Appendices of the 1997 Genomics Strategic Plan

Appendix A: Hereditary hemochromatosis and iron overload diseases

• Hereditary hemochromatosis is a genetic disorder of iron metabolism that increases iron absorption and results in lifelong excessive iron accumulation in the body.
• Hereditary hemochromatosis affects 1 in 400 to 1 in 200 people, and 1 in 10 people is a carrier, which makes the condition the most common known genetic disorder.
• In affected people, excessive iron deposits may result, usually after age 40, in arthritis, cirrhosis of the liver, diabetes, impotence, and heart failure.
• A major gene for hemochromatosis was cloned in 1996. The gene is linked with the major histocompatibility complex region on chromosome 6.
• Lifetime risk for disease is not well defined. Estimates range from 20% for women to more than 80% for men.
• Iron intake in the diet is the interacting factor. Interaction may also occur with infectious agents, alcohol, vitamin C, and other hereditary conditions (such as porphyria).
• Periodic phlebotomy throughout life is a very effective, life-saving intervention.
• Elevated transferrin saturation (TS) is a good screening test for iron overload. The sensitivity of the test is about 90%, and its positive predictive value is 10% to 20%.
• Important public health issues for discussion include whether or not to do population-based screening using TS or a DNA-based test and in which groups, whether to conduct population studies to assess disease risks, how to assess prevention effectiveness of screening, how to educate people about this condition, how to protect people from discrimination, and whether to use blood donated by people with this condition.
• In March 1997, CDC, in collaboration with National Human Genome Research Institute, held an expert panel meeting to assess the impact of gene discovery on the diagnosis, management, and prevention of iron overload associated with hereditary hemochromatosis. A summary of this meeting is being drafted for publication.

Appendix B: Hereditary breast cancer in BRCA1 carriers

• About 3% to 5% of breast cancers occur in women who carry mutations of BRCA1. Breast cancer in these carriers has not been shown to be histologically different from sporadic breast cancer. But women who carry these mutations often get cancer earlier and have multiple primary cancers more often than do women with sporadic cancer. Multiple family members get breast cancer in these families, and cancer develops in other sites, such as the ovaries.
• BRCA1 mutations are believed to occur in about 1 in 500 people.
• Breast cancer in BRCA1 mutation carriers is more likely to occur at a younger age than sporadic breast cancer. BRCA1 mutations increase women’s risk for ovarian cancer, and to a lesser degree, men’s risk for for prostate cancer.
• BRCA1 was cloned in 1994 on chromosome 17q. As of 1996, more than 150 mutations had been found in BRCA1. Only about 11 mutations have been found in more than two families.
• In studies of high-risk families, lifetime risk for breast cancer among BRCA1 carriers has been estimated at 50-85%, and the risk for ovarian cancer at about 15-40%.
• Little information is available on how BRCA1 interacts with other breast cancer risk factors.
• The efficacy of prophylactic mastectomy for preventing breast cancer has not been established. Prophylactic oophorectomy is believed to decrease risk for ovarian cancer, but a percentage of women with a family history of ovarian cancer have developed abdominal carcinomatosis after prophylactic oophorectomy. Screening of young women by using mammography, transvaginal ultrasound, or CA-125 concentration has not been proven to save lives.
• Tests are commercially available for BRCA1 mutations, but the risks of testing (psychological distress, insurance discrimination, employment or relationship problems) may outweigh the benefits (relief from anxiety if the test is negative, certainty about medical decisions or psychologic adjustment if the test is positive).
• Important public health issues for discussion include whether the test should be marketed to the general public in the absence of patient counseling services, the penetrance and prevalence of BRCA1 mutations, and the effectiveness of proposed interventions, such as prophylactic surgery and screening for CA-125. Other ethical and social issues about testing in the absence of a proven intervention also need to be addressed.

Appendix C: The importance of a new chemokine receptor allele (CCR5 D32) in HIV infection

