Genomics and the Future of Public Health and Training

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Genomics and the Future of Public Health (and
Training)

• Peter D. Rumm, MD, MPH
• Chief Medical Officer, Chronic Disease, DPH, DHFS
• 608-267-3835, Rummpd_at_dhfs.state.wi.us

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Professional Background Related to This Topic
caveat, this is not my primary training

• Graduate studies in laboratory medicine and
  protein chemistry - Auburn Univ. 1980, one
  seminar in my MPH at the other UW.
• DOD Project Manager, Virtual Public Health
  Laboratory, Walter Reed Army Institute of
  Research, 1998-1999.
• Chair, Council of State and Territorial
  Epidemiologists Committee and Workgroups on
  Genetics 1999-2000,
• Chair, Epidemiology and Informatics Workgroup for
  the Public Health Competency Project on
  Genetics/Genomics, CDC, 1999-2000
• DHFS Consultant to State of Wisconsin Genetics
  Plan 2000 and Co - author - Special Chapter on
  Genetics and Public Health - Healthiest Wisconsin
  2010
• Various topic lectures at state, regional and
  national conferences on genetics and genomics and
  chronic disease, other public health issues.

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Primary Topics

• Introduction to genomics vs. genetics.
• Introduction to the CDCs Public Health
  Competencies how they might impact your Ph.D.,
  M.P.H (future) or MS programs.
• Brief special topics
• colorectal cancer
• pharmacogenetics
• role in infectious diseases
• developing relationship in homocysteine and heart
  disease

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The Old Genetics

• Main feature low prevalence, high severity
  (often fatal)
• Great importance to individuals and their
  families/public health (often absorbed high
  medical costs) but added together are fairly rare
• Overall, small effect on health care and
  society
• However, collective grouping has an
  underestimated large economic impact - est. 5-10
  of all admissions related to known genetic
  diseases from classic mutations/mendalian
  genetics -various economic research studies in
  last 5 years.
• Public health with targeted programs, usually
  maternal childhood and laboratory centered
  programs.
• Missing chromosomes - Downs, Turner, cri-du-chat
• Mutation in single gene - cystic fibrosis, Marfan
  syndrome, phenyketonuria

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Old Genetics

• Genetic care primarily supplied by medical
  geneticists and/or specialists of conditions
  directly due to the mutations.
• With the advent of the human genome program -
  much more has actually been elicited about these
  conditions and their variants. (ex. cystic
  fibrosis, UW (Madison) has been on the leading
  edge of research/advanced testing for this
  condition)
• Human genome project and related technology was
  the primary bridge to genomics.

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Human Genome Project

• Three billion chemical bases.
• Disease is often caused by a single alteration or
  variation in this huge number of bases - put in
  scale one letter in 150,000 pages!
• Unique international (led by U.S. in terms of
  most funding and support) governmental project
  that finished ahead of schedule and under budget!
• Earmarked a significant percentage of the funds
  for consideration of ethical, legal and social
  ramifications.

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Genomic Medicine

• Conditions caused partially by mutations in
  genes. (Colon cancer, breast cancer,
  atherosclerosis, inflammatory bowel disease,
  alzheimer disease, mood disorders and others).
• Prevented by mutations in genes (HIV,
  atherosclerosis, some cancers ?, ? diabetes and
  many others).
• Important to individuals, families and society -
  high prevalence and variable severity.
• Should allow both individual and population
  disease risk identification, targeted therapies,
  some cures.

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Genomics - we are not truly there yet

• Most current success has been to identify alleles
  that are still low frequency and high penetrance
  (among most cited ex.)
• BRCA1 and 2 (Breast and ovarian CA)
• HNPCC (colon cancer)
• MODY 1,2,3 (diabetes)
• Alpha-synuclein (Parkinson disease)

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Last couple of years

• Increased identification of diseases that are
  caused from high frequency but low penetration
  (known manifestations) alleles
• APC I13070K and colon cancer
• ApoE and Alzheimer disease
• CCR5 and HIV/AIDS resistance
• Factor V Leiden and thrombosis

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Current various NIH/CDC estimates of role of
genetics' role in some leading causes of death (
some - age, gender and race/ethnic specific)

• Heart Disease ?
• Cancer ? (some)
• Stroke to ?
• COPD ?
• Pneumonia/Flu ?
• Diabetes ? (obesity genes to NIDDM )
• Kidney diseases ?
• Chronic Liver ?
• HIV - small protective link, other ?

