By Michael A. Nasiak, Xiangning Chen, Ging Wu, Mira Han, Justin Zhan, Jingchun Chen, Jenica L. Abrudan & Martin R. Schiller
Already, elements of genomics are being incorporated into standards of care, while continued consumer-driven marketing tactics have been successful in capturing the imagination of the public seeking its potential. Our patients have therefore become acutely aware that their health can be impacted in some positive way. With the nearly daily discoveries heralded in the news – and, at times, with concurrent and possibly misleading hype – of how the knowledge of applying genomics can counteract the afflictions endured by humanity, those seeking guidance will turn to us for clarifying how we can make a real difference in their well-being. Our duty must be ensuring we have a familiarity of the fundamentals concerning what Personalized Medicine can (and can’t) promise, as the applications currently available are but a fraction of what is forthcoming.
Of course, conceptually we all can appreciate the potential power in knowing one’s genetic code to assess risk and offer selected care for disease, but the application of using this information is only now beginning to permeate all of the different aspects of clinical practice, and requires our vigilance to ensure we engage and adopt strategies that will ultimately incur the best benefit for our patients. The discoveries of associations, or even (if fortunate) the causality, of medical ailments are continually improving our diagnostic and therapeutic acumen, and with this current revolution in healthcare being still in its infancy, we are all on a journey of learning and teaching ourselves, our colleagues, and our patients on how to apply what is known in a meaningful and practical way. Meanwhile, the staggering speed of technical advancements which has permitted us to peer at our DNA so precisely, and has made all of this possible, continues its monotonic trend of faster, cheaper, and frankly just better genetic testing and treatment protocols progress. The clinician of this era has an opportunity to impact the health of others in a manner unknown even a generation ago. This is an exciting time to be in Today’s Practice.
The genetic blueprint which makes us who we are is almost the exactly the same in all of us. However, our individual genomes contain over a million scattered variations, giving each of us our uniqueness not only in the specialness of our individuality, but also in our vulnerabilities. Although only about one percent or so of our genome makes up the coding portion (that is, where the directions for protein structure are transcribed), this fraction, called the “Exome,” is where we currently know the most in terms of the litany of genetic disorders so far described by medical science. If you will, the Exome encompasses where the genes are. This is not to say the vast bulk of the noncoding so-called “junk” DNA doesn’t play an important role in disease, as it clearly does, but we’re still learning how our health is specifically impacted by these regions and presumably by the various complex epigenetic mechanisms involved. Instead, with a recent focus on the Exome, each variant discovered within
a gene, representing an allele of this gene, can now be recognized and catalogued with any discovered association amongst a myriad of diseases. The power of such information is (as best as the data allows) that this can then permit us to classify whether a benign versus a pathogenic assignment should be ascribed to a variant based on the ascribed clinical effect.
We already know of thousands of variants in regards to their clinical phenotype, and we’re even certain of many hundreds gleaned from combing a multitude of patients’ Exomes of ones that are considered “clinically actionable,” meaning intervention on the person’s behalf has demonstrable benefits concerning their health and outcome, which is a triumph of Personalized Medicine. Yet, in certain instances when trying to label a variant’s role in disease pathogenicity, we’re still struggling as we can’t always definitively say as to how it is behaving, and are forced to call such variants “of undetermined significance.” This only adds to the frustration seen when healthcare professionals in Today’s Practice inform our patients, and care must be taken to not convey an unfounded conclusion as to the significance (or lack thereof) of what can be a confusing topic. As more data accumulates in the realm of variant classification, we can hope to supply better answers to those perplexed by formerly uninformative information. The understanding of these variant changes is truly crucial, as eluding their disease-causing potential will clearly affect how to offer valued management while not overcompensating in regards to actions which would be deemed unnecessary to advance our patients’ health. This current quagmire remains one of the most vexing challenges facing the implementation of Personalized Medicine today, but is ultimately solvable, is an active area of ongoing research, and can impact whole cohorts of persons who are carriers of variants and are justifiably worried of their individual risk for disease. That’s why we’re in the business of healthcare, and this is why we’re dedicated to find the answers our patients seek for their benefit.
