Genomic Medicine – Promises and Problems

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					 Genomic Medicine –
Promises and Problems
  Timothy J. O’Leary
 Medical practice based on a
 knowledge of gene sequence and
 “Personalized medicine”

                        Association for Molecular Pathology
            Public Interest
 Human Genome
 Research Institute
 Genetic
 VA Genomic
 Medicine Program
 Others

                       Association for Molecular Pathology
          Technical Capability
 Most clinical laboratory tests assess one to a
 few dozen genetic questions simultaneously
 at a cost of $10-100/assay
 Research laboratory capability is on the order
 of one million assays performed
 simultaneously, at a cost of a few hundred
 dollars ~ $0.0005/assay
 The cost per assay (research) is dropping by
 50% every six - 12 months
 Clinical laboratory technology significantly
 lags research laboratory technology
                               Association for Molecular Pathology
 Dozens – perhaps hundreds – of
 papers relating gene sequence and
 expression to disease etiology,
 prognosis and treatment are published
 Why are we talking about genomic
 medicine in the future tense? Why isn’t
 it here now?

                         Association for Molecular Pathology
       Linking Test to Treatment
 Thrombophilia Genes

     Factor V Leiden
     Prothrombin G20210A
     Methylene Tetrahydrofolate Reductase C677T
     Antithrombin
     Protein C
     Protein S

 Warfarin

     VKORC1
     CYP2C9
     CYP4F2
                                  Association for Molecular Pathology
           Clinical Presentation of
 Venous thromboembolism (VT) most common

   1 in 20 adults will develop a VT event at some time in their
   VT causes nearly 100,000 deaths annually
   Risk of VT increased by environmental or therapeutic factors:
         Oral contraceptives
         Estrogen replacement therapy
         Tamoxifen
         Serious liver disease
         Immobilization (e.g. after surgery)

   Well over 50% of “thrombophilia” patients demonstrate a
    genetic alteration that predisposes to VT

                                                Association for Molecular Pathology
             Factor V Leiden

 Substitution mutation (Arg506Gln) at one of
  the three APC cleavage sites in the factor Va
 Substantially reduces anticoagulant response
  to activated protein C (APC), because Factor V
  Leiden is inactivated ~10X slower than normal
  factor V
 Leads to increased Factor V levels, increased
  thrombin generation and hypercoagulability

                              Association for Molecular Pathology
       Factor V Leiden (cont.)
 Factor V Leiden heterozygotes: 5-10 fold
  increased risk of VT
 Factor V Leiden homozygotes: 50 to100
  fold risk increase.
 Mutation detection techniques:
   RFLP
   Invader assay
   Allele-specific amplification
   Real-time PCR with melting point analysis or
    probe quenching
   Sequencing
                               Association for Molecular Pathology
   Factor V Testing: Consensus
   Recommendations for Testing

 VT under age 50
 VT in unusual sites such as hepatic,
  mesenteric, and cerebral veins)
 Recurrent VT
 Strong family history of thrombotic disease
 VT in pregnant women or women taking oral
 Myocardial infarction in female smoker under
  age 50

                               Association for Molecular Pathology
    Consider Factor V Leiden Testing

 VT, age >50, except when malignancy is present
 Relatives have factor V Leiden mutation
    May influence management of pregnancy and oral
     contraceptive use.
 Women with:
   Recurrent pregnancy loss                  Mutation
   Unexplained severe preeclampsia           identification may
   Placental abruption                       management of
   Intrauterine fetal growth retardation     future pregnancies

                                   Association for Molecular Pathology
    Screening for Factor V Leiden
 Random screening not recommended
 Routine testing is also not recommended for:
    Patients with a family history of arterial thrombotic
     disorders except for MI in young female smokers
    Prenatal testing
    Routine newborn screening
 Testing may be worthwhile for patients <50 with
  arterial thrombosis and absence of other risk factors
  for arterial thrombosis

                                    Association for Molecular Pathology
How Testing Influences Treatment
 Clinician feels good – s/he now has a “reason” that the patient
    developed VT
   Patient knows that s/he is at increased risk for future VT (just as
    s/he does without the test)
   Relatives know that they may be at increased risk for VT
   All these folks will know just what to do when we have a
    reasonable strategy to reduce the risk of recurrent VT based on
    this test
   Lab has steady source of revenue based on a common and
    straightforward test
   Regulators and public policy folks can be paid for debating the
    usefulness of regulating the test
   Genetic counselors are less certain of whether they will be paid
    for advising patients regarding the meaning of their test results

                                             Association for Molecular Pathology

• Oral anticoagulant
• Inhibitor of the vitamin K cycle
• In 2003, 21.2 million prescriptions written
• Prescribed following MI, atrial fibrillation, stroke,
   venous thrombosis, prosthetic heart valve
   replacement, and following major surgery
• Difficult to determine effective dosage
   - Narrow therapeutic range
   - Large inter-individual variation
    Warfarin Complications

 Major bleeding episodes in 1-2% of
 all patients
 Death in as many as 0.1-0.7%
 However, prevents 20 strokes for
 each bleed

                       Association for Molecular Pathology
         Monitoring Warfarin

 Prothrombin time or INR (normal values)
    PT: 10-13 seconds.
    INR: 1.0-1.4
 Target value on warfarin is typically:
    PT: 20-40 seconds
    INR: 2.0-3.0

                           Association for Molecular Pathology
              Warfarin Metabolism
 Warfarin is metabolized in the liver by CYP2C9
 CYP2C9 SNPs effects:
   CYP2C9*1 (WT) - normal
     CYP2C9*2 (Arg144Cys) - low/intermediate
     CYP2C9*3 (Ile359Leu) - low

