recent genetic advances in cardiovascular disease linnea m. baudhuin, ph.d. mayo clinic dec. 6, 2008
TRANSCRIPT
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Recent Genetic Advances Recent Genetic Advances in Cardiovascular Diseasein Cardiovascular Disease
Linnea M. Baudhuin, Ph.D.Linnea M. Baudhuin, Ph.D.
Mayo ClinicMayo Clinic
Dec. 6, 2008Dec. 6, 2008
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DISCLOSUREDISCLOSUREInformationInformation
Relevant Financial RelationshipsNone
Off Label UsageNone
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Mendelian genetics Autosomal Dominant Hypercholesterolemia
LDLR, APOB, PCSK9
Familial Thoracic Aortic Aneurysm and Dissection syndromes:
FBN1, TGFBR1, TGFBR2, ACTA2, MYH11, NOTCH
Genetic markers for CAD Chromosome 9p21/ANRIL KIF6
Pharmacogenetics Warfarin sensitivity Statin efficacy
Recent Developments in CV Recent Developments in CV GeneticsGenetics
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Unable to predict significant portion of CAD 35% of CAD occurs in population with TC<200 mg/dL
“CAD could be eliminated in 21st century by treating all risk factors” R. Roberts, Genetics of Premature Myocardial
Infarction, Curr Ather Reports, 2008, 10: 186-193
Atherosclerotic CVD has strong heritable component
Estimates as high as >50%
Families with early CAD (14% of population) account for 72% of early CAD cases
Most of the risk factors have predominant genetic component Need for identifying genetic modifiers and their
function
Coronary Artery DiseaseCoronary Artery Disease
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Complex Genetics of CADComplex Genetics of CAD
Minority are single-gene disorders FH, FDB, ARH, Tangier,
Sitosterolemia, etc. What about the majority of CAD? What’s going on genetically?
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Early stages of Early stages of atherosclerosisatherosclerosis
Late stages of Late stages of atherosclerosisatherosclerosis
Lusis et al., Ann Rev Gen Hum Gen, 2004, 5:189-218
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Lusis A, Trends Cardio
Med, 2003; 13:309-16.
Genes Genes contributincontributin
g to CAD g to CAD susceptibilisusceptibili
tyty
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How can we identify genetic How can we identify genetic markers for complex disease?markers for complex disease?
Family studies Genetic variants that segregate with disease in affected
vs. non-affected family members Linkage analysis
Population studies Genetic variants that segregate with disease in cases
vs. controls Candidate genes Localized genomic regions Genome-wide
Association studies
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CAD Linkage StudiesCAD Linkage Studies At least 7 family studiesAt least 7 family studies
Occurrence of MI or subclinical Occurrence of MI or subclinical atherosclerosisatherosclerosis
Linkage: Chr 1, 2, 3, 13, 14, 15, 16, XLinkage: Chr 1, 2, 3, 13, 14, 15, 16, X Lack of replicationLack of replication
Genes identified:Genes identified: MEF2A (Chr 15q26)MEF2A (Chr 15q26) ALOX5APALOX5AP LTA4LTA4
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Generally single gene/single polymorphismGenerally single gene/single polymorphism
Small cohortsSmall cohorts
Inability to replicate findings in additional Inability to replicate findings in additional studiesstudies
Genetic analysis of 103 candidate genes Genetic analysis of 103 candidate genes (n=1400, with follow-up n= 806) unable to (n=1400, with follow-up n= 806) unable to replicate findings (Pare et al, Am Hum Genet, replicate findings (Pare et al, Am Hum Genet, 2007, 80:673-682) 2007, 80:673-682)
Similar results in n=811 ACS patients, 70 genes Similar results in n=811 ACS patients, 70 genes (Morgan et al, JAMA, 2007, 297: 1551-1561(Morgan et al, JAMA, 2007, 297: 1551-1561
Candidate Gene Association Candidate Gene Association Analyses in CADAnalyses in CAD
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Inadequately poweredInadequately powered
Phenotypic heterogeneity and imprecise definition of phenotypesPhenotypic heterogeneity and imprecise definition of phenotypes
Bias (e.g. population stratification)Bias (e.g. population stratification)
Multiple genes each contribute to small percentage of phenotype Multiple genes each contribute to small percentage of phenotype (<5-10%)(<5-10%) A single gene is insufficient to induce diseaseA single gene is insufficient to induce disease
Information from multiple polymorphisms should be integrated to Information from multiple polymorphisms should be integrated to become clinically usefulbecome clinically useful Multiple possible combinations of genotypesMultiple possible combinations of genotypes
Population and disease heterogeneityPopulation and disease heterogeneity
Why are the results of Linkage and Why are the results of Linkage and Candidate Gene studies so Candidate Gene studies so
disappointing?disappointing?
