| Pankaj Mankad |
It was just a decade ago that complete human genome sequence was established by a 13-year-long — Human Genome Project — an international collaborative research programme, at the cost of circa $2.7 billion. Genomic science, since, has progressed in leaps and bounds with a potential to influence our daily life, health and wellness. Peri passu commercial translation of this modern research into personalised medicine is already here in India. It is not a question of if, but when and how these recent advances will be integrated into medicine and will have noticeable impact on our lives? At this early stage the question for consumers could be “Is this all Hype or is there Hope?” Here, we shall address this question objectively looking into the role and current limitations of personal genomics in health and disease.
Personal genomic information has the potential to influence our health through several domains. These include; Disgenomics plus oncogenomics – Science which assesses our genetic predisposition/risk of developing various chronic diseases and certain cancers; Pharmacogenomics – Study of how our genes regulate drug responses, and Nutrigenomics –Science related to interaction between nutritional components and our genes. Let us first examine the basics.
The basics
Genes, storing our unique personal information, are located in 23 pairs of chromosomes, present in every single cell in our body. One member of each chromosome pair is from mother; the other is from father. Genes consist of DNA; which has four nucleotide bases and they must remain in pairs to help form proteins for body functions. The nucleotides are: A (Adenine), T(Thymine), C (Cytosine) and G (Guianine). There are millions of these bases in a chromosome. They always have their fixed location. If a single base is replaced by another base, say A by C, it results in a variant gene and in medical term is called SNP (Single Nucleotide Polymorphism). Not all SNPs are harmful but all problems arise because of SNPs and other gene abnormalities. Over the past two decades, candidate gene association studies and, more recently, Genome Wide Association Studies (GWAS) and International HapMap project have established tens of thousands of SNP associations with common chronic diseases, cancers and metabolic traits. These form the basis of personal genomics in maintaining health and well being.
A particular SNP may either increase or even reduce the risk of developing a disease. Once genome test is done, statistical association of every relevant SNP with many important common diseases is made to derive one’s relative risk of developing a disease. Although ethnic genetic data about Indian population are sparse, it is fair to begin this process using available information from Caucasian population and if possible, creating weighted database to suit our population. Failing this, we will never be able to catch up with the science let alone even begin the process.
Chronic diseases, disgenomics and personalised medicine
Today, chronic non-communicable diseases (NCDs) form nearly two thirds of total disease burden in our country. Deaths due to NCDs are more than double compared to communicable diseases (WHO data). Adverse financial impact of these in the society is devastating. The good news is that nearly three in every four chronic conditions are preventable. Prevention becomes much more focused when one’s risks are known. Genetic assessment, however, is not alone in this game. Genetic predicted risk combined with information about a person’s lifestyle, diet, environment, and medical history will enable doctors to treat disease much more effectively and in many cases even prevent it.
This is personalised medicine. It is a broad and rapidly advancing field of healthcare that is informed by each person’s unique clinical, genetic, genomic and environmental information. Use of this information in an integrated and evidence-based manner to individualising personal care across the continuum from health to disease is the best way forward.
We know that heart disease risk can be reduced by lowering dietary intake of fat and salt, exercising more, and taking a cholesterol lowering medication. However, heart disease is not simply a condition caused by excess fat and cholesterol. There are many other modifiable risk factors, some genetically influenced, which can predispose a person to heart disease.
For example, many people, as high as 40 per cent in some studies, have a genetic inability to properly metabolise folic acid in the body (MTHFR gene). This can lead to a build-up of homocysteine in the bloodstream, causing increased risk of blood clots and atherosclerosis. For a person with this genetic variation, the only way to reduce risk is to take the active form of folic acid, which is not found in common vitamin supplements. Thus genomics-enabled medical technology can run various what-if scenarios and combine related genetic data to disease risk and show whether diet, exercise, medication, or some other factor or combination of factors has the greatest statistical likelihood of reducing that risk.
Epigenetics
If I have a genetic susceptibility to develop heart disease, with a strong family history, is it not the final nail in the coffin (pun intended)? No, not at all. Here comes the science of Epigenetics. In order for a disease to develop, the genes must be expressed in abnormal proteins. Gene expression is governed by the cellular material — the epigenome — that sits on top of the genome, just outside it (hence the prefix epi-above). It is these epigenetic ‘marks’ that tell the genes to switch on or off. A gene that is turned off can cause little harm. It is through these epigenetic marks that environmental factors like diet, stress, exercise, prenatal nutrition etc can make an imprint on genes and is even passed from one generation to the next. So our good habits now may also be beneficial to our children in future!
Pharamcogenomics and personalised medicine
Pharmacogenomics has already been successful in improving drug prescription and dosing. Most prescriptions are written with a ‘one dose fits all’ approach with adjustments based on gender, weight, liver and kidney functions or allergies. Some drugs have more laborious dosing calculations such as the anticoagulant warfarin. Warfarin dosing is traditionally determined by a time-intensive ‘guess and test’ method, until the coagulation tests stabilise. Pharmacogenomics identified several SNPs, such as CYP2C9 and VKORC1, affecting dosing of warfarin. One study found that a hypothetical pharmacogenetically driven clinical trial of the anticoagulant warfarin could save up to 60 per cent of the cost and reduce possible adverse events. Similar studies have been applied to thiopurines trastuzumab and imatinib for cancer, clopidogrel, tramadol, anti-psychotics, abacavir, carbamazepine, clozapine and many other drugs that all have significant genetic associations.
Caveats and challenges
A few caveats about the genomics opportunity are in order here. First, the available databases of known disease-causing genetic mutations, although vast, are still evolving and subject to interpretative error. Prediction studies so far have been rather simplistic in the sense that most were based on a small number of variants that by themselves explain only a fraction of the genetic variability.
Interpretation of results should be also be done with caution, particularly by a lay person. It is important that a medical doctor and preferably a geneticist are involved in interpretation and discussion with a person. Negative risk should not provide false reassurance and be regarded as a licence to indulge! Remember that most conditions are based on many factors; genetics is only one of them.
One of the unknowns is the extent to which genomic information can motivate people to change their health-related behaviours. Can the specificity and personalination of genomic information—i.e., being told that you have an X-fold increased risk of heart disease can motivate change? Ignorance is bliss or Knowledge is power? Time will tell.
Use of the personal genome also raises ethical concerns. If someone has access to an individual’s genetic profile, it could affect decisions made regarding that person, such as denial of employment or life insurance. In the US, the Genetic Information Non-discrimination Act of 2008 protects against discrimination by health insurers and employers on the basis of DNA information.
Despite the need for caution, personal genomic testing provides an opportunity for us — all of us, both providers and patients — to learn about genomics and its role in predicting disease risk and adverse drug responses. It can also provide an opportunity to investigate your heritage and network with others who share similar genealogy and disease risk.
Need of the hour
Critical to the widespread acceptance of the role of personal genomics in health and disease is the need to educate physicians and the public about the realistic benefits and risks of such an analysis to prevent over interpretation and misuse of this valuable information. It is important for everyone to educate themselves on these topics. Two authoritative resources include the Personal Genome Project and the Personalized Medicine Coalition.
The cost to sequence a full human genome is falling like a rock. Estimates suggest that it could be less than $1,000 by the end of this year. What’s more, our ability to analyse the terabyte of data generated by sequencing one genome is also improving. This is a very rapidly evolving field of medicine not only for scientists, researchers, and clinicians but also for investors as dozens of big data start ups and a torrent of venture capital money is pouring into the hot new genome interpretation space. Let us not sit back but remain informed and take proactive steps to lifelong health and wellness.