Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications - PowerPoint PPT Presentation

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Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications

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Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications Mark Bleackley MEDG 505 – PowerPoint PPT presentation

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Title: Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications


1
Association of polymorphisms in the cytochrome
P450 CYP2C9 with warfarin dose requirement and
risk of bleeding complications
  • Mark Bleackley
  • MEDG 505
  • March 10 2005

2
Overview of paper
  • Study of randomly selected patients from
    anticoagulant clinic in north-east England
  • Found that individuals with low warfarin dose
    requirement had higher odds of having one or more
    CYP2C9 variant alleles compared to a normal
    population
  • Patients in low dose group have increased risk of
    major bleeding complications

3
What is warfarin?
  • Drug used to prevent the formation of blood clots
    or to prevent blood clots from becoming larger
  • Often prescribed to patients with irregular heart
    beats and after heart attacks or heart valve
    replacement surgery
  • Acts as a vitamin K antagonist

4
How does warfarin work
  • Interacts with KO reductase enzyme to prevent
    reduction of oxidized vitamin K
  • Reduced vitamin K is required for carboxylation
    of Glu residues to Gla residues in a number of
    blood coagulation proteases and other proteins
  • Gla residues give the proteins Ca2 binding
    properties that are essential for activity

5
Blood coagulation
6
CYP2C9
  • Responsible for metabolism of warfarin
  • Two know allelic variants, CYP2C92 and CYP2C93,
    differ from wild type by one amino acid each
  • Associated with impaired hydroxylation of
    warfarin in inactivation due to an alteration of
    the interaction with cytochrome p450
    oxidoreductase
  • CYP2C92 12 efficiency, CYP2C93lt5 efficiency
    of wildtype

7
Why is this important?
  • Standardized induction regimens with monitoring
    of International Normalized Ratio (INR) over the
    first four days only 69 successful in predicting
    correct dosage
  • Understanding genetics of warfarin dose response
    will minimize clinical difficulties associated
    with warfarin therapy

8
Methods
  • 36 patients with low warfarin dose requirement
    selected (17 male, 19 female) aged 55-88 (median
    73)
  • No apparent cause for low dose requirement (eg
    drug interaction, disease)
  • 52 patients with wide range of warfarin dose
    requirement (26 male, 26 female) aged 33-94
    (median 70.5)
  • Control 100 individuals (58 male, 42 female) aged
    38-91 (median 69) not on warfarin

9
Genotyping
  • Take blood from each patient, extract DNA
    analyzed by PCR
  • CYP2C92 detected by AvaII digestion
  • CYP2C93 detected by NsiI digestion

10
Bleeding Complications
  • Review history of low dose group
  • Determine difficulties during induction of
    anticoagulation
  • Categorized bleeding complications associated
    with a raised INR (gt4) as mild serious or life
    threatening

11
Results
  • Found that 81 of low dose group had one or more
    of the variant alleles, 40 in the control group
    (wide range of doses)
  • 6.21 (CI 2.48-15.6) odds ratio
  • When compared with general population odds ratio
    of only one variant allele 2.68 (CI1.22-5.86)
    with two variant alleles 7.8 (CI1.90-32.1)

12
What does this mean?
  • There is a strong association between CYP2C9
    genotype and warfarin sensitivity
  • Individuals with low warfarin doses are six times
    as likely to possess one of the variant alleles

13
Genotype and allele frequencies
  • Test whether CYP2C9 variant genotypes were
    associated with increased risk of requiring
    anticoagulant therapy
  • Found no significant difference between clinic
    control and general control

14
Response to treatment
  • All patients received an initial dose of 10mg
    warfarin
  • Peak INR during the first week in the low dose
    group ranged from 2.0 to 10.0
  • 20 of the 36 had a peak INR above the therapeutic
    range of greater than 4.0
  • Two of these were homozygous wild type
  • 9 of the 20 cases resulted in a prolonged
    inpatient stay while optimum anticoagulation was
    achieved, none of the clinic control group had
    prolonged stays due to poor anticoagulation

15
Bleeding episodes
  • During 132.8 patient years of warfarin treatment
    7 minor, 5 serious and 6 life threatening bleed
    episodes occurred in 11 patients in the low dose
    group
  • In the clinic control, 311.1 patient years had 6
    minor, 5 serious and 2 life threatening episodes
    in 11 patients
  • Significantly higher number of serious and life
    threatening episodes in low dose group

16
Risks associated with CYP2C9 variants
  • Significant proportion of individuals with
    variant alleles have difficulty at the onset of
    treatment and are more likely to have a serious
    or life threatening bleeding event while on
    warfarin

17
What can we take from this paper?
  • Variant alleles that have no apparent phenotype
    with regards to disease or susceptibility to
    disease can have a significant influence on
    response to specific treatments
  • Can use genotypic information to design better
    methods of treatment for individuals as well as
    more effective methods that are less of a burden
    on the medical system

18
Questions
  • Can this type of information be used to develop
    drugs that are specific to variant alleles?
  • How quickly does the complexity of personalized
    medicine escalate as more of these situations are
    realized?
  • Social aspect Will the public allow themselves
    to be genotyped?
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