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What about What about Genome Wide Genome Wide Association Association
Studies?Studies?
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Genome-wide association Genome-wide association studiesstudies
Previously: single SNP/single cohort Previously: single SNP/single cohort associations with little replicationassociations with little replication
Now: large international consortium Now: large international consortium studies of tens of thousands of studies of tens of thousands of individuals and hundreds of thousands individuals and hundreds of thousands of SNPsof SNPs
TechnologyTechnology Ultra high-throughput genotyping with Ultra high-throughput genotyping with
ability to analyze 500K to >1M SNPs in ability to analyze 500K to >1M SNPs in each individualeach individual
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Topol, EJ et al., JAMA, 2007; 298:218-221
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Multiple GWASs confirming Multiple GWASs confirming 9p21 in Caucasian populations9p21 in Caucasian populations
McPherson et al, Science (316), June 8 2007, 1488-91McPherson et al, Science (316), June 8 2007, 1488-91 Initial study, 322 cases vs 312 controls; 73K SNPsInitial study, 322 cases vs 312 controls; 73K SNPs
Confirmed in 5 independent Caucasian populations Confirmed in 5 independent Caucasian populations (n=23,000)(n=23,000)
Helgadottir et al, Science (316), June 8 2007, 1491-3Helgadottir et al, Science (316), June 8 2007, 1491-3 Initial study, 1607 cases vs 6728 controls; 306K SNPsInitial study, 1607 cases vs 6728 controls; 306K SNPs
Replicated in Replicated in 665 cases and 3533 controls665 cases and 3533 controls
Three other case control populations Three other case control populations Philadelphia, Atlanta, & Durham, NCPhiladelphia, Atlanta, & Durham, NC
4587 cases, 12,767 controls4587 cases, 12,767 controls
Wellcome Trust Case Consortium, Nature, 447:661-Wellcome Trust Case Consortium, Nature, 447:661-678, 2007678, 2007
Samani et al, NEJM (357), Aug 2 2007, 443-53Samani et al, NEJM (357), Aug 2 2007, 443-53
PROCARDIS Consortium (Broadbent et al, Hum Mol PROCARDIS Consortium (Broadbent et al, Hum Mol Gen, 2008, 17)Gen, 2008, 17)
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Chromosome 9p21Chromosome 9p21 9p21 confined to 58K bp region9p21 confined to 58K bp region
Risk associated with MI and CAD independent of Risk associated with MI and CAD independent of known risk factorsknown risk factors
50% of individuals heterozygous for allele50% of individuals heterozygous for allele 15-20% increased risk of CAD15-20% increased risk of CAD
25% of individuals homozygous for allele25% of individuals homozygous for allele 30-40% increased risk of CAD30-40% increased risk of CAD
Odds ratio Odds ratio Heterozygous: 1.3-1.5Heterozygous: 1.3-1.5
Homozygous: 1.8-2.1Homozygous: 1.8-2.1
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9p21 and ANRIL9p21 and ANRIL High-risk CAD 9p21 haplotype overlaps with exons High-risk CAD 9p21 haplotype overlaps with exons
13-19 of ANRIL13-19 of ANRIL
Newly annotated gene, encodes large antisense non-Newly annotated gene, encodes large antisense non-coding RNA (ncRNA)coding RNA (ncRNA)
Identified through deletion analysis of French family Identified through deletion analysis of French family with hereditary melanoma-neural system tumorswith hereditary melanoma-neural system tumors
Expressed in atheromatous human vesselsExpressed in atheromatous human vessels Comparable cell type profiles to atherosclerotic arteriesComparable cell type profiles to atherosclerotic arteries
Expressed in vascular endothelial cells, monocyte-Expressed in vascular endothelial cells, monocyte-derived macrophages, and coronary smooth muscle derived macrophages, and coronary smooth muscle cellscells
