated that, with pharmacological doses of berberine (200 mg/kg by gavage in mice), the hepatocyte nuclear factor 1alpha, which is known to be an obligate transactivator for PCSK9 gene expression, was inhibited, thereby reducing the genetic expression of PCSK9 and improving LDL metabolism. This is an interesting study in that it suggests that there are multiple ways in which a risk gene can be modulated in its expression through different environmental exposures. It is often thought that to block the effects of a risk gene you have to directly inhibit its expression, but in fact there are many upstream and downstream events linked to lifestyle, diet, and environmental factors that can modify the expression of the genetic risk factor. This demonstrates the concept that regulatory functions can be connected to the uniqueness of an individual’s gene-environment status.
Within cardiology, there has been a long-standing belief that elevated serum LDL cholesterol is always a risk factor for CVD, but recent cardiogenomic studies have found that, when serum LDL is elevated but apoB is low, cardiovascular risk is low.21 This suggests that omnigenic regulation of cardiovascular signaling processes—as reflected in the level of apoB—is more important than a single surrogate marker for CVD, such as serum LDL.22 Infiltration of an apoB particle into the arterial wall is the first step in initiating the atherosclerotic process. We are now learning that this process is the result of many genetically controlled functions that relate to lipid metabolism, immune function, inflammation, coagulation factors, and vascular smooth muscle cell proliferation, all of which can be influenced by lifestyle, dietary, and environmental factors.
Ference et al have found that genetic variants that regulate cholesterol transport through the cholesterol ester transport protein system (CETP) and its impact on apoB structure and function impart varying degrees of CVD risk. This team conducted a retrospective analysis of 14 cohort or case-controlled studies conducted in North America or the United Kingdom between 1948 and 2012. When the results of this effort were published in the Journal of the American Medical Association in 2017, the following conclusion was reached: “Combined exposure to variants in the genes that encode the targets of CETP inhibitors and statins was associated with discordant reductions in LDL-C and apoB levels
and a corresponding risk of cardiovascular events that was proportional to the attenuated reduction in apoB but significantly less than expected per unit change in LDL-C.”21
and a corresponding risk of cardiovascular events that was proportional to the attenuated reduction in apoB but significantly less than expected per unit change in LDL-C.”21
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