How Personalized Medicine can tailor Coronary Artery Disease Management based on Genotype?
M3 India Newsdesk Oct 05, 2017
Cardiovascular disease (CVD) which include hypertension, coronary artery disease, myocardial infarction and stroke are the bane of modern society having reached epidemic proportion.
Indians have a high propensity to develop coronary artery disease (CAD), it has been estimated that 60% of the world’s cardiac population will be in India by the year 2020. Further deaths due to CAD occur almost 5-10 years earlier in India than the west, resulting in tremendous loss of productive working years and increase of economic burden. In 2000, in the age group of 35 to 64, India lost 9.2 million years of productive life (PYLLs), almost six times the figure for US. The economic impact of cardiovascular disease is also huge between 2005 and 2015 India was projected to cumulatively lose USD 236.6 billion because of heart disease, stroke, and diabetes, shaving 1% off the GDP.
The Framingham Heart Study (FHS) followed by a large number of cardiovascular cohort studies have carefully catalogued numerous demographic, behavioral and physiological parameters to search for “risk factors” that predispose to CAD. Classic risk factors such as smoking, dyslipidemia, obesity, diabetes, hypertension, alcohol consumption, lack of exercise, stress play an important role in the disease. Recent studies however show that besides physiological and behavioral risk factors, the individual genetic predisposition contributes significantly to the development of the disease. One of the strongest determinants of CAD is a positive family history, emphasizing the heritability of this condition.
Genetic susceptibility may be caused by mutations and single nucleotide polymorphisms (SNPs) in candidate genes representing pathways of haemostasis, lipid metabolism, inflammation, endothelial dysfunction as well as blood pressure regulation. The “common disease, common variants” hypothesis proposes that SNPs present in many normal individuals contribute to overall CVD risk2. This premise has paved the way for an important area in health care i.e. Personalized Medicine
What is Personalized Medicine?
Personalized medicine is the application of genomic and molecular data to help determine an individual’s predisposition to a particular condition (Predictive) to know the best suited medicines and dosage for him/her (Pharmacogenetics) to know the best suitable lifestyle practices for him/her
What are the benefits of Personalized Medicine in coronary artery disease?
Coronary Artery Disease is a multifactorial disease, by that we mean there is an almost equal interaction between your environment and genetic predisposition. Often the gun and bullet analogy is used to describe this relationship, your genetic information is the gun and the environment is the bullet. So though your genes remain invariant and you cannot do anything about them, you can modify your lifestyle and environmental conditions to reduce your risk and predisposition. The awareness that you are genetically predisposed to a particular disease can provide the critical lead time for implementation of vital pre-emptive and precautionary measures.
Personalized Medicine which is of predictive nature, helps individuals take a more proactive approach towards risk reduction.However for predictive medicine to be really effective, the genetic variation should be actionable.
To illustrate with an example, Apolipoprotein E (Apo E) is an important marker since it can modify the cardiac risk due to its interaction with environmental cues. Apo E protein exists in 3 isoforms E2, E3, and E4, the genotype resulting in these isoforms is determined by DNA analysis by PCR (polymerase chain reaction) PCR). These isoforms can interact with diet and lifestyle factors thereby altering the metabolic profile and consequently the risk3. Personalized recommendations based on the genotype can result in risk reduction/modification.
- For Apo E2 genotype: Moderate (35%) fat dietary restriction recommended, low fat diet may increase small dense LDL. These individuals also respond particularly well to statins.
- For Apo E4: Very low (20%) fat dietary restriction recommended. These individuals also show limited response to statins and alcohol intake tends to have a negative effect
- For Apo E3: Normal treatment guideline recommendations. Preventive (25%) fat or moderate (35%) fat dietary restriction determined by overall lipid profile
In some aspects the presence of the genetic variation may just act as an additional risk marker and its presence may necessitate therapeutic or lifestyle modifications to reduce the risk.
For e.g The 9p21 ( chromosome number 9, p arm and band 21) region was first seen to be associated with increased risk of CAD in several genome-wide association studies with an increase in risk ranging from 1.23X to almost 2 fold(4-6). Accordingly knowing that 9p21 carriers are at increased risk health care providers can take steps to characterize and reduce other risk factors that may contribute to the initiation or progression of the disease.
- optimize LDL-C to 100mg/dl in intermediate risk patients
- 70mg/dl in high risk patients
Personalized Medicine (Pharmacogenomics) does away with the one-size fits all concept. In this case the drug dosage is tailored as per the genotype (DNA sequence at a particular position, on a specific gene or locus). Several pharmacogenetic tests are now available and often indicated as a black box warning for drugs. These are often drugs which have a narrow therapeutic index e.g Warfarin, or need to get converted into active form within the body e.g Clopidogrel or are highly toxic e.g Thipurines.
Clopidogrel an anti-platelet agent is administered to individuals who have suffered from cardiac events, to prevent secondary myocardial infarction and stroke and also after percutaneous coronary interventions. Yet a significant number of patients remain at risk for subsequent death because the drug which is in inactive form (pro-drug) is not getting converted into the active form efficiently thereby resulting in insufficient clopidogrel-induced platelet inhibition. The conversion is dependent on the genotype of the hepatic enzyme CYP2C19 which is responsible for the conversion of the pro-drug.
The CYP2C19 *2 (c. 681G>A) genotype and *3 (c. 636G>A) results in a reduced function allele, so there will be slower conversion, poor drug efficacy and patients at risk of therapeutic failure due to lower levels of active drug. These individuals could be heterozygotes (one normal and one reduced function allele) or homozygotes (both reduced function alleles), increase in the dosage or alternate therapy is recommended in such cases.
In summary, there is a rapid health transition in India where the load of communicable and non-communicable diseases (NCDs) is projected to get reversed in 2020 from its distribution in 1990. A large section of the population has moved towards unhealthy lifestyles with decreasing physical activity, increasing stress levels, and increasing intake of saturated fats and tobacco. The average lifespan has increased due to improvements in medical care; the rapidly ageing population, more prone to NCDs, One of the biggest challenges of the present society is to control the rising incidence of Heart Diseases. The cycle of cardiac care starts from the Prevention of the occurrence of any such disease. Measures need to be taken to control risk factors which lead to the development of heart diseases.
Preventive tests which include biochemical parameters determine the current status and help risk estimation. Since heart disease involve both an environmental and a genetic component. It is also necessary to determine the contribution of genetic factors to the risk. Adding genetic markers to routine tests can also help as a compliance tool with which health care practitioners can engage patients in treatment recommendations. Moreover, genetic factors significantly help in personalized prevention plans and treatment. This results in a paradigm shift way from the one size fits all model empirical treatment to a personalized approach.
Contributed by Dr Aparna Bhanushali, PhD, Research Scientist & Senior Manager, R&D, SRL Limited and Dr B R Das, PhD Advisor & Mentor-R&D, Molecular Pathology & Clinical Research Services, SRL Limited.
Disclaimer-The information and views set out in this article are those of the author(s) and do not necessarily reflect the official opinion of M3 India. Neither M3 India nor any person acting on their behalf may be held responsible for the use which may be made of the information contained therein.
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