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Commentary From Genes to Public Health: Applications of Genetics in Disease Prevention by Muin J. Khoury & the Genetics Working Group* Background: With advances in the Human Genome Project, the public health community should assess the implications of genetic technology in disease prevention. Methods: The paradigm suggested by the Institute of Medicine's the Future of Public Health was used in examining the continuum from genetic technology to public health practice: assessment, policy development, and assurance. Results: First,an important public health function is to assess the impact of genes and their interaction with modifiable disease risk factors on the health status of the population, and to assess the impact and safety of genetic testing on the population. Second, given the many implications of genetic testing, the public health community should participate in policy development related to the timing and the manner of utilization of genetic testing in disease prevention. Third, whenever appropriate, the public health community needs to assure the development of public health genetics programs (e.g. newborn screening), evaluate the quality and effectiveness of the use of genetic testing in disease prevention. Conclusions:
Although most current genetic tests are not ready for disease prevention, there is an
important role for the public health community to translate genetic technology into
disease prevention. During the past decade, there have been tremendous advances in molecular genetic technology. These advances have led to the Human Genome Project, a long-term initiative to map and sequence the human genome. In the next decade, most if not all human genes will be mapped and sequenced (1-3). Relatively simple technology such as the polymerase chain reaction is now available to examine genetic variation at many gene loci by using small amounts of human tissues (e.g. blood spots and cheek swabs) (4). This emergence of genetic technology is accompanied by increasing concern regarding the use and misuse of genetic information in society (5-8). Despite the advances in
molecular genetics, and their implications in disease prevention (9,10), it is not
entirely clear when and how genetics can be applied in the prevention of human disease. As
genetic tests are proliferating in the U.S. population, their appropriate utilization in
the public health setting needs careful scrutiny. In its evaluation of the future of
public health in the United States, the Institute of Medicine defined the core functions
of public health agencies: 1) assessment, 2) policy development, 3) and assurance (11). In
this commentary, we discuss the potential applications of genetics in public health
practice in the context of these core functions. The human genome project is targeting our estimated 50,000-100,000 human genes. Of these genes, only a small fraction have been identified so far (12, 13). Most identified human genes are associated with relatively uncommon disorders such as phenylketonuria, and hemophilia. Also, there are disease genes that account for a small fraction of the more common chronic diseases (such as alpha-1 antitrypsin deficiency in pulmonary emphysema) (14). Furthermore, genes play important roles in the etiology of most, if not all, human diseases ranging from cancer to coronary heart disease (15). The roles that genetic factors play differ greatly, ranging from single genes completely determining the disease state (i.e. disease genes) to genes that interact with other genes and environmental factors in causing disease (susceptibility genes). These genetic risk factors include numerous polymorphic traits and enzyme systems involved in the metabolism of drugs and carcinogens (16-18). Molecular technology is
allowing research applications in family studies to identify disease and susceptibility
genes. These studies are mostly based on high-risk families with multiple affected
individuals. They rely on the use of genetic analysis methods such as linkage and
segregation analyses (10). A notable example is the intense search for breast cancer genes
in high risk families. Using linkage analysis (19) and more recently direct sequencing of
the gene (20,21), investigators have identified a gene on chromosome 17 (BRCA1). Women who
inherit BRCA1 mutation(s) have more than 90% lifetime risk of developing either breast or
ovarian cancer (22). The application of the identification of such genes has been in the
context of genetic counseling and the delivery of preventive medical health care to
individuals in high-risk families. However, the only available means of primary prevention
thus far has been prophylactic mastectomy, which may not provide full protection against
the development of breast cancer (57,58), and raises important issues regarding widespread
genetic testing for BRCA1. In addition, the contribution of the apparently numerous BRCA1
mutation(s) to the overall risk of breast and ovarian cancer in the population needs