 CYP2C9 allele frequencies
                                     2*     3*
              European             10-11% 8-9%
                 Asian              0%    1-2%
      African-American              3%    1%

                                       Association for Molecular Pathology
                      Interactive Effect of CYP2C9 (*1, 2, 3) and
                     VKORC1(1639G>A) on Warfarin Metabolism

Daily maintenance Dose (mg)


                              4                                                           A/A     19%
                                                                                          G/A     56%
                                                                                          G/G     25%


                                  *1*1   *1*2   *2*2       *1*3       *2*3/*3*3

                                                       Adapted from Sconce et al, Blood, October 2005
                                                                  Association for Molecular Pathology
              Factors to Consider for
                 Warfarin Dosing
     Cytochrome P450
           CYP2C9*3                    -38%/allele
           CYP2C9*2                    -17% per allele
     Vitamin K epoxide reductase (VKORC1)
           - 11% per copy of haplotype A
     INR value after 3 doses
           -47% reduction per 0.25 unit rise
           +7% per 1 mg for first Warfarin dose
     Smoking status
           +20% for current smokers
     These factors explain four-fifths of the variability
         in therapeutic dose (R of 79%).

E Millican et al, e. Blood First Edition Paper, prepublished online March 26, 2007

                                                       Association for Molecular Pathology
   Ethnicity/Dose Relationship

 European           ~ 5.0 mg/day
 African-American   ~ 6.0-7.0 mg/day
 Asian              ~ 3.0-3.5 mg/day

                     Association for Molecular Pathology
      When Does Bleeding Occur
    During Anticoagulation Therapy?
 1989 record review of 562 patients starting outpatient therapy upon
    discharge from a university hospital were reviewed
   The cumulative incidence of bleeding was estimated by means of survival
   Major bleeding occurred in 65 patients (12%) and was fatal in 10 patients
   The cumulative incidences of major bleeding

        One month:           3%,
        One year: 11%
        Four years:          22%,

 The monthly risk of major bleeding decreased over time, from 3% during
    the first month of outpatient therapy to 0.3% per month after the first year
    of therapy.

                Landefeld and Goldman Am J Med. 1989 Aug;87(2):144-52.

                                                   Association for Molecular Pathology
 Testing for Factor V Leiden and Prothrombin
  G20210A indicated in a variety of
 Testing for CYP2C9 and VKORC1 account for
  some dose variation, but algorithms for using
  this information are not yet tested and
  accepted. Based on timing considerations,
  this could reduce major bleeding by about
  15%, but it could be cheaper than repeated
  INR determinations
 FDA Labeling for Warfarin now includes
  genetic information

                             Association for Molecular Pathology
     Some Challenges for Health
        Services Research
 Meaning of a test result in the face of interlaboratory
 When we know that a test is worth doing, how to we
  get it to happen throughout the health system?
 How do we deal with information overload?
 Do we change practice when the price point
  changes? If we drop the cost of HFE testing to a
  penny a snip, for example, does one consider DNA-
  based screening and to identify individuals for follow-
  up biochemical testing?
 How do we deal with the complex issues surrounding
  informed consent and family?

                                    Association for Molecular Pathology
    VA is Uniquely Positioned
 5.5 million patients annually
 153 hospitals
 718 outpatient clinics
 135 nursing homes
 46 rehabilitation treatment programs
 207 readjustment counseling centers

                        Association for Molecular Pathology
                Electronic Medical Record
           • Includes virtually all clinical information
           • Provides broad research value in genomic medicine

Information Characteristic     Added per Workday          Added in 2006

 Progress Notes,                      +638k                         874 M
 Orders                               +955k                        1.65 B
 Images                               +884k                         590 M
 Vital Signs                          +729k                        1.06 B
 Inpt Meds Administered               +607k                         850 M
                                                Statistics through December 2006

                                           Association for Molecular Pathology
  Health Services Genomic Medicine:
           Research Needed
 Outcomes
   Develop evidence regarding health outcomes
   Integrate successful models of genomic
    medicine delivery into clinical practice
 Workforce
   Prepare health care providers to deliver
    genomics care
 Consumers / Patients
   Create educational programs for patients
                                Association for Molecular Pathology
     VA HSR&D Genomics Research
          Program Priorities
Establish how genetic information will be used in VA
clinical care:
    Measure impacts:
         outcomes (organizational, provider, & patient)
         costs
    Understand VA organizational, provider, & patient
     needs; barriers & challenges for effective delivery of
     evidence based genomic care
    Develop & test VA healthcare delivery models

                                      Association for Molecular Pathology
     VA HSR&D Genomics Research

Collect and link genetic information with VA EHR to:
    Discover genetic predispositions, causes &
     mechanisms of disease
    Enhance development of tests for relevant diseases
    Better define treatments to optimize veteran health care
Improve research capabilities of EHR
    Medical Informatics Consortium - CSC
    Explore new research methodology to mine health
     record data

                                    Association for Molecular Pathology
             Initial Steps
 Conversations with Veterans Service
 Organizations, Focus Groups,
 Veteran Survey.
 Genomic Medicine Program Advisory
 Genomic epidemiology studies on
 ALS and Serious Mental Illness

                        Association for Molecular Pathology
 Power corrupts.
 PowerPoint corrupts absolutely.
                   Vincent Cerf

“Science is fascinating. One gets such
 wholesale returns of speculation
 from such trifling investment of fact.”
                   Mark Twain
                        Association for Molecular Pathology

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