Are Genetic Tests for Atherosclerosis Ready for Routine Clinical Use?

Pharmacogenetics and personalized medicine is a relatively new field of research, and as of yet has stayed mostly in the realm of pharmaceutical science research, not yet moving into clinical guidelines and practice. In a review done by Brighman and Women’s Hospital of Boston, researchers investigated 3 areas of pharmacogenetics associated with prevention, diagnosis, and treatment of atherosclerosis. They assessed each area on how effective it would be to incorporate genetic information into clinical guidelines and practice, as well as if more research may need to be done to make an effective incorporation.

The 3 areas investigated included: 1) familial hypercholesterolemia (FH), 2) prediction of cardiovascular (CV) risk, and 3) genetic interactions with treatment.

FH is caused by a dominant autosomal genetic defects in low-density lipoprotein (LDL) cholesterol, or bad cholesterol, metabolism which produces unusually high amounts of LDL. Because of this genetic, determining HL status of patients via genetic analysis represents a strong case for incorporating genetic analysis into clinical care.

CV risk presents a slightly less convincing case for pharmacogenetic incorporation into clinical practice, as the risk factors for CV events are numerous, varied, and compound with many comorbidities, and not strongly genetically defined. However, with more research, this may create a stronger case for using pharmacogenetics in clinical practice.

Finally, genetic interactions with treatment has large potential utility to improve efficacy and safety of drug therapy and treatment, both in terms of pharmacodynamics and pharmacokinetics. Factors causing variance are less numerous in treatment than in CV risk, so implementing genetic information to guide clinical prescription and optimization presents an even stronger case than CV risk. It is, however, limited by the necessity to identify candidate genes which vary safety and efficacy of treatment therapies. Additional research to identify these genes will continue to increase the case to use pharmacogenetics in determining optimal treatment options.

I think that this is a good article in that it very clearly makes the connection between the research and clinical components of pharmacogenetic testing. It questions how effective pharmacogenetics would be in actually adjusting clinical practice for a number of areas for this disease state. My question is: which area analyzed by this review do you think will have the biggest impact on the emerging field of personalized medicine, and why do you believe so?

Paynter NP, Ridker PM, Chasman DI. Are genetic tests for atherosclerosis ready for routine clinical use? Circ Res. 2016;118(4):607-19.

Polymorphism Associated with the Selective Serotonin and Serotonin-Norepinephrine Reuptake Inhibitor Response in Depression

Are pharmacogenetics-based strategies the key to effective depression treatment? This study set out to dig deeper into this questions by researching additional polymorphisms affecting the efficacy of SSRIs. Previously, a polymorphism in the serotonin transporter linked promoter region was found to be associated with a difference in SSRI efficacy. This polymorphism, however, only explained a small amount of the differences in efficacy seen in the treatment of those with depression. So this study intended to find additional polymorphisms in the gene coding for the serotonin transporter (SLC6A4) accounting for different responses in SSRI/SNRI treatment. (Remember that the serotonin transporter is the target of serotonin uptake inhibitors)

A 6-week randomized controlled trial of 201 patients with major depressive disorder was performed. Subjects were given paroxetine 20-40 mg/d (SSRI), fluvoxamine 50-150 mg/d (SSRI), or milnacipran 50-75 mg/d (SNRI). Efficacy of the therapy was measured by comparing baseline Hamilton Depression Rating Scale (HAM-D) values with those from the end of the 6 week treatment period. Genomic DNA was gathered from each patient and sequenced so that SLC6A4 mutations could be analyzed. 32 variants were found, and 17 of these were new polymorphisms. One of the polymorphisms, rs3813034, resulted in significantly altered HAM-D scores for each medication administered, suggesting it has an effect on SSRI/SNRI response.

Considering all the treatment hurdles those with depression face (medications take a lot of time for effects to be realized and they may not be effective for many people), I think it is important to research the pharmacogenetics involved with SSRIs. This can help create more individualized treatments for patients who do not have months to spend time putting their well-being on hold while they try numerous antidepressants before finding one that works. Do you think it would be practical and possible to someday have a genotype-based protocol for antidepressant treatments?

Nonen, S et al. Polymorphism of rs3813034 in Serotonin Transporter Gene SLC6A4 Is Associated With the Selective Serotonin and Serotonin-Norepinephrine Reuptake Inhibitor Response in Depressive Disorder: Sequencing Analysis of SLC6A4. J. Clin. Psychopharmacol. 2016; 36(1):27-3.

