These biomarkers—and others—can be used to study both normal physiologic function and pathophysiologic states. Findings from such studies are being incorporated into clinical decision making for the prevention, screening, diagnosis, prognosis, treatment, and monitoring of disease and to predict responses to environmental exposures or medical interventions.8, 9
Predictive biomarkers. In humans, for example, a number of drugs are metabolized by the cytochrome P-450 (CYP) 2D6 enzyme, which is encoded by the CYP2D6 gene. More than 100 CYP2D6 alleles (alternative forms of the gene) have been defined by the Cytochrome P450 Nomenclature Committee and can be used—some now and some in the future—to predict which patients are more likely to have desired or adverse responses to various drugs, including codeine, a prodrug that the CYP2D6 enzyme converts to morphine (the active drug) for pain relief.10 This knowledge has been used to create a scoring tool that classifies people by likely codeine metabolism phenotype into poor, intermediate, extensive, or ultrarapid metabolizers.10
Normally, people have copies of two functional alleles of the CYP2D6 gene (one from each parent), but as many as 2% of the population inherit more than two functional copies. Such people are referred to as ultrarapid metabolizers because their CYP2D6 enzyme system processes codeine at a much faster rate than that of those who have copies of only two functional alleles.10 On the other end of the spectrum, as many as 10% of the population are poor metabolizers of codeine because they have no functional alleles of the gene. Whereas ultrarapid metabolizers quickly convert codeine into morphine, potentially leading to morphine toxicity, poor metabolizers receive little to no analgesia from the administration of the drug. The CYP2D6 genotype is thus a useful biomarker for predicting which patients might have adverse or inadequate responses to codeine and other drugs.
Tailoring patient care based on genomic biomarkers requires highly competent practicing physicians, advanced practice nurses, RNs, LPNs, and pharmacists who understand the omics sciences.11
THE PRECISION MEDICINE INITIATIVE
The idea underlying precision medicine isn't new. Prescription eyeglasses and blood typing have been in use for more than a century. Just as ophthalmology and blood typing reveal people's unique characteristics, the technologies used in precision medicine uncover distinctive biomarkers, such as gene variants and altered levels of certain hormones or metabolites, which may be used in conjunction with lifestyle and environmental information to prevent, diagnose, treat, and monitor disease. The National Institutes of Health notes, however, that “while some advances in precision medicine have been made, the practice is not currently in use for most diseases.”12
Concerns about the initiative. Many have expressed concerns that despite precision medicine helping only a small proportion of the population, its funding may come at the expense of other initiatives with much broader applicability.13 Although precision medicine holds much hope for some patients, many groups, including lower-income populations, the uninsured, and racial and ethnic minorities, have not been well represented in research studies, in part because of lack of access and the high cost of health care.13 There are thus fears that the findings of precision medicine studies may be inherently biased. Furthermore, precision medicine studies often require participants to allow significant amounts of biological data and specimens to be stored for use in future research whose specific purpose is not yet known, a practice that may breed mistrust and fears of stigmatization or loss of privacy, further limiting the diversity of the populations studied.13-15
‘All of Us.’ An important component of the Precision Medicine Initiative is the creation of a research cohort comprising at least 1 million volunteer participants who represent the diversity of the U.S. population with regard to age, health status, race, socioeconomic background, and environmental exposures. This cohort, referred to as “All of Us” (see https://allofus.nih.gov), lays the groundwork for a new way of conducting research. The underlying idea is that response to therapy, which varies among patients from highly effective to ineffective to detrimental, is often rooted in unrecognized pathophysiologic, environmental, behavioral, and genetic factors.16 But a diverse cohort, 1 million strong, could enable researchers to identify many of the unknown circumstances that influence both disease risk and response to treatment, allowing them to develop better targeted preventive and therapeutic strategies. Just as lung, breast, and colon cancers are treated based on tumor genotype rather than disease site, it's now possible to treat chronic myeloid leukemia, in which the BCR-ABL fusion gene is a driving force, with imatinib (Gleevec), a tyrosine kinase inhibitor that targets BCR-ABL.17 The hope is that the data obtained from the All of Us cohort will reveal more about drug–gene (pharmacogenomic) and gene–gene associations, lead to the discovery of new biomarkers and drug therapies, and illuminate the effects of lifestyle and environment on patients' responses to numerous therapies.16 (See How to Be a Part of ‘All of Us.’)