Very little known about functionVery little known about function
Gene class is thought to be involved in transcriptional Gene class is thought to be involved in transcriptional controlcontrol Broadbent, et al, Human Mol Gen, 2008, 17: 806-14
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KIF6KIF6 Variant and CAD Variant and CAD
CARECARE: Cholesterol and Recurrent Events : Cholesterol and Recurrent Events
WOSCOPSWOSCOPS: West of Scotland Coronary Prevention Study: West of Scotland Coronary Prevention Study
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Association of Association of KIF6KIF6 with with CADCAD
2 Prospective Trials of 2 Prospective Trials of PravastatinPravastatin
CARE: Cholesterol and Recurrent EventsCARE: Cholesterol and Recurrent Events Secondary prevention in patients with a prior MI Secondary prevention in patients with a prior MI 40 mg pravastatin vs placebo40 mg pravastatin vs placebo 87% men and 13% women87% men and 13% women LDL-C 115 to 174 mg/dL at baselineLDL-C 115 to 174 mg/dL at baseline 2,697 participants studied2,697 participants studied
WOSCOPS: West of Scotland Coronary Prevention StudyWOSCOPS: West of Scotland Coronary Prevention Study Primary preventionPrimary prevention 40 mg pravastatin vs placebo40 mg pravastatin vs placebo Men aged 45 to 64Men aged 45 to 64 LDL-C 174 to 232 mg/dL at baselineLDL-C 174 to 232 mg/dL at baseline 1,527 participants studied1,527 participants studied
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Risk of CAD in CARE Placebo Risk of CAD in CARE Placebo ArmArm
KIF6 Variant and Traditional Risk KIF6 Variant and Traditional Risk FactorsFactors
KIF6 Variant
Age ≥ 55
Smoking
LDL-C ≥130
HDL-C < 40
Hypertension
Diabetes
Magnitude of risk predicted by KIF6 variant was: Similar to that of traditional risk factors
Independent of traditional risk factors
Adjusted Hazard Ratio0.5 21 1.5 2.5 3
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Risk of CAD in WOSCOPS Placebo Risk of CAD in WOSCOPS Placebo ArmArm
KIF6 Variant and Traditional Risk FactorsKIF6 Variant and Traditional Risk Factors
KIF6 Variant
LDL-C ≥ 189*
HDL-C < 40
Hypertension
Diabetes
Magnitude of risk predicted by KIF6 variant was: Similar to that of traditional risk factors
Independent of traditional risk factors
Adjusted Risk Ratio
Case and control patients were matched for age and smoking; all were men
* Median level in placebo arm
0.5 21 1.5 2.5 3
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KIF6KIF6 variant predicts risk of CAD variant predicts risk of CAD Up to 55% increased risk in untreated populationsUp to 55% increased risk in untreated populations
Hazard Ratio*
*Adjusted for traditional risk factors
Untreated patients
Some treatment
KIF6KIF6 Variant is Associated Variant is Associated with CAD with CAD
5 Prospective Studies5 Prospective Studies
ARIC
WHS
CHS
WOSCOPS
CARE
0.5 21 1.5 2.5
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Mendelian genetics Autosomal Dominant Hypercholesterolemia
LDLR, APOB, PCSK9
Familial Thoracic Aortic Aneurysm and Dissection syndromes:
FBN1, TGFBR1, TGFBR2, ACTA2, MYH11, NOTCH
Genetic markers for CAD Chromosome 9p21/ANRIL KIF6
Pharmacogenetics Warfarin sensitivity Statin efficacy
Recent Developments in CV Recent Developments in CV GeneticsGenetics
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PROVE IT - TIMI 22 studyPROVE IT - TIMI 22 study Pravastatin or Atorvastatin Evaluation and Infection Pravastatin or Atorvastatin Evaluation and Infection
Therapy, Thrombolysis in MI Therapy, Thrombolysis in MI
Patients hospitalized within 10 days after an acute Patients hospitalized within 10 days after an acute coronary syndromecoronary syndrome
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0
2
4
6
8
10
12
14
Prevention of CHD Events by Prevention of CHD Events by Statins Statins