• Controversial
• Relationship of injury to genetic components
• Suicide (excluding that related to MI)
• Homicide (related to studies on behaviors)

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Genomic Medicine

• Should change health care and research by
  creating a more fundamental understanding of
  genetic and non-genetic roles in disease.
• Research prevalence of conditions will lead to
  increased studies into drugs and screening tools
  for chronic conditions.
• Primary care physicians will eventually have
  access to most genetic tools.
• Executive or marketed medicine (social and
  ethical implications).

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Genomic Medicine

• Should lead to markedly improved knowledge of
  both individual and population based risk
  screening.
• Targeted drugs.
• Specific health maintenance programs.
• ? How many conditions will eventually prove
  amenable to genetic treatments, most dramatic
  have been a few severely congenital.
  immunosuppresed patients - with 3 year plus
  cures.

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Introduction to Genomics implications for public
health and its training needs

• Screening issues.
• Ethical issues.
• What do different public health specialists need
  to know about this complex area (more on this
  later)?
• Some have predicted that genetics/genomics will
  be to the 21st century to public health what
  infectious disease was in the 20th century.
• CDC just renamed the Division of Genetics to the
  Office of Genomics and Disease Prevention.
  Recently funding has 4x (still well behind ID
  and bio-terrorism).

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Cancer and Genomics

• Knowledge rapidly expanding, with implications
  toward screening, primary prevention and
  treatment.
• Large ongoing internal and extramural research
  programs at NCI and other NIH Centers.
• Dtrict biological terms all cancers have a
  genetic basis, due to changes at the micro
  chromosomal and DNA levels.
• Current consensus public health experts relate
  5-15 of cancers to environmental causes. Most
  other causes are linked to a mix of behavior risk
  factors. Both are surely influenced by genetic
  pre-dispositions.

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Cancer and Genetics - continued.

• Relating to Mendelian genetics, many known cancer
  pre-dispositions are AD. The term carrier is
  often used in such cases (not truly correct) to
  denote those predisposed.
• Perhaps, most commonly discussed in public health
  today are the BRAC mutations linked to ovarian
  and breast cancer.
• There has been significant renewed controversy
  about the preventive value/risk benefit of
  mastectomy or ovarian removal, and future genetic
  and research studies are underway at NIH to try
  to bring further light on this issue.

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Cancer continued

• The NCI, NIH in conjunction with the CDC and the
  ACS have put out an excellent synopses on cancer
  screening, prevention and genetics -
  www.cancer.gov/cancerinfo/pdq/genetics/overview
  and linked cites.
• Colorectal Cancer - topic of special state
  conference.
• As a review colon cancer and its relative rectal
  cancer the 2nd leading cause of cancer
  mortality in WI and the U.S. and the 3rd leading
  cause of cancer mortality for both males and
  females.

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Colorectal Cancer and Genomics

• 75 of colorectal cancer patients with sporadic
  disease with no potential link to a genetic
  history.
• Known genetic mutations so far account for only
  5-6 of the total or about 1/4 of such cases.
  Almost all of these include the colon as the
  primary cite.

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Biological Background

• There are very complex transitions among normal
  ephithelium to adenoma (25 go on to CA in 20
  years) to carcinoma are due to acquired
  molecular events.
• 85 of CR, CA are due to events in chromosomal
  instability and the remaining 15 due to
  mircrosatellite (MIN) instability.
• CIN changes typically in 5q, 18q, 17p, and/or a
  mutation in the KRAS oncogene.

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The Two Major Known Genomic Forms

• Familial adeunomatous polyposis (FAP), including
  the attenuated form (AFAP) mutation in the APC
  gene.
• Hereditary nonpolyposis colorectal cancer,
  (HNPCC) caused by germline mutations in
  mismatched repair genes.
• How good is family history for these conditions
  or for situations such as a 1st degree relative?
• Recent University of Utah study found an overall
  sensitivity of 73 (95 CI 54-88) and a kappa
  score of 0.56 for known increased genetic risk
  situations.

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Estimated Lifetime Risk of CRC (NCI, NIH)
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NIH on Modifying Screening if Family Hx - Promote
Frequent and Earlier Screening

• First degree relative overall replicated several
  major studies increased risk 2-3X.
• FAP, HNPCC - Begin screening earlier in life,
  some recommendations suggest young adulthood.
• Colonoscopy strongly recommended by ACS, NCI etc.
  as screening current primary screening modality
  of choice in FAP and HNPCC.
• Most likely reasonable for 1st degree relatives
  as early as age 40 (some cancer experts argue for
  earlier).
• Prophylactic resection is often considered.
• FAP and HNPCC have been linked to other cancers -
  frequent HX and PE with low threshold to screen
  for other cancers.