further evaluation. Prevention strategies include primary, secondary or tertiary interventions. Primary prevention is the prevention of disease before it occurs. For rare, fully penetrant, lethal single gene and chromosomal disorders, medical and community-based intervention thus far have focused on carrier detection, premarital counseling, as well as prenatal diagnosis and pregnancy termination (the latter may not be considered primary prevention). Such approaches have been applied for several single gene conditions such as Tay-Sachs disease (23) and chromosomal disorders such as Down syndrome (24,25). Nevertheless, primary prevention of genetically-influenced disorders other than the rare and lethal single gene disorders does have a role in public health. An excellent example here is the exciting opportunity for primary prevention of neural tube defects. While prenatal diagnosis of these conditions has become increasingly possible through the advent of alpha-feto protein screening and ultrasonography, a more promising avenue for primary prevention is the discovery that maternal periconceptional folic acid use reduces both the risk of recurrence of neural tube defects among women with a previously-affected pregnancy, as well as the risk of first-time occurrence of neural tube defects in the population (26). A recent analysis of the relationship between folate levels and neural tube defects suggest that food fortification with folic acid may be the most cost-effective way to reach women of reproductive age (55,56). Secondary prevention targets disease clinical manifestations by early detection and intervention during the preclinical phase of the disease. A classical example in public health genetics is newborn screening for metabolic disorders such as phenylketonuria and galactosemia (27), with resulting early intervention. Tertiary prevention minimizes the effects of disease by preventing complications and deterioration. One example of a tertiary prevention effort for a genetic disease is that of antibiotic prophylaxis and immunization for individuals with sickle cell anemia to prevent life-threatening bacterial infections (28). Another example is the identification of factor VIII gene mutations and associated HLA genotypes that predispose hemophilia A patients to develop factor VIII inhibitors (29,30). Early identification of this propensity can provide an opportunity for intervention with an immune tolerance program to prevent life-threatening bleeding complications of hemophilia. Nevertheless, most chronic
diseases are etiologically heterogeneous. No single gene is likely to account for a
significant attributable fraction of cases of the disease. Furthermore, not all persons
with a susceptibility genotype will develop the disease. Since most nongenetic risk
factors for chronic diseases usually have low predictive value for these diseases (31),
the use of genetic tests is likely to improve the disease predictive value of
environmental risk factors (32). Therefore, a new paradigm of the primary prevention of
many chronic diseases could be the identification and interruption of environmental
cofactors that lead to clinical disease among persons with susceptibility genotypes (32).
For most diseases and genetic risk factors, such cofactors are poorly understood and much
work is needed before the results of basic genetic research and gene findings in high risk
families can be translated into population-based interventions (33). The Institute of Medicine recommended that every public health agency regularly and systematically collect, assemble, analyze and make available information on the health of the community, including statistics on health status, community health needs, and epidemiologic and other studies of health problems" (11). If the public health applications of the Human Genome Project are to be widespread, the impact of genetic testing in the population at large has to be carefully evaluated through epidemiologic studies. Such studies quantify the impact of positive genetic tests (i.e, susceptibility alleles) on disease incidence and prevalence. Population-based cohort, cross-sectional, and case-control studies are needed to estimate relative and absolute risks (positive and negative predictive values) associated with each genetic test, and estimate the population attributable fraction for the disease of interest (10). The case-control method which compares the frequency of specific alleles between affected and unaffected individuals drawn from the same population has great appeal, since DNA studies provide biological markers for susceptibility that do not change over time (34). Also, multiple genes can be assessed in case-control studies as independent factors in epidemiologic analyses. Case-control approaches also provide an important way to look for effect modification and to illuminate biologic interaction between genes and non-genetic risk factors (such as occupational exposures, diet and lifestyle factors) (34). The study of gene-environment interaction can provide an important basis for refining the predictive value of traditional epidemiologic risk factors and for targeting intervention and prevention activities for individuals in high risk groups (10). One example of a population study
is the evaluation of the association between the HLA system and rheumatoid arthritis (RA).
The contribution of this genetic system to the genetic etiology of RA is estimated to be
on the order of 30% of the total risk (35). The immune response HLA-DR4 allele (DRB*0401)
is associated with up to 6-fold relative risk of disease. Among whites, it is also
associated with a more severe form of RA, in which a gene dosage effect is observed (36).