Carriers of the KIF6 Variant Benefit the Carriers of the KIF6 Variant Benefit the MostMost
KIF6KIF6 carriers received significant risk reduction from atorvastatin in carriers received significant risk reduction from atorvastatin in PROVE IT, suggesting PROVE IT, suggesting KIF6 may alsoKIF6 may also predict response with other predict response with other statinsstatins
KIF6KIF6 carriers also received significantly greater benefit than carriers also received significantly greater benefit than noncarriers (p=0.003 for WOSCOPS and 0.018 for PROVE IT)noncarriers (p=0.003 for WOSCOPS and 0.018 for PROVE IT)
3.5% 10.0%6.2%0.1% 0.8%5.5%
WOSCOPS PROVE ITPravastatin 40 mg
All CarriersNon-
carriers
Atorvastatin 80 mg
All CarriersNon-
carriers
Absolute Risk Reduction
(%)
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Dea
th o
r m
ajo
r C
V e
ven
tsStatin Intensity and CHD Event ReductionAccording to KIF6 719Arg Carrier Status
KIF6 carriers received greater benefit from 80 mg atorvastatin, compared with 40 mg pravastatin, than did noncarriers
Number Needed to Treat with atorvastatin for 2 years to prevent 1 event was 10 for KIF6 carriers and 125 for noncarriers
KIF6 Carriers Noncarriers
Months of follow-up Months of follow-up0 3 6 9 12 15 18 21 24 27 30
0
10
20
30
40
0 3 6 9 12 15 18 21 24 27 300
10
20
30
40
p≤0.001P=1.0
Pravastatin
Atorvastatin
Pravastatin
Atorvastatin
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KIF6KIF6 Summary SummaryRisk for CAD and Risk Reduction from Risk for CAD and Risk Reduction from
StatinsStatins
KIF6 carriers, ~60% of the population, have greater risk for CAD Up to 55% increased risk of CAD
Independent of traditional risk factors, but similar in magnitude of risk
Associated with CAD risk in men (WOSCOPS), women (WHS), the middle aged (ARIC) and the elderly (CHS)
KIF6 carriers treated with pravastatin or atorvastatin had a greater reduction of coronary events than noncarriers
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Warfarin PGxWarfarin PGx Warfarin is commonly prescribed drug Variants in CYP2C9 and VKORC1 account
for high percentage of variability of warfarin response
FDA relabeled warfarin in Aug. 2007 to encourage pharmacogenetic testing
Utility still remains low Controversial topic Unanswered questions
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Warfarin PGx: Ready for Prime Warfarin PGx: Ready for Prime Time?Time?
How is the information applied to clinical practice? Can genetic testing be used to determine the right
warfarin dosage? Does it add significantly to the information discerned
by careful INR monitoring and other factors (e.g. age, underlying disease state, drug-drug interactions)?
Will it really reduce clinical complications? Will it result in shorter time to stable INR? Is it cost-effective?
Should genotyping be ordered on all patients taking Warfarin?
Can the information be obtained in a timely fashion?
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WarfarinWarfarin Widely prescribed anticoagulantWidely prescribed anticoagulant 1212thth most commonly prescribed drug most commonly prescribed drug
Wysowski, D. K. et al. Arch Intern Med 2007;167:1414-1419.
0
5000000
10000000
15000000
20000000
25000000
30000000
35000000
Annual Number of
Prescriptions
1998 1999 2000 2001 2002 2003 2004
Year
Annual Number of Outpatient Warfarin Prescriptions, 1998-2004 45% increase from
1998 to 2004
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WarfarinWarfarin Challenges in regulating warfarin dosing Prothrombin time (INR) must remain in
narrow therapeutic range Elevated INR: risk for major bleeding
complications Risk for serious bleeding increases with INR > 4.0 Most likely to occur within first few weeks of
initiating treatment Subtherapeutic INR: thrombotic
complications
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Budnitz et al, Ann Intern Med 2007;147:755-765.
