Transcript Genetics and Primary Care: A Research Agenda

Genetics and Primary Care:
A Research Agenda
Leigh LoPresti, M.D.
Waukesha Family Medicine Residency Program
Medical College of Wisconsin
November 12, 2009
Why Me?
• Family Physician
 Full-time practice for 15 years after
residency
 Mostly rural
• Transition to academics was
genetics driven
• Lucky in genetics
Primary Care
• “A primary care physician is a generalist physician
who…takes continuing responsibility for providing
the patient's care…for substantially all of the
patient's medical and health care needs - not
limited by problem origin, organ system, or
diagnosis. Primary care physicians are advocates
for the patient in coordinating the use of the entire
health care system to benefit the patient.”
• We:
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Diagnose
Treat
Prevent
Care for multiple family members
Genetics
• “Medical geneticists are health professionals who
are dedicated to using and interpreting genetic
information to maintain and improve the health of
individuals, their families and communities.”
• They:
 Diagnose
 Treat
 Care for multiple family members
Genetics Progress
• Old Well-Known News:
Human Genome Project
 1990-2003
 Sequenced genome, found MANY
fewer genes than expected
 Purpose of large parts of genome
unknown
 Identified 1.8 million SNP’s
Genetics Progress
• Not Well-Known News:
HapMap Project
 2002-ongoing
 Identified larger sections of DNA that cn be
identified by a single SNP: a haplotype
 Characterized haplotype variability in 3
populations in Phases 1-2.
 Now Phase 3: 11 populations, 1100+
individuals
 Basis for current GWAS studies
Genetics Progress
• Ongoing Work
 GWAS studies
 Cancer Genome Project
 Human Microbiome Project
 Pharmacogenomics
 RNA interference
GWAS
• Associations between genes and
disease
 OFTEN unexpected associations
 Requires very low p values due to more
associations being looked for
 We are looking for genes of at most
moderate effect (RR 1.4-2.0, most
commonly)
 They can still be important in disease by
being commonly found alleles
Published Genome-Wide Associations through
Published Genome-Wide Associations
439 published GWA at p < 5 x 10-8
NHGRI GWA Catalog
www.genome.gov/GWAStudies
Cancer Genome
• Cancer is a disease of DNA!
• Goal is to define the differences
between a cancer cell and normal
cells
• 2007-2010 for pilot project
• Working so far with glioblastoma, lung
(squamous cell), and ovarian cancers
• Next up: 20 more, most types
undetermined, but will include breast
and renal cell
Microbiology
• Pathogens
• Some bacteria (MRSA) are now
identified genetically in hours
• Most have now been sequenced and
proteomics and expression profiling
are at least promising new targets for
drugs and vaccines.
Microbiome
• The Human Microbiome Project
 2008 to present (planned end 2013?)
 Now working to understand:
 Composition
 Communities
 Roles
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of our commensal (mutualistic?) organisms
and how they change in
 Health
 Disease, and
 with medical treatments
Microbiome
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Estimates
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1000 species
1013 organisms
1.5 kg of bacteria
in GI tract alone
}
Significant variation across people:
may only be about a 1% match across
people
Microbiome
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Current areas of suspected involvement
—
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Obesity (lactobacillus protective?)
Colorectal Cancer (lactobacillus protective?)
Inflammatory Bowel Disease
Irritable Bowel Syndrome
Alcoholic Encephalopathy (lactobacillus protective?)
Fibromyalgia
Sepsis Syndrome
Journal of Leukocyte Biology 2008. 83: 461-466.
Pharmacogenetics
• Early well established examples
 TPMT
 Her-2
• Emerging Areas
 Warfarin
 CYP2C19 for Plavix (clopidogrel)
• Other areas
 Drug Interactions: omeprazole,
fluoxetine
RNA Interference
• Discovered in 1998 (Nobel Prize, 2006)
• Two types of small RNA molecules
 siRNA: double stranded RNA 21-23 bp
Transcription inhibition;
 miRNA: single stranded RNA, 20-25
bp
Translation inhibition
Targets mRNAs for destruction
• Highly conserved in evolution:
present from C. elegans to humans
RNA Interference
• Both might be used in therapeutics
 580 articles in last three years on
human RNAi therapeutics
• Current therapeutic targets under
investigation (#1)
 Infectious Diseases
Hepatitis C
HIV-1
RSV
 Oncology (cancer is a disease of DNA)
RNA Interference
• Therapeutic targets under
investigation (#2)
 Common Diseases
Type 2 diabetes
Hypercholesterolemia
Rheumatoid Arthritis
 Neurologic Diseases
Parkinson’s Disease
Amyotrophic lateral sclerosis
Huntington Disease
Genetics and Primary Care I
• Diagnosis
 Newborn Screening
State testing is expanding, now up to
48 disorders in Wisconsin
Includes genetic diseases with early
effect
—Sickle cell
—Cystic Fibrosis
 Genetic Diseases with later effects
Hemochromatosis or  -1 antitrypsin
BRCA and Lynch Syndrome
Genetics and Primary Care II
• Diagnosis in the future
 Microbiology
 Early diagnosis of organisms and
sensitivities?