Personalized Medicine can also offer and inform tremendously to our society the risks of disorders we didn’t know had such a pervasive genetic component. And as the tenets of Personalized Medicine becomes more robust and ubiquitous in clinical practices, we need to know when and how to apply this approach against the conditions afflicting our patients individually, while recognizing and addressing the burden of disease endured by the public. With so much to pick from, perhaps considering a few examples of where genes and their manifestations have been coupled can offer germane insights within the rubric of frequently-seen clinical care encounters, and comment on how these can be applied in a clinical practice setting.
A Novel Way to Treat Hypercholesterolemia: Using the PCSK9 Gene…
Let’s consider first the value of understanding the genetics of a gene known as PCSK9 (note the gene name is italicized by convention), which is intimately involved with how needed LDL-Cholesterol (LDL-C) is taken into the cells of our body. The resultant translated protein (called the PCSK9 protein, which is not italicized) from this gene is secreted by the liver into the circulation and can bind concurrently to the LDL-Receptors (LDLR) present on the cellular surface of end-organ tissues; when LDL-C binds to LDLR (which it must for subsequent endocytosis and transport into the cell) with a PCSK9 protein also present, the LDLR is then degraded in the cellular lysosomes (the cell’s “garbage and recycling center”) and can no longer return to the cell membrane for further LDL-C particles to bind. With this knowledge, researchers have been looking at how this gene is affecting public health, and their findings were stunning. Heterozygous carriers of mutations in the PCSK9 gene, where one of two copies of the gene encode a loss of function of the PCSK9 protein, lead to more cell surface LDLR to be present on cell surfaces. This is because less PCSK9 protein binds to the LDLR, and therefore less LDLR is degraded, allowing for continued tissue LDL-C uptake from the bloodstream. Those who happen to have this type of genetic variant were recognized to have significantly lower LDL-C levels when measured on a lipid panel; as compared to the general public, these carriers were then confirmed to have lower incidences of cardiovascular disease, as might be expected.
Homozygous or compound heterozygous individuals had even better results, implying there is a gene-dosage effect. Conversely, and of enormous clinical importance, there turned out to be a percentage of the population which has a different set of mutations in this gene which instead led to the PCSK9 protein product having increased activity. This results in more cell-surface LDLR undergoing lysosomal degradation after endocytosis, and therefore leading to higher serum LDL-C levels; this can cause a form of hypercholesterolemia, specifically a subtype of Familial Hypercholesterolemia (FH), and afflicted individuals have been shown to have higher established rates for cardiovascular disease. Recall, however, that most cases of hypercholesterolemia don’t have this mechanism, but the sequelae are still the same: higher LDL-C has been firmly tied to progressive atherosclerotic vascular changes detrimental to cardiovascular health, and therapies to reduce serum LDL-C levels have proven paramount in primary and secondary disease prevention. To address this, statins remain of enormous help in cardiovascular disease reduction over the past few decades, but the ability to tolerate this class of drugs is an ongoing common clinical problem well-known in clinical practice. Instead, if another mechanism to lower cholesterol could be employed, the benefits would be of true value. Ezetimibe, even with its side-effects, is an example of an alternative approach, with modest benefits noted in high-risk cases, but statins must be continued as well.
Alternatively, researchers began questioning if decreasing the activity of the PCSK9 protein could be an option, as then the expected reduction of LDL-C should only add to cardiovascular disease reduction. Such therapies are now already in development, with the use of monoclonal antibodies against the PCSK9 protein, and current clinical trials so far in treating hypercholesterolemia appear to show measureable improvements for our patients. As the use of such agents enter Today’s Practice, these therapies are predicted to add tremendously to the medical armamentarium confronting atherosclerotic cardiovascular disease. In fact, there even is a likely extra benefit, as one apparent effect of statin therapy is to cause a compensatory inducement of higher PCSK9 production and serum levels. Coadministration of PCSK9 protein inhibitors with a statin protocol should then supply an additively efficacious response in dropping LDL-C values. Although initially everyone may potentially benefit by the use of PCSK9 inhibition, in cases of hypercholesterolemia, ongoing studies should answer how best to apply directed treatment for established disease-causing PCSK9 variants amongst the populace; this represents a future paradigm of possibly only prescribing this drug, with its potential side effects (and cost), to those who would incur the best results. The era of individualized therapies for the treatment of hypercholesterolemia is now within reach, and the implications for our patients’ health will be truly tremendous.
