?????????? Warfarin Pharmacogenomics

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• ????????
• ?????????? Warfarin Pharmacogenomics

????? ???????? ????????????
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• Anti-coagulants
• Wafarin
• Heparin
• LMWH
• Fondaparinux
• Bivalirudin
• Rivaroxaban

• Antithrombin III
• Protein C
• Protein S
• Tissue factor pathway inhibitor

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???????????????K????

• ????????????????
• ??????????????????????r-carboxylation??????K?

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???K
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• ???????? 1.??? 2.???
• ??????????????,?????????????
• ?????????????????(INR),??????????????

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???(PD)??????(PK)
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?????(PK)

• Drug metabolizing enzymes (DME)
• Prodrugs gt active drugs (Codeine/Morphine)
• Active drugs gt inactive compounds (warfarin)
• Drug transporters
• Influence intracellular drug concentrations much
  less well-studied

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• Phase I
• Oxidation, reduction, hydrolysis
• Phase II
• Attach other chemical entities acetylation,
  glucuronidation, sulfation, methylation

Pharmacogenomics Translating Functional Genomics
into Rational Therapeutics. Evans and Relling
Science 1999
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??????29???
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VKOR?? CYP2C9??

• Vitamin K epoxide reductase complex , subunit 1
  (VKOR)
• Cytochrome P450, family 2, subfamily C,
  polypeptide 9 (CYP2C9)

II,VII,IX,X
II,VII,IX,X
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• Sickle cell anemia
• CAG ? CTG (Glu ? Val)
• Polymorphism allele gt 1

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CYP2C9 VKOR????
II,VII,IX,X
II,VII,IX,X

• VKOR???? -1639 G?-1639A
• CYP2C9???? CYP2C91(wild ), CYP2C92, CYP2C93

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Ethnicity Warfarin dose References
Asian Asian Asian
Chinese 3.3 (mg/day) Q. J. Med. 89,127-135
Japanese 3.3 (mg/day) Clin. Pharmacol. Ther. 63, 519-528
Caucasian Caucasian Caucasian
American 5.1 (mg/day) JAMA, 287, 1690-1698.
Italian 5.5 (mg/day) Blood, 105, 645-649.
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Genetics points the gun but enviroment pulls the
trigger!
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VKORC1 CYP2C9???????
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VKORC1 CYP2C9????????
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VKORC1?????????
aP value of comparison between AA and AGGG
groups. P-valuelt0.0001 using T test. Data
represent mean SD.
VKORC1???-1639????G?A????? -1639AA???????????????
?-1639AG?-1639GG?????????
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VKORC1????? G,A??
E-box consensus CANNTG Hypothesis -1639AgtG
abolish the Ebox CAGGTG (E-box) CGGGTG
(E-box abolished)
VKORC1-1639 A has less VKORC1 promoter activity
and less VKORC1
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Clin Pharmacol Ther 2008 Jul84(1)83-9.
????????????????? ????????????
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?????
108??
VKORC1?CYP2C9????
VKORC1 -1639 GgtA GG GG GG AG AG AG AA AA AA
CYP2C9 1/1 1/3 3/3 1/1 1/3 3/3 1/1 1/3 3/3
Starting Dose (mg) 5 3.75 3.75 3.75 2.5 2.5 2.5 1.25 1.25
1?
PT INR (2-3)??????
1?
PT INR (2-3)??????
1?
2?
PT INR (2-3)??????
1?
4??8??12??6???
Clin Pharmacol Ther 2008 Jul84(1)83-9.
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?12???????????
VKORC1 -1639 GgtA CYP2C9 Starting Dose (mg/d) Frequency n () Dose Match n ()
GG 1/1 5 3 (2.8) 2(66.7)
GG 1/3 3.75 0 0
GG 3/3 3.75 0 0
AG 1/1 3.75 17 (15.7) 12(70.5)
AG 1/3 2.5 1 (0.9) 1(100)
AG 3/3 2.5 0 0
AA 1/1 2.5 83 (76.9) 58(69.9)
AA 1/3 1.25 4 (3.7) 2(50)
AA 3/3 1.25 0 0
Total n() 108(100) 74(68.5)
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?12???????????
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• 83?????????2?????????????INR??????4????90?
• ???12?,????????2.76?0.88 mg (16 mg)? ?74/108
  (69)?????????
• ???????(1 mg)????(5 mg)??????

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?????????????????
NEJM 2009360753-64
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Dose algorithm
Dose - 0.432 0.769 x predict dose - 0.015 x
Age 1.125 x BSA
These factors in this model accounted for 48.
R2 0.482
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Warfarin Sensitivity Test

• CYP2C9 Polymorphisms produce defective CYP2C9
  protein that reduce metabolism of warfarin, thus
  more sensitive to warfarin
• VKORC1 (vitamin K epoxide reductase complex
  subunit 1) warfarin inhibits VKORC1, and
  haplotypes associated with change in activity and
  warfarin dose

Verigene (Nanosphere Inc.)
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FDA Clears Genetic Lab Test for Warfarin
Sensitivity

• The U.S. Food and Drug Administration today
  cleared for marketing a new genetic test that
  will help physicians assess whether a patient may
  be especially sensitive to the blood-thinning
  drug warfarin (Coumadin), which is used to
  prevent potentially fatal clots in blood vessels.
• One-third of patients receiving warfarin
  metabolize it quite differently than expected and
  experience a higher risk of bleeding. Research
  has shown that some of the unexpected response to
  warfarin depends on variants of two genes, CYP2C9
  and VKORC1. The Nanosphere Verigene Warfarin
  Metabolism Nucleic Acid Test detects some
  variants of both genes.
• "Todays action offers physicians the first FDA
  cleared genetic test for warfarin sensitivity,
  which is another step in our commitment to
  personalized medicine, said Daniel Schultz,
  M.D., director, FDAs Center for Devices and
  Radiological Health. With this test, physicians
  may be able to use genetic information along with
  other clinical information to treat their
  patients.
• Warfarin is the second most common drug, after
  insulin, implicated in emergency room visits for
  adverse drug events.

FOR IMMEDIATE RELEASESeptember 17, 2007
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If it were not for the great variability
among Individuals, medicine might as well be a
science and not an art. - Sir William Osler,
1892
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• ??????????????,????????INR,????????????
• ?????????????VKORC1?CYP2C9???????
• VKORC1-1639 G?A????,??VKORC1???????-1639AA????????
  ????????-1639AG?-1639GG????????
• CYP2C9????CYP2C91?CYP2C92?CYP2C93???CYP2C91???
  ?????????CYP2C92?CYP2C93??????????????
• ????????,??????????,????????????,?????????????????
  ?,????????????????????

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Thank You for your Attention!