Pharmacogenomics, which combines pharmacologic and genomic data to predict a patient's response to medications, underlies the basic premise of the Precision Medicine Initiative. Through pharmacogenomics, we have learned that alterations in DNA sequences can change the expression or function of proteins that are targeted by drugs or involved in drug metabolism or absorption, possibly affecting the patient's response. Genomic variations affecting drug metabolism are explored using targeted single-gene techniques (pharmacogenetics) or global techniques that consider the entire genome (pharmacogenomics).
Pharmaco-omics, which grew out of pharmacogenomics, is the study of how data from the various omics sciences can be used to individualize and optimize drug therapy.18 Each year, adverse drug effects are responsible for more than 1 million ED visits in the United States.19 In fact, approximately 7% of the medications approved by the U.S. Food and Drug Administration (FDA), which represent 18% of U.S. outpatient prescriptions, are affected by “actionable pharmacogenes”—that is, genetic variants for which there is clear evidence of a clinical effect.20
Lifestyle and environmental exposures must also be considered in precision medicine, because while genetic information flows from DNA through mRNA to proteins, lifestyle and environmental exposures can influence the process at every step. The study of environmental influences on gene expression is called epigenetics. By extension, the study of environmental influences on the expression of genes that affect response to drugs is known as pharmacoepigenetics. Together, pharmacoepigenetics and pharmaco-omics can help clinicians tailor treatments to patients' unique needs, which is the practice known as precision medicine (see Figure 1).
PRECISION MEDICINE AND NURSING CARE
In precision medicine, a patient's course of treatment, medications, and dosages are influenced by pathophysiologic, behavioral, genetic, and environmental (including socioeconomic) factors. Precision medicine affects nearly every aspect of nursing care, from admission assessment and collection of family history to postdischarge monitoring, regardless of the nurse's work setting, academic preparation, or clinical specialty.21 During the initial patient encounter, nurses document a comprehensive list of health issues experienced by all family members, including those who have died, especially if death was sudden or occurred at an early age. For example, a family history of sudden death in a patient presenting with syncope and a prolonged QTc interval should alert the nurse to refer the patient for further testing, including genetic testing. Studies have shown that long QT syndrome (LQTS) has genetic causes in at least 75% of those affected.22 However, congenital LQTS and drug-induced LQTS share many common features. Referral will expedite appropriate diagnostic testing, including genetic testing as indicated, and determine the appropriate diagnosis and treatment. Working as a team, the nurse and the patient or family members identify health trends in the family history, paying special attention to diagnoses, symptomology, causes of death, and sensitivity or adverse reactions to any drugs, such as those metabolized by the CYP2D6 enzyme.
Ultrarapid metabolizers. In 2012, Kelly and colleagues reported on two cases of death and one case of life-threatening respiratory depression following codeine administration to children who had undergone adenotonsillectomy for obstructive sleep apnea.23 Postmortem genotyping revealed that one of the children who died was an ultrarapid metabolizer of codeine owing to CYP2D6 gene duplication. In the second case of death, postmortem blood samples strongly suggested that the child was also an ultrarapid metabolizer of codeine because the concentration of morphine was exceptionally high compared with that of codeine. In the third case, the child was successfully resuscitated after having been found unresponsive with a fever of 100°F (37.8°C) and an oxygen saturation level of 65%. Subsequent genotyping suggested she was an extensive codeine metabolizer, but morphine levels suggested ultrarapid metabolism, which was inconsistent with her genotype.
Restrictions on codeine and tramadol. CYP2D6 genetic variability among patients has led the FDA, American Academy of Pediatrics, Clinical Pharmacogenetics Implementation Consortium (CPIC), World Health Organization, and European Medicines Agency to issue restrictions, strong warnings, and recommendations on codeine.10, 24-26 In addition, the FDA has restricted the use of tramadol (Conzip, Ultram), which is also metabolized, at least in part, by the CYP2D6 enzyme. Both drugs are now contraindicated by the FDA in the treatment of children under age 12 and in those under age 18 in the presence of obesity, obstructive sleep apnea, or severe lung disease. Tramadol is further contraindicated in the treatment of pain in children under age 18 following tonsillectomy or adenoidectomy. Likewise, breastfeeding mothers are warned not to use medications containing either of these drugs.24, 26 The CPIC guidelines recommend that codeine should be avoided in all CYP2D6 ultrarapid or poor metabolizers to lower the respective risks of toxicity and poor analgesia, and they point out that CYP2D6 is also involved in the metabolism of other opioids, including hydrocodone (Hysingla, Zohydro) and oxycodone (OxyContin and others).10
While nurses may not know a patient's genotype at the point of care, they can report any family history of codeine sensitivity to the prescribing clinician and take precautions any time codeine is administered, monitoring patients—particularly pediatric patients—frequently for signs of respiratory depression. Nurses can also bear in mind that patients who report no response to codeine may not be drug seeking but rather poor metabolizers of the drug. Alternative analgesics may be considered.