• CCR5 is a chemokine receptor on cell surfaces. It binds cell-signaling molecules called chemokines (e.g., RANTES, MIP-1a, and MIP-1b). This interaction results in the activation and movement of immune cells to sites of infection, leading to enhanced clearance of pathogens.
• HIV, the virus that causes AIDS, has usurped this normal cellular receptor and uses it to enter immune cells.
• The CCR5 receptor occurs in at least two forms, wild type (W) and deleted (D32). The deletion of 32 base pairs of DNA in the CCR5 gene results in a CCR5 receptor that does not get to the cell surface.
• People with two copies of the deleted CCR5 receptor (D32/ D32), while appearing to have no immune system abnormalities, may be strongly protected from HIV infection. This is because the virus can no longer enter some immune system cells, specifically those most implicated in HIV transmission and early infection.
• Because HIV can enter immune cells by using other cell surface receptors, not all people with the D32/D32 CCR5 genotype are likely to be protected from HIV infection. To date, only one person with two copies of the deleted CCR5 gene has been reported to be HIV positive.
• People with HIV infection who have one copy of the deleted gene (W/D32 CCR5 genotype) may not develop AIDS as quickly as do people who have the wild type allele (W/W) only.
• The D32 CCR5 allele is found predominantly in people of European descent. So far it has not been found in people from parts of Asia and Africa. Homozygosity for the D32 CCR5 allele is found in about 1% of white people, and heterozygosity is found in 10% to 20%. Three to four percent of black people have the heterozygous (W/D32) genotype.
• The D32 CCR5 allele is easily detected by using PCR and restriction digest techniques. However, genetic testing for CCR5 allele status remains a research tool because protection associated with having two copies of the D32 allele appears not to be complete. It is not yet known whether testing for the heterozygous state (W/D32) is truly predictive of outcomes among people with HIV/AIDS.
• In response to questions from the public about these new findings, CDC and other HIV/AIDS research organizations prepared public health messages. These messages emphasized the need to continue proven methods for reducing exposure to HIV regardless of CCR5 genotype (CDC HIV/AIDS Prevention Newsletter, February 1997: 1-2 ).
• The data about CCR5 and HIV have stimulated the development of potential therapies for the prevention and treatment of HIV infection.

Appendix D: Examples of CDC activities in genetics

I) Public health assessment

Surveillance

• Birth defects and developmental disabilities
• Hemophilia

Molecular and genetic epidemiology

• Genetic risk factors for spina bifida
• CCR5, HLA, and other immune system genes in HIV+ and HIV- populations
• HLA genes in people with measles, hantavirus, human papillomavirus, malaria, coccidiomycosis, rheumatoid arthritis, and cervical neoplasia
• DNA adducts, metabolic enzyme polymorphisms, HLA, oncogenes, and other genetic biomarkers in people with occupational diseases
• Vitamin D receptor alleles and osteoporosis risk
• HLA-H and disease in people with hemophilia
• Thrombosis and CVS-related genes in people with hemophilia or people with vascular disease

Other

• NHANES DNA bank: Establishment of cell lines from a representative U.S. sample
• Assessment of fetal risk from chorionic villus sampling
• Assessment of newborn screening for cystic fibrosis (workshop)

II) Evaluation of genetic testing

• Newborn Screening Quality Assurance Program
• CLIA 88 regulations

III) Intervention development, implementation, and evaluation

• National program to prevent iron overload
• Evaluation of reduction of morbidity following newborn screening for sickle cell disease
• Prevention of joint disease in people with hemophilia
• Prevention of factor VIII inhibitor formation in people with hemophilia

IV) Communication and information dissemination

• CD-ROM project on the genetic basis of cancer
• CDC statements on hemochromatosis, CCR5, and HIV infection
• Electronic communications on news in genetics and disease prevention

Appendix E: CDC Task Force on Genetics in Disease Prevention

1. Rob Anda, M.D., National Center for Chronic Disease Prevention and Health Promotion
2. Timothy Baker, B.S., National Immunization Program
3. Carol Boussy, Ph.D., National Center for Environmental Health
4. Joanne Cono, M.D., M.Sc. National Center for Environmental Health
5. Gayle DeBord, Ph.D., National Institute for Occupational Safety and Health
6. Julie Fishman, M.P.H., National Center for Chronic Disease Prevention and Health Promotion
7. Gale Gardiner, Ph.D., National Center for Health Statistics
8. Wayne Giles, M.D., M.S., National Center for Chronic Disease Prevention and Health Promotion
9. Barbara Gray, M.Ln., National Center for Chronic Disease Prevention and Health Promotion
10. Harry Hannon, Ph.D. National Center for Environmental Health
11. Dick Keenlyside, M.D., Public Health Practice and Program Office
12. Muin Khoury, M.D., Ph.D., National Center for Environmental Health
13. Ellen King, National Center for Environmental Health
14. Paula Kocher, J.D., Office of the Director
15. Deena Koniver, M.S., Office of the Associate Director for Science
16. Janet McNicholl, M.D., National Center for Infectious Diseases
17. Leslie O’Leary, Ph.D., National Center for Environmental Health
18. Fred Rickles, M.D., National Center for Infectious Diseases
19. Dawn Smith, M.D., National Center for HIV/AIDS, STD, and TB Prevention
20. Karen Steinberg, Ph.D., National Center for Environmental Health
21. Deborah Tress, J.D., Office of the Director
22. Ben Truman, M.D. Epidemiology Program Office
23. Diane Wagener, Ph.D., National Center for Health Statistics
24. Dometa Williams, National Center for Environmental Health