Screening for HLA-DR4 among patients with RA may therefore be useful in disease
management. Although no single environmental factor or infectious agent has been
associated with RA, it is interesting that HLA-DR4 is also associated with an increased
risk of chronic Lyme arthritis (B.burgdorferi infection) (37). Other genes such as T-cell
receptor sequences may also be involved in RA etiology. Another example of a population
study is the evaluation of the association between Alzheimer's disease (AD) and the
apolipoprotein E (Apo-E) E4 allele. Mounting evidence suggests that the Apo-E E4 allele is
strongly associated with both late-onset familial AD and the more common sporadic AD
(38-40). Among families with high-risk of late-onset AD, disease risk has been shown to
increase with the number of E4 alleles; 47% of people heterozygous for the E4 allele and
91% of people homozygous for the E4 allele were shown to be affected (38). Risk ratios for
heterozygotes and homozygotes were 2.8 and 8.1, respectively. The Institute of Medicine recommended that public health agencies use the scientific knowledge base obtained from assessment of the health of the population in decision making and formulation of public health policy. In the arena of genetics, one goal will be the utilization of genetic testing in medical practice as well as population programs designed to reduce morbidity and mortality associated with disease genes and disease susceptibility genes. In formulating sound public health genetic policy, several issues need to be considered before genetic tests can be applied in population-based prevention programs (Table 2). The avalanche of genomic information expected to accrue over the next decade has already led to concerns regarding the potential misuse of such information (5-8). Holtzman (6) argues that there is a great need to "proceed with caution" in applying genetic testing in human populations because: I) society's use of genetics has, in the past, led to human rights abuses; ii) an accelerating trend toward commercialization of DNA technology, and motivation for profit could lead to differential development for testing for certain diseases but not others, iii) indiscriminate application of genetic tests could occur without an understanding of the limitations in interpreting their results; and iv) our ability to detect disease susceptibility genes will outpace the ability to provide effective intervention after these genes are detected. Nevertheless, the detection of disease susceptibility genes provides the exciting possibilities of learning gene functions and could open entirely new approaches for treatment as well as prevention. Steps and safeguards have been suggested to deal with ethical issues surrounding genetic testing. These include protection of individual autonomy and the right to decide based on a proper informed consent process, preservation of confidentiality of results of genetic testing, limiting genetic testing in the workplace and by insurance companies, careful scientific evaluation of the ability of genetic tests to measure the underlying susceptible genotype, and education of the medical profession and the general public (6). One example of the ethical questions involved in genetic testing is the use of DNA testing in detecting predisposition to cancer. In spite of the recent successes in identifying breast and colon cancer genes, the National Advisory Council for Human Genome Research recently concluded that "it is premature to offer testing of either high-risk families or the general population as part of general medical practice..." (41). Similarly, ethical issues in genetic testing in the workplace have been reviewed for use in job placement, relocation, and the targeting of medical surveillance (42-46). The objectives of such testing in the workplace could include differential diagnosis in cases with clinical symptoms, monitoring for toxic effects, and screening for susceptibility to the effects of chemicals. Important considerations in workplace genetic testing include preserving individual autonomy and confidentiality and the need to have a healthy and safe work environment. There are definite concerns regarding employment discrimination against individuals with specific genotypes. At present, genetic screening tests are not generally recommended because of a lack of information on their predictive value. This suggests that applied epidemiologic studies are necessary to evaluate genetic tests both within and outside the workplace. Increasingly, many people will belong in one or more genetically sensitive subgroups to the effects of exposures. There are presently no good models in dealing with genetic variation in environmental and occupational regulations. Furthermore, as the genetic basis for complex behavioral disorders is increasingly unraveled (47-49), ethical issues will become prominent in potential applications of genetic testing for predispositions to behavioral patterns and psychiatric disorders. Discussions about these issues should be ongoing before any genetic tests are applied in a medicine and public health. Finally, enacting new laws which
serve as guidelines or restrictions for applying genetics in public health programs seems
prudent, as current regulations do not adequately protect individual's privacy regarding
genetic information. Detailed discussion of these issues is beyond the scope of this
article. Assurance can be viewed in the context of the three overlapping strategies for disease prevention: I) behavior prevention strategy, ii) environmental prevention strategy and iii) clinical prevention strategy (50). The behavior prevention strategy requires the ability to educate individuals regarding their risks for diseases in them, their progeny, and their relatives based on the unique combinations of their genetic background and their lifetime experiences. Although human gene therapy trials are in progress for a multitude of single gene disorders, it is unlikely that this form of intervention will be readily available for common human diseases in the near future. Thus, while genotypes of individuals remain unchanged, environments can be modified either at the level of individuals or of populations, and behavior prevention efforts could be targeted toward elimination, reduction or change of the environmental exposures to individuals. Education and behavior modification can sometimes be most effective in population groups at highest risk for the disease in question (e.g. HIV infection,(51)). In genetics, the basic premise is that education and behavior modification can be targeted toward individuals with differential genetic susceptibilities to specific environmental factors, in order to reduce the risks for specific diseases. The environmental prevention strategy is oriented toward reducing exposures in the workplace and in the home, and reducing disease risks by supplementing food or water with certain essential nutrients. For example, water fluoridation programs have contributed to the tremendous decline of dental caries in