Warfarin is the Most Commonly Warfarin is the Most Commonly Implicated Medication in U.S. ED VisitsImplicated Medication in U.S. ED Visits
0 5 10 15 20
WarfarinInsulinAspirin
ClopodigrelDigoxin
MetforminGlyburide
VicodinPhenytoinGlipizide
LevofloxacinLisinopril
BactrimFurosemide
Frequency
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180
750780
390
180
7030 25 120
100
200
300
400
500
600
700
800
Nu
mb
er o
f P
atie
nts
0.5
to 2
3 to
4
5 to
6
7 to
8
9 to
10
11 to
12
13 to
14
15 to
16
17 to
20
Daily Dose, mg
Variability in Warfarin Dose Requirements, N = 2305
James AH. J Clin Path 1992;45:704-06
Wide Range in Warfarin Dose Wide Range in Warfarin Dose RequirementsRequirements
Warfarin Resistance
Warfarin Sensitivity
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Sources of variability in Sources of variability in Warfarin dosingWarfarin dosing
VKORC1 25%
CYP2C9 17%
CYP4F2 2%
Weight 9%
Age 7%
Other 28%
Drugs 12%
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Warfarin PharmacologyWarfarin Pharmacology Racemic mixture of R- and S-enantiomersRacemic mixture of R- and S-enantiomers
S-Warfarin approx. 7-10X as potent as R-S-Warfarin approx. 7-10X as potent as R- Majority of Majority of in vivoin vivo activity of warfarin resides activity of warfarin resides
in S-warfarinin S-warfarin Metabolized mainly through CYP2C9Metabolized mainly through CYP2C9
Targets VKORC1 (Vitamin K epoxide Targets VKORC1 (Vitamin K epoxide reductase complex subunit 1)reductase complex subunit 1) Interferes with recycling of Vit K in the liverInterferes with recycling of Vit K in the liver Reduced activation of clotting factorsReduced activation of clotting factors
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Pharmacokinetics Pharmacodynamics
CYP2C9
CYP2C19CYP3A4CYP1A1CYP1A2CYP2C8CYP2C9
4-hydroxywarfarin
6-hydroxywarfarin
7-hydroxywarfarin
8-hydroxywarfarin
10-hydroxywarfarin
VKOR
(hepatocyte) (hepatocyte)
S-WarfarinR-Warfarin
6-hydroxywarfarin
7-hydroxywarfarinVitamin K (oxidized)
Inactive Vitamin K-dependent clotting
factors
Active Vitamin K-dependent clotting
factors
Vitamin K (reduced)
S-WarfarinR-Warfarin
inactive
GGCX
Elimination
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Warfarin PGxWarfarin PGx CYP2C9CYP2C9
CYP2C9*2 variantCYP2C9*2 variant Arg144CysArg144Cys 30% decrease in enzymatic activity30% decrease in enzymatic activity
CYP2C9*3 variantCYP2C9*3 variant Ile359LeuIle359Leu 70%-95% decreased enzymatic activity70%-95% decreased enzymatic activity
VKORC1VKORC1 Promoter SNP -1639G>A Promoter SNP -1639G>A 44% decrease in promoter activity44% decrease in promoter activity
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Allele FrequenciesAllele Frequencies
CYP2CCYP2C9 *29 *2
CYP2CCYP2C9*39*3
VKORC1VKORC1
--1639G>1639G>
AA
CaucasianCaucasian 8-13%8-13% 6-10%6-10% 42%42%
AsianAsian 2-5%2-5% <1%<1% 89%89%
African African AmericanAmerican <1%<1% 1-4%1-4% 8%8%
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Genotype-guided Warfarin Genotype-guided Warfarin DosingDosingCYP2C9 GenotypeCYP2C9 Genotype
VKORC1VKORC1 RapidRapid IntermediIntermediateate
SlowSlow Very Very SlowSlow
GenotypGenotypee
*1/*1*1/*1 *1/*2*1/*2 *1/*3*1/*3 *2/*2*2/*2 *2/*3*2/*3 *3/*3*3/*3
Low Low SensitivitySensitivity
(GG)(GG)140%140% 113%113% 94%94% 92%92% 75%75% 63%63%
Med Med SensitivitySensitivity
(AG)(AG)100%100% 81%81% 67%67% 67%67% 54%54% 46%46%
High High SensitivitySensitivity
(AA)(AA)73%73% 58%58% 48%48% 48%48% 40%40% 33%33%McClain, et al., Gen Med, 2008, 10(2): 89-98
www.warfarindosing.org
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Can Pharmacogenomics Can Pharmacogenomics Assist Warfarin Dosing?Assist Warfarin Dosing?