Appendix F: Meeting participants, Translating Advances in Human Genetics into Public Health Action, January 27-28, 1997

Name, Organization, & Affiliation

1. Thom Berry, South Carolina Department of Health and Environmental Control; National Public Health Information Coalition
2. Karina Boehm, MPH, National Human Genome Research Institute
3. Donna Brown, Research Genetics
4. James Cheek, MD, MPH, Indian Health Service
5. Roberta Crawford, Iron Overload Diseases Association
6. George Cunningham, MD, California Department of Health Services
7. Mary Davidson, MSW, Alliance of Genetic Support Groups
8. Franklin Desposito, MD, UMDNJ – New Jersey Medical School, Department of Pediatrics; American Academy of Pediatrics
9. Louis J. Elsas II, MD, Emory University Department of Pediatrics, Medical Genetics Pediatrics; Council of Regional Genetic Networks
10. Tom Frank, MD, Myriad Genetics, Inc.
11. John Gallicchio, Health Resource and Service Administration, Maternal and Child Health Bureau
12. Rani George, MPH, Association of Asian Pacific Community Health Organizations
13. Wayne Grody, MD, PhD, UCLA School of Medicine, Division of Medical Genetics and Molecular Pathology; College of American Pathologists
14. Steve Groft, PharmD, National Institute of Health, Office of Rare Diseases
15. Joseph Hackett, MD, Food and Drug Administration
16. Arthur Hackman, National Hemophilia Foundation
17. James W. Hanson, MD, National Institute for Child Health Development
18. Stanley Inhorn, MD, Wisconsin State Laboratory of Hygiene; Association of Public Health Laboratories
19. Fatimah Jackson, PhD, University of Maryland, Department of Applied Biological Anthropology Research; Human Biology Association
20. Michael Katz, MD, March of Dimes
21. Heidi L. Keller, Office of Health Promotion, Washington Department of Health; Association of State and Territorial Directors of Health Promotion and Public Health Education
22. Michael Knapp, National Center for Genome Resources
23. Michael Langan, National Organization for Rare Disorders
24. David Lanier, MD, Agency for Health Care Policy and Research
25. Linda R. Lebovic, MT, Health Care Financing Administration, Health Standards and Quality Bureau
26. Eugene Lengerich, VMD, North Carolina Department of Health, Division of Health Promotion; Council of State and Territorial Epidemiologists
27. Glenn McGee, PhD, University of Pennsylvania, School of Medicine, Center for Bioethics
28. Patricia Murphy, PhD, GeneWise
29. Daniel W. Nebert, MD, University of Cincinnati Medical Center
30. Pat J. Numann, MD, State University of New York, College of Medicine, Health Science Center; American Medical Association
31. Victoria Odesina, RN, Sickle Cell Service, Gengras Ambulatory Center, Sickle Cell Service
32. Reed Pyeritz, MD, PhD, Allegheny General Hospital, Department of Human Genetics; American College of Medical Genetics
33. Ana Rivas Beck, JD, National Coalition of Hispanic Health and Human Services Organizations
34. Mark Rothstein, JD, Health, Law and Policy Institute, University of Houston
35. Sheldon Samuels, Ramazzini Institute
36. Katherine Schneider, Dana-Farber Cancer Institute; National Society for Genetic Counselors
37. Morton Schwartz, PhD, Memorial Sloan-Kettering Cancer Center; CLIAC Genetics Committee
38. Stephanie Sherman, PhD, Emory University School of Medicine, Department of Genetics and Molecular Medicine; American Society of Human Genetics
39. Brad Therrell, PhD, Texas Department of Health, Chemical Services Division; International Society for Neonatal Screening
40. Elizabeth Thomson, National Human Genome Research Institute
41. Martin Wasserman, MD, JD, Maryland Department of Health and Mental Hygiene; Association of State and Territorial Health Officials
42. Robert Weir, PhD, Program in Biomedical Ethics and Medical Humanities, University of Iowa
43. Ann M. Willey, PhD, Division of Laboratory Quality Certification, New York State Department of Health
44. Kathleen Zeitz, JD, National Breast Cancer Coalition