many countries. Environmental strategies for intervention are geared toward the population as a whole and do not inherently address genetic differences among individuals. Sometimes, global programs such as food supplementation, while beneficial to most people, may be deleterious to a relatively small fraction of genetically susceptible individuals who could be more sensitive to adverse effects from this intervention (such as deleterious effects of iron supplementation for persons with hereditary hemochromatosis). The clinical prevention strategy emphasizes preventive medicine in the health care setting. This is the traditional method of family-based intervention through genetic counseling. In an era of health care reform and cost control, the delivery of high-quality preventive care is essential. Although new medical technologies can be expensive, the appropriate use of molecular genetic technology is likely to improve the cost-effectiveness of screening and intervention strategies by targeting prevention strategies to persons at high risk of developing diseases. This is true for several reasons. First, procedures used to amplify DNA obtained from blood samples and to identify specific disease-related alleles are becoming increasingly automated and refined. As a result, the cost of DNA-based testing will continue to decrease dramatically. Second, many traditional methods used to identify persons at increased risk of disease such as a family history of cancer or heart disease, analysis of blood lipids, dietary assessment, and blood pressure measurement are often weak predictors of disease risk and frequently result in either false positive and false negative classification of an individual's risk status. Thus, the improved ability to accurately classify risk factor status that molecular genetic techniques provide can reduce the costs as well as increase the effectiveness of intervention strategies. An important public health application of genetics is to evaluate the effectiveness of population-based programs (e.g. follow up after newborn screening) and to assure the quality of genetic testing in the population. One essential public health function is to translate research into practice. Although research efforts can identify the efficacy of specific interventions, the effectiveness of such interventions needs to be carefully evaluated in population settings. For example, sickle cell disease is an autosomal recessive disorder affecting about 1 in 400 African-American newborns. Affected children have long been known to be at increased risk for mortality and morbidity because of complications such as septicemia, especially between the ages of 1 and 3 years (52). Using a randomized controlled clinical trial, researchers have shown that the early institution of penicillin prophylaxis is highly effective in reducing morbidity and mortality among infants and children with sickle cell disease (28). Penicillin prophylaxis is now used widely in the comprehensive primary care of children with sickle cell disease. This has led, in part, to the initiation of pilot newborn hemoglobinopathy screening programs in the 1970s. A National Institutes of Health Consensus Conference concluded that screening newborns for sickle cell disease could reduce morbidity and mortality (53). By 1993, more than 40 states had responded with programs for screening at least selected newborns (53). In spite of the well-documented beneficial effects of early medical intervention for sickle cell disease, no population-based national data are yet available with which to assess and track the effectiveness of preventing morbidity and mortality among infants with sickle cell disease ascertained through newborn screening. In particular, more information is needed regarding determinants of morbidity and mortality among such infants. Finally, an important component of assurance is quality assurance of genetic testing. For more than 17 years, the Centers for Disease Control and Prevention has conducted research on material development and has assisted laboratories with the quality assurance (QA) for newborn dried- blood-spots screening tests. These QA services primarily support newborn screening tests performed by state laboratories (e.g., tests for congenital hypothyroidism, phenylketonuria, and hemoglobinopathies). The QA program enables screening laboratories to achieve high levels of technical proficiency and continuity that transcend changes in commercial assay reagents. In addition, the program provides laboratories with quarterly panels of blind-coded dried blood specimens and gives them an independent external assessment of their performance. In addition to conducting
newborn screening, laboratories that perform genetic tests and report those test results
back to patients must comply with the regulations put forth by the Clinical Laboratory
Improvement Act of 1988 (54). Prior to reporting test results, laboratories must
establish, for each method, the performance specifications for the accuracy, precision,
analytical sensitivity and specificity, and reportable range of patient test results; the
reference range of normal values; and any other applicable performance characteristic.
These regulations have obvious implications not only in clinical medicine but also in
public health programs (e.g., newborn screening) as well to assure that genetic tests can
have high sensitivity, specificity and predictive value for the genotype they are
measuring. If the Human Genome Project
is to have widespread applications in disease prevention. population-based epidemiologic
studies are needed to assess the positive and negative predictive value of genetic tests
for specific diseases, and the interaction with known and modifiable disease risk factors.
Such studies provide the scientific foundation for validating genetic tests in the
population. Ethical, legal and social issues need to be carefully evaluated before
developing any public health genetic programs. Finally, essential public health functions
are to evaluate the effectiveness of these programs and to ensure the quality of genetic
testing in the U.S. population.
Table 1. From Genes to Public Health: Public Health Core Functions In Applying Genetics in Disease Prevention
Table 2. Issues to Consider in Using Genetic Testing in Disease Prevention 1) Public health impact of disease:
incidence, prevalence, morbidity, mortality * Members of the Genetics Working Group who prepared this paper include: Myron Adams (1), Robert F. Anda (2), Carol Ballew (2), Vicki Brown (1), Andrew T.L. Chen (1), Janet B. Croft (2), J. David Erickson (1), Mark Eberhardt (3), Wayne H. Giles (2), William Hannon (1), Gail Janes (2), Juliette Kendrick (2), Nancy C. Lee (2), Geraldine, McQuillan (3), Janet McNicholl (4), Joanne Mei (1), Cynthia Moore (1), Patricia Mueller (1), Godfrey Oakley (1), Richard Olney (1), Chin-Yih Ou (1), John A. Reidy (1), Frederick Rickles (4), Paul Schulte (5), Karen Steinberg (1), Diane Wagener (3), Nedra Whitehead (6).
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