Progressive Renal failure in African-Americans:
The APOL1 Variants and the Havoc Inflicted…
In trying to understand why African-Americans (e.g., those of former African Ancestry) have a several-fold increase of developing kidney failure as compared to Americans of European decent, linkage studies led to the realization that at least one of the culprits was an interesting gene known as APOL1. Two important variant alleles called G1 and G2 have been identified (and different from the wild-type seen in most individuals), and apparently these seem to have been evolutionarily selected for only a few thousand years ago. We all have two homologous copies of the APOL1 gene, which produces the Apol1 protein to aide in lipid transport in the circulation, but specifically in African-Americans, up to half of this distinct population carries either the G1 or the G2 alleles (each with two specific mutations), or both.
With such a strikingly high frequency of these variant alleles in such a short period of time, the only explanation which makes sense is that the benefits to the African ancestors who carried these alleles must have been quite pronounced, and indeed further studies have indicated that these alleles (whether either one or two are present) are successful in specifically supplying pathogen resistance to African trypanosomiasis, also called “African sleeping sickness.” This awful parasitic disease has had a longstanding endemic presence throughout Sub-Saharan Africa. However, with the cultural development of pastoral societies at the dawn of human civilization, environmental circumstances allowed for trypanosomiasis to spread and become more prevalent, placing selective pressures favoring either the G1 or the G2 alleles, thereby explaining their common current allelic frequencies. These same alleles, although protective regarding the potential for contracting this parasitic infection, which is not present in the temperate climates of North America in modern times, also now seem to have placed hypertensive carriers at risk for a higher chance of renal failure and accelerated kidney disease progression even if their concurrent hypertension is well-controlled on standard antihypertensive medications. However, this APOL1-associated renal deterioration is seen specifically if a homozygous or compound heterozygous genotype with the G1 or G2 alleles is present, and not with only one allele in an individual; hence this very much behaves like an autosomal recessive disorder, where there appears to be other modifying factors (likely genetic, but not necessarily so) which have yet to be clarified. Note too that not all at-risk individuals with two variant alleles appear to develop renal disease. Also, idiopathic focal segmental glomerulosclerosis and even HIV-associated nephropathy are believed to be associated with the same genotypes seen in APOL1-associated renal disease, but delineating factors are still not certain.
Current assessments suggest a net value of about 40% of African-Americans who will end up in renal failure and on some form of dialysis can be attributable to these allelic mutations in this gene, which is a staggering number. Note that efforts to combat such disease progression in these individuals have, so far, met with little success, and this point cannot be overstated. Often clinicians misdiagnose progressive renal impairment with resultant end-stage renal failure in African-Americans on occult uncontrolled high blood pressure (even when normotensive values are encountered), when in actuality these patients instead are carriers of the G1 and/or G2 alleles which produce a defective Apol1 protein that literally damages their kidney cells. Hence, with genotyping now available, the assessment of ongoing and unexplained progressive renal impairment in this population can include the evaluation of the APOL1 gene, and if the result establishes a diagnosis, a directed plan as to how to manage the expected sequelae can then be devised. The hope eventually is how to choose or approach untested options as potential therapies which might effectively ameliorate this newly recognized disorder, and there is significant interest already in the discipline of Nephrology for just this purpose. For our patients and at this time, however, even offering a diagnosis has immeasurable value, and this discovery can begin to open the search for ways to combat what is a major health issue amongst the African-American community.