Preemptive genotyping. With pharmacogenomic data increasingly incorporated into drug labels, researchers have begun to suggest that there may be a role for preemptive genotyping in such areas as anesthesia27 and statin therapy.28 Nurses may soon find pharmacogenomic data with clinical decision support incorporated into electronic health record systems.28
Targeted cancer therapies. Oncology nurses have long helped patients understand how precision medicine affects cancer treatment, explaining how cancers are evaluated for specific treatments; how treatments are administered; and the treatment's mechanism of action, as well as associated risks, benefits, and adverse effects. Numerous cancers can now be targeted by small molecule inhibitors, such as monoclonal antibodies, which are created in a laboratory to find and destroy particular cancer cells. For example, bevacizumab (Avastin) is a monoclonal antibody that destroys cancer cells by stopping angiogenesis. Others, such as trastuzumab (Herceptin) and cetuximab (Erbitux), target epidermal growth factor receptors that are important for cell growth in some breast and colorectal cancers.29
PRECISION MEDICINE IN NURSING RESEARCH
In 2012, the Genomic Nursing State of the Science Advisory Panel developed a blueprint that identified priority areas for nursing research in genomic science.30 Williams and colleagues expanded the work of the panel in a bibliometric review that examined data-based genomic nursing articles published between 2010 and 2014.31 Their findings indicated that the majority of nursing research conducted within that period had focused on biologic plausibility and that there were substantial gaps in the areas of ethics and clinical usefulness. The National Institute of Nursing Research (NINR) incorporated elements of the blueprint into its 2016 strategic plan, and Eggert outlined how the blueprint and the NINR strategic plan link to nursing research categories, suggesting opportunities for nurse researchers in this area.32
Nurse scientists at the NINR have developed a model to guide research in symptom science.33 The model begins with a patient presenting with complex symptoms. The symptoms undergo phenotypic characterization based on biological and clinical data, which provide the researcher a means of identifying biomarkers. Ultimately, the biomarkers yield clinical applications that improve symptoms. Nurses at all levels of education, working in all health care settings, can use this model to inform potential research projects.
For example, when a team of researchers led by a nurse scientist investigated the clinical usefulness of plasma tau concentrations after sport-related traumatic brain injury (TBI), they discovered that athletes who had elevated levels of this biomarker after sustaining a concussion demonstrated delayed recovery.34 The work of these researchers could lead to the development of a reliable, rapidly available test for identifying athletes requiring a longer recovery period before returning to play after TBI.
IMPLICATIONS FOR NURSE EDUCATORS
In 2009, the American Nurses Association (ANA) published Essentials of Genetic and Genomic Nursing: Competencies, Curricula Guidelines, and Outcome Indicators, which recommends that academic faculty collaborate with other disciplines to incorporate genetic and genomic information in courses and participate in both National Council Licensure Examination (NCLEX) and certification test development to ensure that test items assess knowledge of pertinent aspects of genetics and genomics.35 Practicing nurses are encouraged to pursue this information through continuing education. Calzone and colleagues describe outcome indicators for genetics and genomics nursing competencies.36 Several resources are available to nurses working to advance their knowledge in these areas (see Selected Genetics, Genomics, and Precision Health and Medicine Resources).
Key competencies for nursing practice include the following35:
- advocating for patients' access to genetic and genomic resources, services, and support groups, such as condition-specific groups, genetic support groups, and rare diseases groups
- incorporating technologies specific to genetics and genomics into nursing practice
- presenting information to patients in a way that is appropriate to their culture, religion, knowledge, and literacy level, and in their preferred language
Nurses may need to expand or acquire skills in the following areas35:
- identifying relevant genetic, environmental, and genomic information in patients' health histories
- generating and documenting a pedigree based on available family history
- identifying patients who may benefit from genetic and genomic information based on assessment data
- understanding the ethical, legal, fiscal, and societal issues related to genetic and genomic information
Since patients may need help interpreting and understanding genetic and genomic information, nurses need to have a good understanding of these topics in order to provide appropriate support.
