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Genetic Susceptibility to Birth Defects in Humans: From Gene Discovery to Public Health Action by Muin
J. Khoury M.D., Ph.D.
Advances in Human Genetics Research With the relentless progress of the Human Genome Project, by the year 2003, most--if not all--of the estimated 100,000 human genes will have been found (Collins, 1998). Close to 10,000 genes have already been cataloged (Online Mendelian Inheritance in Man, 1998), and tests for more than 500 genes are already available in medical practice (Pagon, 1998). The genes identified thus far range from those associated with rare metabolic disorders to common diseases including cancer and adult onset conditions. Genetic variants confer increased susceptibility to a variety of environmental factors (including chemical, infectious, physical, social, psychological, behavioral, and nutritional factors) to increase the risk of many diseases including birth defects. Although birth defects remain the leading cause of infant mortality in the United States (CDC, 1998), the causes of most remain elusive. Nevertheless, an increasing number of clinical and epidemiologic studies are beginning to unravel some birth defects risk factors (Khoury, 1995). Over the last two decades, numerous investigators have identified malformations associated with rare single gene disorders. Table 1 shows the results of a quick search of the Online Mendelian Inheritance in Man Catalog on the Internet. As can be seen, dozens of genes have been reported with a variety birth defects, mostly in a few families leading to malformation syndromes. Increasingly, more common gene variants are suggested to be associated with the risk of common birth defects such as the methylene tetrahydrofolate reductase (MTHFR) polymorphism in relation to the risk neural tube defects (MTHFR) (Posey, 1996). The interaction between gene variants at multiple loci with environmental exposures is likely to explain the majority of common defects such as neural tube defects, oral clefts and congenital cardiovascular malformations. As a result of genetic research, information on differential genetic
susceptibility to the risk of birth defects will be accumulating. Ideally,
information on genetic susceptibility to birth defects will be used to target
beneficial interventions that reduce the risk of birth defects (e.g. nutritional
interventions such as folic acid), or to avoid certain pregnancy exposures for
individuals at greatest risk (e.g., avoiding certain anti epileptic drugs on the
basis of genetic metabolic profile). However, complex ethical, legal, and social
issues are already being raised on the pitfalls of genetic testing in general (Lewontin,
1996) . The effective use of genetic knowledge and technology is becoming a
crucial challenge to the public health community. The manner with which genetic
information can be used to promote health and prevent disease and disability,
especially birth defects has scarcely been explored. Information is lacking
about the population distribution of genotypes associated with birth defects,
the benefits and risks of genetic testing, and the efficacy of interventions.
The complex and controversial issues that have emerged--about quality assurance
for laboratory testing, rapid commercialization of genetic tests, lack
availability of and access to effective and acceptable interventions, and
potential discrimination against and stigmatization of individuals and
groups--call for public health leadership (CDC, 1997). In 1997, the Centers for Disease Control and Prevention created the Office of Genomics and Disease Prevention to highlight the emerging role of genetics in the practice of public health in the United States, and to provide internal coordination and promote external partnerships in activities related to genetics and disease prevention and health promotion. This action was recommended in an agency-wide strategic plan that outlines a conceptual framework for a public health program in genetics (CDC, 1997). The strategic plan is based on the assumption that, broadly defined, virtually all human diseases of important public health impact are the result of the interaction between human genetic variation and the environment. It is also based on the assumption that the use of genetic information in public health is appropriate in diagnosing, treating and preventing disease, disability, and death among people who inherit specific genotypes. Prevention includes the use of medical, behavioral, and environmental interventions to reduce the risk for disease among people susceptible because of their genetic makeup. The plan supports the responsible use of genetic tests and services, including adequate family history assessment and genetic counseling, for promoting health and preventing disease in different communities. The plan assumes that much of the delivery of genetic tests and services will be done within the context of the evolving health care system, including managed care organizations, rather than under public health agencies. Public health agencies will have an increasing role in assessing the health needs of populations, assuring the quality of genetic tests and services and evaluating the impact of interventions. The framework for the role of genetics in public health is based on an extension of the Institute of Medicine model of the Future of Public Health (IOM, 1988). This extended framework identifies four essential public health genetics program components:
