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Copyright © 1998 by The Johns Hopkins University Press. All rights reserved.
Kennedy Institute of Ethics Journal 8.2 (1998) 131-144
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The Question Not Asked: The Challenge of Pleiotropic Genetic Tests
Robert Wachbroit
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Abstract. Nearly all of the literature on the ethical, legal, or social issues surrounding genetic tests has proceeded on the assumption that any particular test for a gene mutation yields information about only one disease condition. Even though the phenomenon of pleiotropy, where a single gene has multiple, apparently unrelated phenotypic effects, is widely recognized in genetics, it has not had much significance for genetic testing until recently. In this article, I examine a moral dilemma created by one sort of pleiotropic testing, APOE genotyping, which can yield information about the risk of two different conditions--coronary heart disease and Alzheimer's disease. A physician administering APOE testing for the beneficial purpose of assessing the risk of heart disease may discover medically useless and socially harmful information about the patient's risk of Alzheimer's disease. I explore how much providers should disclose to patients about pleiotropic test results and whether patients are obligated to know as much about their genetic condition as possible.
Discussion regarding genetic testing have gone through two stages. Inthe first, the focus was primarily on single- gene disorders--those in which a particular gene mutation is causally necessary and sufficient for a disease to occur. These discussions centered on the ability of genetic tests to predict the onset of a disease or to confirm its diagnosis and on the associated ethical issues, such as who should have access to this information, what restrictions should be placed on its use, and, in the case of diseases where therapies were not yet available, whether the genetic tests should be performed at all. While these concerns were important, they did not seem applicable to many situations, since single-gene disorders such as Huntington's disease are relatively rare. [End Page 131]
In the second stage, attention has centered on more common diseases to which genes have a more complex relation--those for which a genetic mutation may be neither causally necessary nor sufficient for the occurrence of the disease. Discussions now focused on diseases such as cystic fibrosis, various types of cancer, and heart diseases, where the presence of particular environmental conditions or family histories is an essential part of the causal nexus that links a specific genetic mutation and a disease. (Indeed, in some cases the genetic mutation may not even be a partial cause but rather a risk factor--e.g., the genetic mutation may be associated with a disease via a causal factor common to them both.) These discussions have responded to the complexity of the connection between genes and diseases by adding considerations of risk communication and risk perception to the earlier concerns about privacy, discrimination, and other issues.
For the most part, second-stage discussions have addressed only one type of complex causal relation, called "heterogeneity," where multiple gene mutations are involved in a single disease. The converse type of complexity, called "pleiotropy," where a single-gene mutation is involved in multiple, apparently unrelated diseases, has received hardly any attention at all. This relative neglect, insofar as it is intentional, might indicate a belief that pleiotropy raises no special ethical issues. Perhaps it has been assumed that if a single genetic test indicates a risk of contracting two (apparently unrelated) diseases, the ethical issues it raises are identical to those raised if two distinct tests, one for disease A and the other for disease B, had been performed. On this view, pleiotropic genetic tests may be more efficient ("two conditions for the price of one"), but they do not raise ethical questions different from those created by two separate tests.
This conclusion would be justified if the response to concerns raised by disease A were always compatible with the response to concerns raised by disease B. If, however, there is a conflict--e.g., the recommendations regarding testing for disease A conflict with the recommendations regarding testing for disease B--then the pleiotropic genetic test would appear to present a special ethical issue. The latter possibility is not merely theoretical. The test for the allele of the APOE gene is a case in point.
Apoe Genotyping
Coronary heart disease (CAD) and Alzheimer's disease (AD) are two apparently unrelated diseases. Nevertheless, testing for the *4 allele of the apolipoprotein E (APOE) gene can yield information about both conditions.[End Page 132] A positive test result indicates a high risk of hyperlipidemia and, consequently, a high risk of atherosclerosis and myocardial infarction (Wilson et al. 1994). At the same time, for reasons we do not fully understand, a positive test result is strongly associated with a high risk of contracting AD (Strittmatter et al. 1993). Because of the profound differences in our understanding of these two diseases and in their social meanings, this pleiotropic test appears to generate a moral dilemma.
On the one hand, since CAD is in many cases treatable, there are clear medical benefits to administering an APOE test to identify those at risk. Problems of discrimination in employment or insurance as a result of being tested might arise in particular situations, but they rarely will outweigh the benefits of treatment. Thus the APOE test is part of the cardiologist's standard repertoire. On the other hand, since AD is, as yet, untreatable, the medical benefit of a test that might identify those at risk is unclear. Furthermore, there are considerable uncertainties in the interpretation of an APOE test for AD. Because of these uncertainties as well as the lack of a treatment, many researchers have concluded that APOE genotyping should not be used either as the sole diagnostic tool or as a predictive tool for AD (Mayeux et al. 1998). Given the various harms resulting from the belief that an individual is at risk for AD, including stigmatization, discrimination, and the psychological burden associated with the prospect of having AD, several commentators and organizations, including the National Institute on Aging, the Alzheimer's Association (NIA/AA 1996), the American College of Medical Genetics, and the American Society of Human Genetics Working Group on ApoE and Alzheimer Disease (ACMG/ASHG 1995), have recommended against using the APOE test at this time to assess AD risk.
