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: 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 Associations439 published GWA at p < 5 x 10-8

NHGRI GWA Catalogwww.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

of our commensal (mutualistic?) organisms and how they change in

Health Disease, and with medical treatments

Microbiome

• Estimates 1000 species 1013 organisms 1.5 kg of bacteria

• Significant variation across people: may only be about a 1% match across people

}in GI tract alone

Microbiome

• Current areas of suspected involvement— 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 inhibitionTargets 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 CHIV-1RSV

Oncology (cancer is a disease of DNA)

RNA Interference

• Therapeutic targets under investigation (#2) Common Diseases

Type 2 diabetesHypercholesterolemiaRheumatoid Arthritis

Neurologic DiseasesParkinson’s DiseaseAmyotrophic lateral sclerosisHuntington 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 effectsHemochromatosis or α-1 antitrypsinBRCA 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

UnderwayWarfarinPsych drugs

To come?Hypertension, Diabetes, and Asthma drugs

Microbiology and microbiome issuesShorten 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 corporationsWorking 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 issuesPharmacogeneticsLoading and using genomes or DTC findings

A Research Agenda

A Research Agenda

• Where we can LEAD! Primary prevention

Type 2 Diabetes mellitusMost 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

A Research Agenda

• Where we can LEAD! Primary prevention

Alcohol and Drug AbuseRisks 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

naltrexoneGenetic 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 interactionsWhat patient education/other interventions make a

difference?BRCA and breast/ovarian cancer preventionTCF7L2

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…