Early-Onset familial Alzheimer Disease: Three Genes So Far…
The development of dementia from Alzheimer disease (AD) is devastating enough when patients and their families are confronted with this diagnosis, with little positive to say except usually this is seen in the advanced years of life – an unfortunate but common ailment amongst our senior citizens. The majority of cases seen in clinical practice are sporadic, however about 1-5% of those who are diagnosed with this affliction occur before their 65th birthday, with just over half of that number displaying other family members with the same clinical phenotype; under such circumstances, these cases are given the label of having Early-Onset Familial Alzheimer disease (EOFAD) if there is what appears to be a classic autosomal dominant Mendelian inheritance. Such a delineation has proven distinctly helpful as three indistinguishable subtypes have now been recognized, each the result of a mutation in a specific gene. As there is high penetrance of these conditions, there designations are labeled as Alzheimer disease type 1 designation (AD1) caused by APP gene mutations, AD type 3 (AD3) caused by PSEN1 gene mutations, and AD type 4 (AD4) caused by PSEN2 gene mutations. (The AD2 designation is for the better-known and sporadic Late-Onset Familial Alzheimer Disease.) This stated, AD1, AD3 and AD4 are still, overall, relatively rare, and genetic testing at this point, although available, is usually investigational (mostly in research laboratories). However, recognizing EOFAD remains important as specifically looking for APP, PSEN1 and PSEN2 mutations can now be an option to patients exhibiting symptoms at an unexpectedly young age, and this should be discussed with them (or their caretakers); the benefit of this strategy is, when the diagnosis is confirmed, this allows for early intervention of observed clinical manifestations already known to be present in this disorder, or concurrently to preemptively consider therapies which may prove to delay or protect against the progressive nature of AD.
The more complex issue is if asymptomatic family members at risk for EOFAD want testing, which although possible to adults contemplating “the Test,” is fraught with ethical considerations (including patient privacy of testing results) of ensuring they understand what the results will mean and can cope with their awareness if discovered to be carriers of their family’s heritable condition. This stated, currently herculean efforts to diagnose, and therapeutically treat, patients presymptomatically are underway. Much more is yet to come as medical researchers continue aggressively to find ways to ameliorate or at least retard the advancement of cognitive decline so well characterized by the most common cause of dementia seen in our patients
As Personalized Medicine in the era of genomics begins supplying discovery after discovery of associations, and even many causations, to the litany of medical disorders continually seen in clinical practice, the relevance of applicability must also be at the forefront. We must each assess the attained benefits in terms of diagnosis and management, and this must outweigh the risks and ethical concerns of testing as well as any attached resource utilization (please read “cost”). Whether direct therapeutics, or offering indirect therapy for primary or secondary prevention, or even if testing stops the ongoing nightmare of a “diagnostic odyssey,” the application of applying medical care which can be individualized should advance our goals of supplying better healthcare as per every measure – that, at least is the belief. The practical use of looking at the genomes of persons and then utilizing the results directly to them is still relatively new to clinical care, and might be seen a novelty to all involved. But the reports supplied and the data they contain (and don’t contain), when unleashed in Today’s Practice, may not be of complete certainty with regards to significance or even completeness, and this informational relevance often becomes a judgment call when added to the assessment of all of the other parameters phenotypically recognized when evaluating a single individual. The results of testing, for example, may not be as valued as hoped for, or worse, may be of no use whatsoever. This is where the decision of when Personalized Medicine is applicable for direct clinical intervention and therapeutics becomes essential; application guidelines are still formative, and will be a point of ongoing dialogue within the healthcare community as our experience and familiarity with the subtleties of genomics matures. This should not, however, prohibit our pursuit of implementation when we feel our patients will incur benefit.
Also, we must be mindful too when choosing how to use this new discipline in a way where privacy is strictly protected with well-defined and limited data access, as the information obtained is about as personal as one can get – knowing something about another’s genetics and the personal and societal implications which can result. In structuring the pursuance of applying Personalized Medicine, therefore, transparency and buy-in from our patients is as important as acceptance of the use of these strategies from those who care for them. This is why our educational familiarity to how we should (and, at times, shouldn’t) use the tenets of Personalized Medicine is of paramount importance. Our oath as healthcare providers dictates in no uncertain terms the admonition to “First, do no harm.” However, the application of Personalized Medicine as a directional approach to care clearly ensures that this pledge is met, and does so at many levels: with a precision rarely available in traditional models of clinical practice, our goal becomes giving our patients the maximum benefits reflecting their individuality and not just applying generalized standards of care which may or may not incur the best outcome. By not treating each person with a “One Size Fits All” approach, we can limit the harm of wasted time, resources and possibly injury to those who entrust their health to us. The promises of what this new paradigm of healthcare delivery can give cannot be overstated. Yes, it’s certainly an exciting time to be in Today’s Practice.