 Pre-morbid risks
 Obesity
 Type 2 DM
 Macular degeneration
Genetics and Primary Care III
• Treatment: Pharmacogenetics
 Activation of Drugs
 Clopidogrel (CYP2C19)
 Tamoxifen (CYP2D6)
 Metabolism of drugs
 TPMT
 Warfarin
 Receptors for Drugs
 Warfarin
Genetics and Primary Care IV
Primary and Secondary Prevention
Nothing
Yet
A Research Agenda
• What we won’t do
 Discover new genes
 Link genes to diseases (GWAS)
 Link genes to treatment issues
 Make discoveries in proteomics
A Research Agenda
• What we can be involved with
 Practice studies of pharmacogenetics
Underway
 Warfarin
 Psych drugs
To come?
 Hypertension, Diabetes, and Asthma drugs
 Microbiology and microbiome issues
Shorten hospital stays based on early and
accurate microbiologic diagnosis?
Effects (short- and long-term) on and
recovery of microbiome after treatments
A Research Agenda
• Where we can LEAD!
 Provider education
Interpreting Direct to Consumer
(DTC) studies
Work with the DTC companies
proactively
Point-of-care resources for
community practitioners
Expanding list of genetic diseases and
influences
A Research Agenda
• Where we can LEAD!
 EHR’s and family history
Again, proactive contact with corporations
 Working with structured data
 Importing from other sources (Surgeon General)
 Computerized decision support
Are these measures more effective for patients
and providers?
 EHR’s and other issues
Pharmacogenetics
Loading and using genomes or DTC findings
A Research Agenda
• Where we can LEAD!
 Primary prevention
Obesity
Highly heritable
Human genome…and microbiome
—Combination of genes and environment: can
we control latter better in those at risk from
former?
— currently >18 suspect genes, RR 1.03-1.6
—Suggestive data that microbiome of gut may
contribute
» Animal models very good
» Human models early and suggestive
A Research Agenda
• Where we can LEAD!
 Primary prevention
Type 2 Diabetes mellitus
Most important gene is TCF7L2; first
associated 2006
—Allele frequency 22-29% (several close mutations
known) in general population
—Stunningly consistent results (different
populations)
—A few papers show interaction with obesity
measures
—Unknown interactions with other genes,
metabolic syndrome, age, gender, lab values
—Mechanism unknown
From BMC Medical Genetics 2009, 10:15
A Research Agenda
• Where we can LEAD!
 Primary prevention
Macular degeneration
—1.75 million in United States, risk as high as 30%
over age 75
—At least six genetic influences clearly identified
» allele frequencies as high as 0.3-0.4!
» common odds ratios 2 when heterozygous,
10-12 homozygous
» One associated with several other important
conditions (heart disease, Alzheimer’s)
» At least three inflammatory in character
» 4 different chromosomes
—Smoking a multiplicative risk (obesity? other
environmental issues?)
A Research Agenda
• Where we can LEAD!
 Primary prevention
Alcohol and Drug Abuse
 Risks for alcohol abuse, nicotine abuse, other
drug abuse, and “externalizing” psych conditions
all somewhat related in inheritance
 Heritability of alcohol abuse in 50-60% range; at
least 15 possible genes
 No GWAS as yet!
 Possible pharmacogenetics predicting response
to naltrexone
 Genetic harm? Less likely to quit if genetically
programmed?
BRCA, Lynch and other cancer syndromes
A Research Agenda
• Where we can LEAD!
 “Secondary” prevention
What do genetic predispositions MEAN?
 Using GWAS data in prospective trials
—TCF7L2: minimum of 1500 people needed; more if
looking at other variables as well
 Gene-Environment interactions
What patient education/other interventions make
a difference?
 BRCA and breast/ovarian cancer prevention
 TCF7L2
Does premorbid pharmacologic treatment
change outcomes?
 Is it cost-effective?
A Research Agenda
• Where we can LEAD!
 More secondary prevention
As a consequence of any of the above, can we
avoid secondary co-morbidities (diabetes on
hypertension?)
Does use of pharmacogenomics in practice
reduce adverse drug reactions and decrease
costs?
A Call to Action?
• Genetics is well suited to primary
care
• There are studies that can be best
done in large systems that some of
us work in
• We are the experts in what will
work in “real” practices
• There are many untouched places
that we can lead…