For nurses in advanced practice, the ANA and the International Society of Nurses in Genetics published the Essential Genetic and Genomic Competencies for Nurses with Graduate Degrees, which identifies 38 competency areas, ranging from genetic risk assessment and clinical management to leadership and research.37
AN INTEGRAL PART OF HEALTH CARE DELIVERY
The rapid development of genetic and genomic technologies and related discoveries has dramatically changed the delivery of health care. Nursing science will continue to contribute to this area of research. Incorporating knowledge gained from the various omics sciences helps nurses build on skills they already possess, such as collaboration, patient advocacy, patient and family education, patient assessment, and documentation. Developing a strong knowledge base in these sciences and technologies will ensure that nurses can collaborate effectively with patients and other health care providers to advance the goal of precision medicine for the benefit of all patients.
1. Cohen FL. Genetic knowledge possessed by American nurses and nursing students. J Adv Nurs
2. Forsman I. Education of nurses in genetics
. Am J Hum Genet
4. Aiello LB. Genomics
education: knowledge of nurses across the profession and integration into practice. Clin J Oncol Nurs
8. Califf RM. Biomarker definitions and their applications. Exp Biol Med (Maywood)
9. FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools)
. Bethesda, MD; Silver Spring, MD: National Institutes of Health; Food and Drug Administration; 2016. https://www.ncbi.nlm.nih.gov/books/NBK326791
10. Crews KR, et al Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Clin Pharmacol Ther
13. Ramaswami R, et al Precision medicine
from a public health perspective. Annu Rev Public Health
14. Beskow LM, et al Thought leader perspectives on benefits and harms in precision medicine
research. PLoS One
15. Kraft S, et al Beyond consent: building trusting relationships with diverse populations in precision medicine
research. Am J Bioeth
17. Iqbal N, Iqbal N. Imatinib: a breakthrough of targeted therapy in cancer. Chemother Res Pract
18. Weinshilboum RM, Wang L. Pharmacogenomics: precision medicine
and drug response. Mayo Clin Proc
20. Relling MV, Evans WE. Pharmacogenomics in the clinic. Nature
21. Calzone KA, et al Nurses transforming health care using genetics
. Nurs Outlook
22. Ackerman MJ, et al HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Europace
23. Kelly LE, et al More codeine fatalities after tonsillectomy in North American children. Pediatrics
25. Tobias JD, et al Codeine: time to say “No.” Pediatrics
27. Morgan B, et al The role of pharmacogenomics in anesthesia pharmacology. Annu Rev Nurs Res
28. Bielinski SJ, et al Preemptive genotyping for personalized medicine: design of the right drug, right dose, right time—using genomic data to individualize treatment protocol. Mayo Clin Proc
29. Beatty K, et al Advances in oncology care: targeted therapies. AACN Adv Crit Care
30. Genomic Nursing State of the Science Advisory Panel, et al. A blueprint for genomic nursing science
. J Nurs Scholarsh
31. Williams JK, et al Five-year bibliometric review of genomic nursing science
research. J Nurs Scholarsh
32. Eggert J. Genetics
in oncology nursing: what does every nurse need to know. Nurs Clin North Am
33. Cashion AK, Grady PA. The National Institutes of Health/National Institutes of Nursing Research intramural research program and the development of the National Institutes of Health symptom science model. Nurs Outlook
34. Gill J, et al Acute plasma tau relates to prolonged return to play after concussion. Neurology
35. Consensus Panel on Genetic/Genomic Nursing Competencies. Essentials of genetic and genomic nursing: competencies, curricula guidelines, and outcome indicators
. 2nd ed. Silver Spring, MD: American Nurses Association; 2009.
36. Calzone KA, et al Establishing the outcome indicators for the essential nursing competencies and curricula guidelines for genetics
. J Prof Nurs
For five additional continuing nursing education activities on the topic of genomics, go to www.nursingcenter.com/ce.
Keywords:Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
genetics; genomics; nursing practice; nursing science; omics; pharmaco-omics; precision health care; precision medicine; Precision Medicine Initiative