The IGNITE Network: A Model for Genomic Medicine Implementation

Pharmacogenomics is an up-and-coming field which has a lot of potential to contribute to personalized medicine and optimizing drug therapy outcomes for patients. However, since pharmacogenetics is such a new field, patients, clinicians, and researchers alike are attempting to understand how to gather and use genomic data in order to optimize clinical decision-making, prescribing, and treating.

The National Institutes of Health funded the IGNITE (Implementing GeNomics In pracTicE) Network in 2013 to suport the development and investigation of genomic-based medicine. The goals of IGNITE are to 1) expand genomic medicine implementation efforts, 2) develop collaborative projects in genomic medicine, 3) contribute to evidence-based medicine outcomes using genomic information, and 4) define and share the best practices of genomic medicine. IGNITE consists of 6 members at Duke University, Icahn School of Medicine at Mount Sinai, Indiana University, University of Florida, University of Maryland, and Vanderbilt University, with the Coordinating Center located at University of Pennsylvania. Each center conducts collaborative research on family health history, diabetes, chronic kidney disease, underserved health populations, cancer, and other disease states, all with the goal of determining how genetic libraries and pharmacogenomics can fit into diagnosing, prescribing, and achieving optimal health outcomes.

I am personally very interested in pharmacogenomics and love to see this new field getting national funding which is being participated in by such prestigious universities around the country. However, I wonder if other people feel differently. Do others feel that too much emphasis in modern medicine being placed on the role of pharmacogenomics? Are we pouring too much money into a new field which hasn’t had adequate time to prove its value in informing clinical decision-making? Some people don’t even want to have their genome sequenced (we learned that in Drug Development with Dr. Empey the other week) – are we pouring money into something that most patients won’t even want to participate in? Or do we all believe that sometime in the not-so-distant future we will all have our genomes sequenced for reference at each PCP check-up visit?

Weitzel, KW, Alexander M, Bernhardt BA, et al. The IGNITE network: a model for genomic medicine implementation and research. BMC Med Genomics. 2016;9(1):1.

Racial Differences and the Need for Personalized Medication

The topic of personalized medications has become increasingly prevalent these past few years – and for a very good reason. Genetics evidently play a major role in an individual’s body composition, which affects an individual’s predisposition towards a medical condition and his or her ability to metabolize certain drugs.

This particular study compares testosterone levels among white and black males, which may contribute to the racial discrepancies seen in prostate cancer incidence and mortality. Black men have the highest incidence of prostate cancer in the world. Researchers examined the 1999-2004 National Health and Nutritional Examination Survey, comparing testosterone levels of 355 black and 631 white males. The results of this study demonstrated that between the ages of 12 and 15, black males had lower testosterone levels than white males and levels continued increasing until reaching a peak. Black males’ testosterone levels reached a higher peak at an earlier time and declined faster afterwards than those of the white males. The rapid decrease in testosterone levels of black males in comparison with white males may very well parallel the high number of prostate cancer incidences seen in black males.

The results of this study emphasize the effect genetics has on an individual’s health and pharmacological needs. Due to the correlation between rapidly dropping testosterone levels and high incidences of prostate cancer among black males, personalized medication for hormone replacement therapy could be a necessity for black males.

While patients are usually aware of their family history of medical conditions, they may not be aware of the extent to which genetics plays a role in many aspects of their health and well being. Personalized medications could be the answer to patients’ questions regarding why they need to take a certain medication or why certain medications do not work on them. Educating both health care practitioners and patients on the importance of genetics and personalized medication can pave the way to prevent or treat many of today’s prevalent diseases and improve the overall health of patients.

Hu H, Odedina FT, Reams RR, et al. Racial Differences in Age-Related Variation of Testosterone Levels Among US Males: Potential Implications for Prostate Cancer and Personalized Medication. J Racial Ethn Health Disparities. 2015 Mar;2(1):69-76

Pharmacogenomics & A New Target Therapy for Schizophrenia

Schizophrenia is one of the earliest recorded and least understood mental illness that we face today. Schizophrenia is a chronic and severe mental disorder characterized by hallucinations, delusions, movement disorders, and withdrawal from others. The current treatments for schizophrenia are limited, and they tend to treat only the psychotic symptoms of the disease. Targeting the cause of the disease has been – until now – impossible, as much remains unknown about the pathology of schizophrenia. While it has been known that schizophrenic symptoms are associated with excessive synaptic pruning (removal of synapses in the brain during adolescence and young adulthood) – and this correlates to the typical interval of onset of the disease during adolescence and young adulthood – the exact mechanism of how the disease develops has remained a mystery until now.

