Over the past 10 years, genetics has hit the media with full force. Health care providers and consumers are bombarded with reports of this new gene, that new gene, this cloned sheep, that cloned monkey, and discussions of what in the world we will clone next. Fueled by the Human Genome Project (HGP), a 15-year international effort to map and sequence the entire human genome, genetic research has made tremendous advances in understanding gene structure and function as well as refining techniques to locate and characterize genes, including genes associated with diseases (National Center for Human Genome Research, 1995).
Alzheimer's disease (AD) is just one example of an illness that has benefited from the techniques and efforts of genetic research. To date, four genetic loci have been associated with four different forms of AD: the amyloid precursor protein gene on chromosome 21 (Goate et al., 1991; St. George-Hyslop et al., 1987); the presenilin genes on chromosome 14 (Mullan et al., 1992; Schellenberg et al., 1992; St. George-Hyslop et al., 1992; Van Broeckhoven et al., 1992) and chromosome 1 (Levy-Lahad et al., 1995; Rogaev et al., 1995); and the apolipoprotein E (APOE) gene on chromosome 19 (Pericak- Vance et al., 1991). Mutations of the chromosome 21, 14, and 1 genes are rare and associated with familial AD of early onset, exhibiting autosomal dominant patterns of inheritance. The APOE gene on chromosome 19, however, is associated with sporadic as well as familial late-onset AD, contributing to as many as 50% to 70% of all cases of AD (Post, 1994). The APOE gene has three alleles, or alternative forms of the gene: E2, E3, and E4. APOE-4 is associated with an increased risk of developing AD and a lowered age of onset (Corder et al., 1993). Lifetime risk of AD for people with at least one E4 allele has been estimated at 29%, compared to 9% in people with no E4 alleles (Seshardi, Drachman, & Lippa, 1995). However, not all people with late-onset or sporadic AD have APOE-4 alleles. In addition, not all people with APOE-4 alleles have AD. See Table 1 for a summary of the genetics of AD.
SUMMARY OF ALZHEIMER'S DISEASE GENETICS*
The long-range benefits of gene identification in AD include improved understanding of disease pathogenesis leading to targeted pharmacotherapy and eventually gene therapy. The most immediate impact of gene identification, however, is the ability to determine disease susceptibility or to diagnose (Collins, 1997). Ideally, early identification of disease susceptibility allows surveillance and prevention strategies; early diagnosis allows earlier treatment. Realistically, diagnostic capabilities through genetic tests are likely to precede an understanding of prevention and treatment by many years. This scenario certainly characterizes AD. While the recent advances in AD research are astounding, treatments and a cure are years away. Yet nurses and other health care providers are currently faced with the challenge of integrating genetic information and tests into clinical practice in a manner that maximizes outcomes for individuals, families, and populations. The purpose of this article is to explore this challenge through a discussion of the following aspects of genetic tests within the context of AD:
* Types and uses.
* Risks and benefits.
* Policy prerequisites for the successful integration of genetic tests into clinical practice.
* Nursing implications.
GENOTYPES, PHENOTYPES, AND GENETIC TESTS
The goal of genetic research, such as the HGP, is to draw a map of a representative example of the three billion nucleotide human genome (Collins, 1997). In fact, 99.9% of every individual's genome is the same. Portions of the .1% of genomes that vary, however, contribute to differences in physical traits, as well as disease susceptibility. Therefore, every individual's actual genetic make-up, or genotype, is unique. The expression of one's genes results in a phenotype, or a person's observed physical characteristics or clinical signs.
Genetic information, or information about an individual's genotype, can be obtained in a variety of ways. Genotype can be inferred through an evaluation of a person's phenotype or family history. Genotype can also be measured indirectly or directly through genetic tests.
Genetic tests are a broad category of diagnostics including cytogenetics, linkage analyses, molecular studies, or biochemical tests. Cytogenetics involve the microscopic analysis of the number, structure, and integrity of chromosomes. Linkage analysis is a technique used prior to the identification of a gene that allows an estimation of probability that a person has inherited a genetic mutation through the use of DNA markers known to be closely linked to a disease locus. Molecular studies, performed after genes are identified, use DNA sequencing to examine targeted areas of chromosomes or genes to determine specific mutations or changes in the nucleotide sequence. Biochemical tests employ assays that measure gene products. Table 2 summarizes these four types and examples of genetic tests. Of importance is the idea that genetic information is not synonymous with genetic tests. Genetic tests are just one way of measuring genotype.