In order for these activities to be done, three cross-cutting critical issues that can affect each program component need to be addressed: partnerships and coordination, ethical, legal, and social issues (e.g. using stored samples such as. newborn blood spots for conducting large scale epidemiologic studies of birth defects etiology), and training of the public health workforce and education of the general public. In the field of birth defects, the existing model of public health assessment
has traditionally focused on surveillance for birth defects followed by
conducting population-based epidemiologic studies to find causes of birth
defects. This model can easily be extended to begin looking simultaneously at
genetic risk factors along with environmental factors to explain the complex
etiology of the most common malformations. In fact, this work is currently been
done collaboratively by several birth defects surveillance programs, members of
the National Birth Defects Prevention Network (NBDPN, 1997), as well as by birth
defects registries and academic institutions from around the world. In
particular, the case-control method based on population-based birth defects
registries will prove to be exceptionally useful to gather information on
gene-environment interaction on birth defects, especially for rare defects (Khoury,
1994). Alternatively, large scale collaborative prospective studies can be
mounted to answer numerous questions regarding the etiology of birth defects and
other reproductive outcomes with a focus on gene-environment interaction. Because of the complexities of information that will emerge from gene discoveries and the need for a systematic epidemiologic approach to the evaluation of new genes and their variants, the CDC, with many partners recently launched a new collaborative initiative, the Human Genome Epidemiology Network (HuGE Net; Khoury and Dorman, 1998)). HuGE Net represents the collaboration of individuals and organizations from diverse backgrounds who are committed to the development and dissemination of population-based human genome epidemiologic information The goals of HuGE Net are to: 1) establish an information exchange network that promotes global collaboration in the development and dissemination of peer-reviewed epidemiologic information on human genes; 2) develop an updated and accessible knowledge base on the World Wide Web; and 3) promote the use of this knowledge base by health care providers, researchers, industry, government, and the public for making decisions involving the use of genetic tests and services for disease prevention and health promotion. The term human genome epidemiology (HuGE) denotes an evolving field of inquiry that uses systematic applications of epidemiologic methods and approaches in population-based studies of the impact of human genetic variation on health and disease. The spectrum of topics addressed in human genome epidemiology range from basic to applied population-based research on discovered human genes:
Given the massive amount of population-based epidemiologic data that will be generated on human genes over the next decades, HuGE Net will represent a coordinated global effort to disseminate human genome epidemiologic information in order to keep up with the progress of the Human Genome Project and its accompanying gene discoveries. HuGE Net will evolve as a collaboration among epidemiologists, geneticists, basic scientists, medical and public health practitioners from government, professional, academic, industry and consumer organizations worldwide. In the field of birth defects, there is a growing need for conducting
epidemiologic studies of genetic susceptibility to birth defects as well as for
disseminating the results of systematic epidemiologic reviews of the association
of specific gene variants with specific defects. Such a public health assessment
can be viewed as the first crucial step in translating discoveries of genes for
birth defects into policies and interventions that reduce the risk of birth
defects among susceptible populations. For further information on joining this
global collaborative effort, please consult the HuGE Net web site at www.cdc.gov/genetics/huge.htm.
Centers for Disease Control and Prevention. Translating Advances in Human Genetics into Public Health Action: A Strategic Plan. http://www.cdc.gov/genetics/Strategic.html, 1997. Centers for Disease Control and Prevention. Trends in infant mortality attributable to birth defects--United States, 1980-1995. Morb Mortal Wkly Rep. 1998;47:773-8 Collins FS, Patrinos A, Jordan E, Chakravarti A, Gesteland R, Walters L, and the members of the DOE and NIH planning groups. New Goals for the U.S. Human Genome Project: 1998-2003. Science Oct 23 1998: 682-689. Pagon RA, Covington M, Tarczy-Hornoch P. Helix: A Directory of Medical Genetics Laboratories. http://www.hslib.washington.edu/helix/ (1998). Hubbard R, Lewontin RC. Pitfalls of genetic testing. N Engl J Med 1996;334:1192-4. Institute of Medicine. The future of public health. Washington, DC: National Academy Press, 1988. Khoury MJ, Beaty TH. Applications of the case-control method in genetic epidemiology. Epidemiol Rev 1994;16:134-50 Khoury MJ. Commentary: contributions of epidemiology to the study of birth defects in humans. Teratology 1995;52:186-9 Khoury MJ, Dorman JS. The Human Genome Epidemiology Network (HuGE Net). Am J Epidemiol 1998;148:1-3. National Birth Defects Surveillance Network. Congenital malformations surveillance report. Teratology 1997;56:1-175. Online Mendelian Inheritance in Man (OMIM) (TM). Center for Medical Genetics, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD), 1998. Posey DL, Khoury M J. Mulinare J, Adams MJ, Ou CY. Is Mutated Methylenetetrahydrafolate Reductase (MTHFR) a Risk Factor for Neural Tube Defects? A Pooled Analysis. Lancet 1996;347:686-687 Address correspondence to Dr Khoury at
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