Appendix G: Summary of conclusions reached at “Translating Advances in Human Genetics into Public Health Action,” a meeting held January 27-28, 1997

• Participants expressed enthusiastic support for CDC’s role in genetics and public health.
• High expectations exist for CDC and the need to set priorities for activities.
• Coordination with other federal agencies is essential.
• Partnerships with numerous stakeholders are necessary.
• Ethical issues are the greatest challenge.
• Communication, education, and community involvement are important.
• CDC’s greatest strengths are epidemiology, surveillance, and population-based data collection.
• Needs assessments should be conducted both internally and at the state level.
• A clearinghouse for genetics information related to public health is needed.
• Support for CDC’s role in laboratory quality assurance and proficiency testing was expressed.
• Diseases of low frequency and high severity should not be ignored.

Appendix H: Selected recommendations* of the joint NIH-DOE Task Force on Genetic Testing

1. The Secretary of Health and Human Services should create an advisory committee on genetic testing involving multiple organizations and federal agencies.
2. Institutional Review Boards must ensure that protocols for the development of genetic tests can be used predictively when subject identifiers are retained and when the tests are to be readily available for clinical use.
3. Highlight CDC’s role in facilitating the collection of data on the safety and effectiveness of new genetic tests. “CDC should play a coordinating role in data gathering and should be allocated sufficient funds for this purpose. CDC’s role is particularly important in collecting data in normal populations, e.g., on disease-related allele frequencies and in collecting data from multiple sources to facilitate review of new tests, particularly for rare diseases. The Task Force welcomes recent CDC initiatives to (1) expand its population-based surveillance systems in order to provide data on the validity of genetic tests and post-test interventions, and (2) conduct follow-up epidemiologic studies on individuals tested for specific genotypes to learn more about test validity, the natural history of genetic disorders, and the safety and effectiveness of intervention. These efforts should be in collaboration with other Federal and State agencies and private organizations.”
4. Genetic test developers should submit validation and clinical utility data to external review as well as to interested professional organizations in order to permit users to make informed decisions about routine use.
5. “The Task Force urges the newly created genetics subcommittee of the Clinical Laboratory Improvement Advisory Committee to consider the creation of a specialty of genetics which would encompass all predictive tests that satisfy criteria for stringent scrutiny. If only a subspecialty for DNA/RNA-based tests is feasible, the subcommittee must then address how to assure the quality of laboratories performing nonDNA/RNA predictive genetic tests. The agencies primarily responsible for administering CLIA, HCFA, and CDC should take the lead in implementing this recommendation.”

* The Final report of the Task Force on Genetic Testing: Promoting Safe and Effective Genetic Testing in the United States – Principles and Recommendations is available on the world wide web at https://www.genome.gov/10001733/genetic-testing-report.

Appendix I: Examples of ethical issues crucial to public health genetics programs

Assuming that knowledge about genetic risk factors can be used to prevent morbidity and mortality, ethical issues include 1) voluntariness of programs, 2) informed consent, 3) disclosure of results of genetic testing, 4) privacy concerns in large scale surveillance programs, and 5) concerns about group stigmatization. The following are examples of specific questions that may arise:

1. How can truly informed consent for genetic testing be obtained in public health practice (versus clinical practice, in which personal contact and the opportunity for one-on-one interaction is greater)? How does informed consent for genetic testing in public health practice differ from informed consent for other public health services?
2. Should counseling services be provided as part of public health practice even when risks associated with different genetic polymorphisms and mutations vary widely? How can such services be provided?
3. How can privacy and confidentiality be maintained in the public health setting?
4. How should population-based disease registries be handled? What are their immediate and long-term benefits? What are their immediate and long-term risks? How can public health agencies maximize benefits and minimize the risks associated with such registries?
5. Under what circumstances, if any, is it appropriate to make specimens anonymous?
6. Are there ethical alternatives to classic reporting* for public health practice, especially when large populations are involved?
7. What rules should exist for making specimens anonymous or destroying specimens obtained in public health practice?
8. Under what circumstances is new consent for archived specimens needed for public health investigations?
9. How can consent be tracked on specimens from many sources, including hospital laboratories?
10. Do situations occur in public health when genetic testing could be done on identifiable specimens without informed consent?

*Classic reporting refers to the one-on-one interaction between a patient and a doctor, nurse, or counselor for explaining a genetic test and its results. An alternative might be to tell all participants that an equal number of those who have and those who do not have a specific mutation will be contacted for post-test counseling. In this way, people who receive a call cannot assume what their results are.