Molecular studies in AD are now a possibility because of the identification of three disease genes and one susceptibility gene. In those families with early-onset AD associated with the amyloid precursor protein gene or the presenilin genes, direct mutation analysis can be used to confirm diagnoses or provide information to asymptomatic family members interested in knowing their risk of developing AD. For individuals without a family history or with a family history of late-onset AD, APOE genotype tests are possible and, in fact, commercially available (Athena Neurosciences, Worcester, MA). However, the ability to interpret APOE genotype for the asymptomatic individual into meaningful risk estimates is currently impossible. As a result, five professional groups and The National Study Group, a multidisciplinary consensus workgroup sponsored by the National Human Genome Research Institute of the National Institutes of Health, recommend against the predictive use of APOE genotyping in asymptomatic individuals (Alzheimer's Disease and Associated Disorders, Inc., 1995; American College of Medical Genetics/ American Society of Human Genetics Working Group on ApoE and Alzheimer's Disease, 1995; Lovestone [with United Kingdom Alzheimer's Disease Genetics Consortium], 1995; Medical and Scientific Advisory Committee of Alzheimer Disease International, 1995; Relkin, Kwon, Tsai, & Gandy, 1996; Post et al., 1997).
SUMMARY OF GENETIC TESTS
There is less consensus on the use of APOE genotype as an adjunct diagnostic test (Post et al., 1997). Roses (1995) indicates there is evidence that the probability of diagnostic evaluations showing a reversible cause of dementia is less in the presence of APOE-4 alleles. Preliminary studies using autopsy-proven cases of AD indicate accuracy of diagnosis of APOE-4 in symptomatic people (Kakulas, Wilton, & Fabian, 1996; Roses & Sanders, 1996; Saunders, Hulette, & Welsh, 1996). Nonetheless, further studies are indicated before APOE genotyping is incorporated into the differential diagnosis of dementia (Post et al., 1997).
BENEFITS AND RISKS OF GENETIC TESTS IN ALZHEIMER'S DISEASE
Genetic tests are associated with both benefits and risks (Codori & Brandt, 1994; Williams & Schutte, 1997). Although these benefits and risks are not yet explored in the research, they are likely to apply to the AD population as well, which necessitates that the integration of AD genetic testing into the clinical practice of health care providers proceed cautiously.
Genetic test results can decrease uncertainty about the presence of an illness or the likelihood of developing an illness, whether the results are negative or positive. Decreased uncertainty about the future may facilitate reproductive and life planning for individuals, couples, and families. Another benefit of genetic testing is the potential ability to specify interventions aimed at preventing or treating illnesses. Genetic test results are also frequently associated with a sense of relief for those who do not carry a gene mutation (Williams & Schutte, 1997). These benefits hold promise for the usefulness of AD genetic testing in the future. However, the current state of knowledge surrounding AD etiology prohibits many of these benefits from being realized.
The only physical risk associated with AD genetic testing is a blood draw. However, other psychological and pragmatic risks are associated with genetic testing. For example, genetic tests may reduce uncertainty, but they do not eliminate it. As discussed with AD, APOE genotyping is probabilistic, not deterministic. Until gene-gene and gene-environment interactions are understood, this will likely remain the case. In the absence of known prevention strategies or treatment choices, positive results may not enhance outcomes for people with AD or a predisposition to AD.
There are also psychological burdens associated with genetic testing, particularly when results indicate the presence of a disease gene, including depression and persistent worries. Negative results do not necessarily guarantee peace of mind.
Genetic testing is also complicated by its impact on families. One individual's genotype provides information about other family members' genotype. Issues surrounding family relationships, disclosure of decisions to test or test results, and feelings of blame and guilt may arise in conjunction with genetic testing. For example, in a study of individuals undergoing genetic testing, Williams and Schutte (1997) describe selective disclosure of genetic information among family members. Codori and Brandt (1994) and Rona et al. (1994) describe a deterioration in relationships among some family members surrounding genetic information, even when test results were favorable.
Another risk of genetic tests is the potential for discrimination based on genetic information. Recent studies report evidence for employer and insurance discrimination based on either having a genetic disorder or being predisposed to a disorder (Billings et al., 1992; Lapham, Kozma, & Weiss, 1996). Families with AD also will need to consider the impact of genetic testing on long-term care insurance.
Because of the risks and uncertainties associated with genetic tests, genetic counseling is a critical component of genetic testing in AD. This is true whether testing is considered as an adjunct to diagnosis or to determine predisposition in an asymptomatic family member. Counseling is recommended prior to testing to ensure individuals are informed of potential benefits and risks. In addition, postgenetic testing counseling is recommended to monitor for and intervene in the event of adverse psychological or social outcomes.
POLICY PREREQUISITES TO SUCCESSFUL GENETIC TESTING
When the HGP was conceptualized, it was recognized that genetic research would be associated with both benefits and risks, raising ethical, legal, and social issues for individuals, families, and society. Consequently, in an unprecedented fashion, the Ethical, Legal, Social Implications (ELSI) branch of the HGP was established to anticipate and address the implications of mapping and sequencing the human genome. The implications of genetic testing were quickly identified as an important area of inquiry and continue to be addressed by the ELSI branch through research funding and special task forces such as the ELSI Committee on Assessing Genetic Risks (Andrews, Fullarton, Holtzman, & Motulsky, 1994) and the ELSI Task Force on Genetic Information and Insurance (National Center for Human Genome Research, 1993). An important goal of these task forces is to make recommendations to policy makers to minimize the risks and facilitate the usefulness of genetic tests for health care providers and consumers.