Caraco, Clin Pharm Ther, 2008
Warfarin DosingInitiation Stabilization
185 Patients
PGx-Informed(CYP2C9 only)
Algorithm Guided(Ageno et al, 2000)
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Time to First Therapeutic INR
PGx-informedControls
P<0.001*
Pro
port
ion
of
pati
en
ts
wit
h I
NR
>2
Days
Caraco, Clin Pharm Ther, 2008
0 5 10 15 20 25
0.0
0.2
0.4
0.6
0.8
1.0
CYP2C9 Genotype-guided CYP2C9 Genotype-guided Warfarin Prescribing Warfarin Prescribing Efficacy and SafetyEfficacy and Safety
*Time to therapeutic INR 2.73 days earlier
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CYP2C9 Genotype-guided CYP2C9 Genotype-guided Warfarin Prescribing Warfarin Prescribing Efficacy and SafetyEfficacy and Safety
Time to First Stable Anticoagulation
PGx-informedControls
Pro
port
ion
of
pati
en
ts
at
stab
le a
nti
coag
ula
tion
0.0
0.2
0.4
0.6
0.8
1.0
DaysCaraco, Clin Pharm Ther, 2008
*Time to stable anticoagulation 18 days earlier(22+7 vs 40+21 days)
P<0.001*
0 25 50 75 100 125
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CYP2C9 Genotype-guided CYP2C9 Genotype-guided Warfarin Prescribing Warfarin Prescribing Efficacy and SafetyEfficacy and Safety
Time spent in the therapeutic range Time spent in the therapeutic range was higherwas higher (80.4 vs. 63.4%)(80.4 vs. 63.4%)
Bleeding incidence was lower (3.2 Bleeding incidence was lower (3.2 vs. 12.5%)vs. 12.5%)
Patients with 1 or 2 variant alleles Patients with 1 or 2 variant alleles required 77% and 52% of dose used required 77% and 52% of dose used by *1/*1, respectivelyby *1/*1, respectively
Caraco, Clin Pharm Ther, 2008
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Using genotyping results Using genotyping results to make Warfarin dosing to make Warfarin dosing
decisionsdecisions No clinically validated algorithmNo clinically validated algorithm A “work in progress”A “work in progress”
Several large multi-center studies being Several large multi-center studies being undertaken to address this questionundertaken to address this question
www.warfarindosing.orgwww.warfarindosing.org
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Warfarin PGx: SummaryWarfarin PGx: Summary Some studies suggest that warfarin PGx testing is beneficialSome studies suggest that warfarin PGx testing is beneficial
Reduced time to stable INRReduced time to stable INR Reduced adverse eventsReduced adverse events
Large multi-center studies currently underwayLarge multi-center studies currently underway Clinical outcomesClinical outcomes Validated dosing algorithmsValidated dosing algorithms
New technology allowing for more rapid resultsNew technology allowing for more rapid results Genetic variants explain 40-45% of variability in response to Genetic variants explain 40-45% of variability in response to
warfarinwarfarin Important to realize the impact of the compound effects of Important to realize the impact of the compound effects of
polymorphisms in polymorphisms in CYP2C9CYP2C9 AND AND VKORC1VKORC1 Drug-drug interactions, co-morbidities, age, BMIDrug-drug interactions, co-morbidities, age, BMI
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Mendelian genetics Autosomal Dominant Hypercholesterolemia
LDLR, APOB, PCSK9
Familial Thoracic Aortic Aneurysm and Dissection syndromes:
FBN1, TGFBR1, TGFBR2, ACTA2, MYH11, NOTCH
Genetic markers for CAD Multiple genes contribute to small percentage of
phenotype Chromosome 9p21/ANRIL KIF6
Pharmacogenetics Controversial, but gathering speed
Warfarin sensitivity Statin efficacy
Recent Developments in CV Recent Developments in CV GeneticsGenetics
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Thank You!!Thank You!!