Here we have one of the starkest conflicts generated by a pleiotropic genetic test. In the context of CAD, APOE genotyping is clinically useful and accordingly recommended when appropriate. In the context of AD, however, APOE genotyping is deemed harmful and is not recommended. Thus, we can have a situation in which a physician administers APOE testing for the beneficial purpose of CAD risk assessment but, in the process, discovers socially harmful or medically useless information about the patient's risk of AD. In what follows, I will explore how such apparent conflicts might be resolved.
I focus on the APOE test in order to make the discussion of pleiotropic genetic testing concrete. The APOE test exemplifies the type of moral dilemma that seems to emerge from pleiotropic genetic testing. It is important [End Page 133] to realize, however, that the particular conflict between the benefits and the harms of APOE testing depends upon the current state of medical science. The availability of a treatment for AD would most likely change the nature of the case but the general questions would remain: When a genetic test may reveal information about two (or more) unrelated conditions, how much should providers disclose to patients? Further, should patients feel obligated to know as much as possible about their genetic condition? As I explore the first question, I shall assume that if the *4 allele of the APOE gene were associated only with AD, testing would not be performed except possibly to support a diagnosis of AD. Later, in an effort to answer the second question, I will drop that assumption (cf. Wachbroit 1996).
Is There an Obligation to Disclose?
Thus far I have presented the conflict arising from pleiotropic genetic tests only as whether to administer such a test--e.g., do the medical benefits of a CAD risk assessment outweigh the social and psychological costs of an apparent AD risk assessment? However, none of the organizations that have recommended against using APOE genotyping for AD risk have made a recommendation against the clinical use of APOE altogether. No one has urged that cardiologists cease using APOE genotyping for the purpose of CAD risk assessment. Indeed, it would be difficult for health professionals to justify forgoing the clear medical benefits of performing the test simply because of the possible social and psychological costs of learning unintended results. Consequently, the issue is not whether the health professional should ever consider administering the test but rather, when a particular use of the test is indicated and appropriate, what the patient should be told. There are three possible responses: compartmentalization, partial disclosure, and consolidation.
Compartmentalization consists of treating the pleiotropic test as if it were two separate tests. With this approach, when the cardiologist uses APOE testing for CAD risk, he or she ignores any information obtained that might indicate a condition other than the one being tested for. By classifying genetic tests in terms of the conditions that they test for, we can easily fail to see the conflicts arising from pleiotropy. For example, in the ACMG's recommendation not to offer APOE testing for susceptibility to AD, no mention is made of the use of this test in identifying CAD risk. It focuses exclusively on one disease. [End Page 134]
Part of the rationale for compartmentalization is that it is of a piece with medical specialization. A neurologist, for example, is not likely to order tests regarding a patient's cardiac condition. One could argue that the results of pleiotropic tests are intended as tools for particular specialties, so that, when medical information is revealed that is outside the clinician's specialty, she can regard it as none of her concern. Nevertheless, this appeal to medical specialization cannot take us very far. No one would argue that if a neurologist prescribes medication, he or she can ignore any cardiac effects the drug might have. Similarly, genetic tests can have "side effects"--consequences in terms of yielding information other than that explicitly being sought. Acting as if they do not is indefensible because the responsibilities of physicians towards their patients are not so neatly compartmentalized.
The difficulties raised by compartmentalization might suggest the need for a more flexible approach--partial disclosure. This approach consists of not informing the patient of the alternative, and presumably unintended, use of the pleiotropic test before the test is administered, but informing the patient later if the test indicates that the patient is at risk for the other disease. Thus the cardiologist practicing partial disclosure uses the APOE test without telling the patient that it may reveal the risk of AD as well as CAD. The patient is informed of this only if the test reveals an AD risk. This approach can be justified by drawing an analogy to what patients must be told about medication. Only the adverse side effects of a drug need to be disclosed, not all side effects. Similarly, with the partial disclosure approach, only the adverse side effects of a genetic test, should they occur, need to be disclosed.
Part of the appeal of this approach is that it does not burden health professionals with matters outside their area of specialization. The cardiologist administering an APOE test can be a cardiologist, confining herself to investigating cardiac issues. She needs to alert the patient to neurological issues only if the test indicates that the patient is at risk for AD. Furthermore, partial disclosure avoids having the benefits of the test from the standpoint of CAD overshadowed by the harms from the standpoint of AD. If patients were told that the test could reveal whether they were at risk for AD, some of them might choose not to be tested. They would rather not know anything about their risk of AD, even if that meant forgoing the benefits of learning about their risks of CAD.
Nevertheless, this partial disclosure approach faces at least two immediate problems. First, the analogy to disclosing a drug's adverse side effects [End Page 135] is flawed in several respects. In some situations, especially where close relatives are suffering from a genetic disease, even a negative test result--showing no increased risk of the disease--can be unwelcome. Some patients might experience "survivor guilt" as they contemplate the prospects of their less fortunate siblings or other relatives. The fear of survivor guilt is sometimes an important reason why patients do not want to be tested for a genetic condition. Thus, unlike the physician in the medication analogy, a physician performing a genetic test would have to treat every test result as having a potential adverse side effect. One could also argue that since learning that one is at risk of AD is itself a harm--albeit a social harm or psychological burden--the medication analogy completely fails. The reasoning that leads to informing patients about the risks of adverse side effects from medication before they take the medication should also lead to informing patients about the adverse effects of learning that one is at risk for AD before they take the genetic test.