Based on the reports of these task forces and other stakeholders, five key prerequisites to the successful integration of genetic tests into health care services can be argued. These prerequisites, which will be considered separately, include:
* The development of safe and effective genetic tests.
* Assured laboratory quality.
* Competent health care providers.
* Assured privacy.
* Informed consumers.
Safe and Effective Genetic Tests
Genetic test validity is of primary importance to clinicians who may be diagnosing disease or counseling clients about lifetime risks and recurrence risks of disease. Safety, effectiveness, and clinical utility of genetic tests must be established prior to their routine use, requiring data about test sensitivity, specificity, and predictive value. Until these parameters are established, genetic tests should be considered investigational devices needing Institutional Review Board approval and Food and Drug Administration regulation (Andrews et al., 1994). Researchbased data on the psychological outcomes of genetic tests and program evaluations of genetic services delivery systems are equally important in determining the safety and effectiveness of genetic tests.
Assured Laboratory Quality
After test validity and safety are established, genetic tests must be conducted in laboratories of assured quality to maintain test reliability. The ELSI Committee on Assessing Genetic Risks (Andrews et al., 1994) recommends all methods of genetic testing be overseen through the existing mechanisms established by the Clinical Laboratory Improvements Amendments of 1988 (CLIA '88, Public Law No. 100-578). Classification of genetic tests as highly complex would require the most stringent oversight, including on-site laboratory inspection and proficiency testing.
Another important prerequisite for effectively integrating genetics into clinical practice is competent health care providers. Genetic content has not been an integral part of the education of health professionals to date. However, it is critical that providers are prepared in the complexities of genetic information, including the ethical, legal, and social implications. To that end, the HGP ELSI branch has established the National Coalition for Health Professional Education in Genetics, in collaboration with the American Nurses Association and the American Medical Association, to develop a national genetic education initiative. Representatives from health professional organizations, industry, government agencies, and consumer groups will discuss methods of collecting, synthesizing, and disseminating genetic research. Topics of discussion will likely include the development of genetic core curricula as well as the establishment of a clearinghouse of information related to genetic curricula, educational programs, grants, and training programs.
Without protection from discrimination based on genetic information, consumers may be reluctant to seek genetic services and testing. Privacy of genetic information is a crucial precondition of widespread genetic testing services. The ELSI Task Force on Genetic Information and Insurance (National Center for Human Genome Research, 1993) recommended universal access to a program of basic health services that includes integrated genetic counseling, testing, and treatment services. Further, this task force recommended that access to, the type of, and the cost of coverage of insurance should not be affected by genetic information. Despite these recommendations and a recent flurry of genetic privacy bills, there is currently no protection at the federal level for genetic privacy and confidentiality.
Similarly, only 11 states have laws prohibiting employers from requiring or requesting genetic tests as a condition of employment.
In light of the complexities of inheritance, genetic tests, and the current health care marketplace, consumers are faced with unique opportunities and challenges. Consumers must be able to make fully informed decisions about obtaining and using genetic information to minimize their risks and maximize their health and well-being. Public education initiatives, responsible researchers and media, and strong advocacy will be essential.
Genetic research in AD and the availability of genetic tests provide unique challenges and opportunities for gerontological nurses as they perform their advocacy role for clients and families with AD. In the current social climate, advocacy necessitates public policy savvy. To date, nursing input into the ELSI task forces and committees has been noticeably minimal. Individual nurses and nursing organizations can strive to participate in subsequent agenda setting and policy formulation efforts. As consumer advocates, nurses are also in key positions to ensure policy evaluation is both planned and implemented as genetic tests are incorporated into the clinical practice of primary care providers and expanded within the practice of genetic specialists. During that time, gerontological nurses are charged to advocate for their clients in clinical settings by ensuring genetic testing is voluntary, informed, and confidential.
Collectively and individually, gerontological nurses also will need to inventory the impact of genetics on all aspects of their clinician role by asking the following questions:
* How does genetics impact my clients with AD and their families?
* Are families or other providers inquiring about genetic tests?
* Are genetic tests available and recommended?
* Am I prepared to answer questions about genetic testing and its risks and benefits for families with AD?
* Are comprehensive genetic health care services available for my clients?
* Where can I refer clients who need specialized genetic counseling and services?
* How is genetic information protected in my state?
The answers to these questions can guide gerontological nurses in seeking resources and building collaborative relationships with genetic specialists to meet client needs related to genetics.
Alzheimer's disease currently may be at the forefront of genetic research efforts and media attention. However, with 50,000 to 80,000 genes in the human genome and the Human Genome Project ahead of schedule, an increased understanding of the genetic contribution to other client conditions and characteristics of interest to gerontological nurses will likely follow. Alzheimer's disease provides the benchmark case for gerontological nurses to prepare to meet the emerging challenge of genetics and gerontology.
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SUMMARY OF ALZHEIMER'S DISEASE GENETICS*
SUMMARY OF GENETIC TESTS