A collaborative research team from Broad Institute, Harvard Medical School, and Boston Children’s Hospital has recently published results that suggest a genetic basis for the onset of schizophrenia symptoms. Their genetic analysis of almost 65 000 people points to overexpression of the complement component 4 (C4) gene in the expression of Alzheimer’s disease. Complement protein genes can be present in varying alleles, and different alleles (DNA) directly affect the overall expression level (mRNA) of the gene. In other words, the variation of the genetic sequence of the gene directly impacts the amount of protein produced.

Complement proteins have a well-established role in the immune system, where they tag foreign pathogens for destruction by phagocytic immune cells. However, their role in neurology is an entirely novel discovery. Researchers were able to localize the C4 proteins to neural synapses in humans, and proved that in mice they contributed to the synaptic pruning process during postnatal development.

Because of this study, a molecular basis of schizophrenia as a disease is now in the works. By understanding the molecular cause of the disease, researchers will be better able to identify therapeutic targets and develop new pharmaceutics and other treatments which go after the cause and onset of disease, rather than just managing the symptoms.

This article made me think about the emerging role of genetics in healthcare. By understanding the genetic expression associated with schizophrenia, researchers will be better able to pinpoint the molecular basis of the disease and create better therapeutics which target the cause of the disease, instead of just the symptoms. There is a new intersection of basic science (genetics) and therapeutics (pharmacy and medicine) that is entirely new to science and healthcare. This makes me wonder – should we be focusing more on basic science, such as genetics, during our professional curriculum so that we will be able to both understand and contribute to emerging healthcare technologies, such as pharmacogenetics? Or is that role reserved for PhDs?

Additionally, what other types of disease states are there out there for which pharmacogenetic analysis would help us to determine the cause, and can we create better medicines that target the cause rather than just the symptoms? One that I think of are benzodiazepines, which treat only the physical symptoms of anxiety instead of the psycho-cognitive causes.

Sekar A, Bialas AR, de Rivera H, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016;530;177–183.

 

Community Pharmacists’ Experience with Pharmacogenetic Testing

This aim of this study was to investigate the experience and perfection of pharmacogenetic (PGx) testing in the community pharmacy setting. PGx testing has had a significant impact on many different health fields such as psychiatry and oncology. The dosing of several drugs now rely on a patient’s genetic profile. For example, it has been found that up to 30% of people of European descent experience a lack of therapeutic effect from clopidogrel. This is due to a variant in the CYP2C19 gene. Also, a variant in the SLOC1B1 gene is associated with reduced efficacy of simvastatin. The PGx services are most commonly utilized in a clinic or in a hospital setting. However, it is only just beginning to be utilized in a community pharmacy setting.

The study focused on patient interest in PGx testing, amount of time pharmacists take to administer PGx testing, patient comprehension of results, pharmacist interactions with the patient’s physician after PGx testing and how the PGx testing affected the patient’s prescriptions. For each patient in the study, pharmacists completed surveys at two different time points that PGx. The participating pharmacies then offered testing for the CYP2C19 for patients who take clopidogrel and/or SLCO1B1 gene for those taking simvastatin. A buccal test was collected using the Harmonyx test kits. Within 1 week, results were sent to the patient’s healthcare provider and pharmacist. Testing took place across 5 independent community pharmacies in North Carolina. Of the patients offered, 81% agreed to the testing. The main reason patients declined was they felt there were no problems with their medications and thought testing was uncessary. 54% of pharmacists reported their patients understood the results “very well”. The amount of time to discuss results was normally brief, and 73% of patients had no questions or concerns about their results. Most results didn’t indicate a need to change a prescription or dose.

The findings of the study suggest that PGx testing is not too time-consuming in the community pharmacy setting. Patients also are interested and have very little concerns about the testing. It possible that so many patients agreed to the testing due to their trust in pharmacists and that the testing was relatively non-invasive. Pharmacists have expressed interest in the PGx testing, but also acknowledge they need more education in that area. This means that additional PGx testing education for pharmacists would be beneficial. This could be a potential limitation for companies that may not want to pay for additional training. Perhaps PGx courses could be added in pharmacy school curricula to avoid this problem. Additional studies could also be useful to further determine patient satisfaction and understanding of the testing. Overall, PGx testing in a community pharmacy setting seems to be feasible. What are some ways we can work towards making pharmacogenetic testing more available in community pharmacies?

 

Moaddeb J, Mills R, Haga SB. Community pharmacists’ experience with pharmacogenetic testing. J Am Pharm Assoc. 2015;55:587-94.