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Pharmacogenetics/genomics - Good and Bad?

• Pharmacogenetics refers in strict scientific
  terms to the interaction of a drug on one gene
  involved typically in the drugs metabolism, while
  pharmacogenomics is the term used for interaction
  with any or multiple genes, or multiple cites
  through the genome.
• This field receiving attention () from the
  major drug firms due to immense potential for
  profits and several recent court decisions
  protecting genetic based patents - Depression,
  CHD, CA etc.
• May have very beneficial effects on reducing side
  effects and patient safety efforts.
• Strong consumer advocate concerns about patient
  confidentiality despite HIPPA, effect on drug
  costs must be weighed against true potential
  for chronic and perhaps, acute disease
  prevention.

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Cardiovascular Disease

• Huge amount of current NIH supported research
  into lipids, hormones, genetic risk of
  inflammatory based plaque formations (now thought
  to be a significant risk factor) etc.
• One of the most interesting cardiovascular
  disease controversies recently has been that
  serum levels of Homocysteine seem to increase the
  risk of stroke and heart disease.

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Homocysteine, Folate and a Rare Genotype -
Implications for Public Health?

• In a just published meta-analysis, homocysteine
  appears to cause a modest) 0.11 OR reduction
  for IHD and a 0.19 lower stroke risk.
  Homocysteine Studies Collaborative, JAMA, vol.
  28816(2015-22), Oct. 2002.
• However, in relation to MTHFR 677C?T Polymorphism
  individuals had a significantly higher risk of
  CHD (OR 1.16) than normal populations. This
  mutation causes impaired folate metabolism which
  has been linked to lower homocysteine levels -
  linked to increased CHD. Klerk et.al. same JAMA,
  pp 2023-2029.
• It might prove cost effective to test those with
  homocysteine levels for this genetic mutation
  or give folate to all. The public health impact
  to be determined!

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Infectious Disease and Genomics

• HIV - delta 32 CCR5 gene seems to provide in the
  homozygous state, near 100 protection against
  acquisition.
• Heterozygous state and certain HLA types appear
  to have better HIV/AIDS disease management
  outcomes.
• Malaria is polygenetic - genes of the chemokine
  receptors, HLA and tumor necrosis factor
  influence parasite entry.
• Genomic experts at the CDC predict that most
  infectious diseases, especially the chronic ones
  (HIV, hepatitis, TB etc.) will have genomic
  predictors of susceptibility and important
  implications for pharmacogenomics and vaccine
  developments within this decade.

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ID and Genomics - Continued

• At NCID (NIH) internal and external research is
  focusing on genetic implications for HIV,
  malaria, acute liver disease, coccidiomycosis,
  resistance to infectious agents for cystic
  fibrosis and sickle cell, vaccines, hantavirus
  and other hemorrhage infections.
• Bio-terrorism agents receiving highest priority
  both for detection and prevention and genetics is
  being increasingly considered in regards to
  laboratory testing, vaccines and drug
  development. DOD has similar programs at
  USAMRIID.
• Additional work is ongoing for Hepatitis C -
  especially in the realm of trying to decide who
  would benefit from costly interferon and other
  therapies.

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CDC Public Health Workforce Competency Project

• Joint effort of the PHPPO, CDC and ASTHO, CSTE
  and ATPM etc.
• Genomics part of larger document.
• My team focused team on epidemiology, informatics
  and surveillance.
• Reviewed by over 500 individuals after completed
  in 2000.

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Implications for the Department of Population
Health

• Ideally, should be integrated into planning for
  all degree programs as same skills will be in
  demand by employers of your graduates.
• For public health the CDC, ASTHO, CSTE and others
  believe the need is critical.
• Potential for emphasis in planned MPH?
• Source of expertise the University of
  Washington is the largest school of public health
  that has recently started a dedicated MPH tract
  for genetics, graduating about 10 MPH students a
  year with 18 in the Ph.D. tract. (Dean Dr. Pat
  Wahl)

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Special Thanks To

• Dr. Khoury and the staff of the Office of
  Genomics and Prevention, CDC.
• NIH, NCI experts in this arena.
• My lifelong friends and committee members on the
  Genomics Workforce Competency Project and on the
  CSTE committees.
• All of you for your attention, dedication and
  continued work in the arena of population health,
  medicine, policy and public health.
• Questions?