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Recent Genetic Advances in Cardiovascular Disease

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Lusis A, Trends Cardio Med, 2003; 13:309-16. Genes contributing to CAD susceptibility ... in a timely fashion? Warfarin. Widely prescribed anticoagulant ... – PowerPoint PPT presentation

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Title: Recent Genetic Advances in Cardiovascular Disease


1
Recent Genetic Advances in Cardiovascular Disease
  • Linnea M. Baudhuin, Ph.D.
  • Mayo Clinic
  • Dec. 6, 2008

2
DISCLOSUREInformation
  • Relevant Financial Relationships
  • None
  • Off Label Usage
  • None

3
Recent Developments in CV Genetics
  • 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

4
(No Transcript)
5
Coronary Artery Disease
  • Unable to predict significant portion of CAD
  • 35 of CAD occurs in population with TClt200 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 gt50
  • 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

6
Complex Genetics of CAD
  • Minority are single-gene disorders
  • FH, FDB, ARH, Tangier, Sitosterolemia, etc.
  • What about the majority of CAD?
  • Whats going on genetically?

7
Early stages of atherosclerosis
Late stages of atherosclerosis
Lusis et al., Ann Rev Gen Hum Gen, 2004, 5189-218
8
Genes contributing to CAD susceptibility
Lusis A, Trends Cardio Med, 2003 13309-16.
9
How can we identify genetic 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

10
CAD Linkage Studies
  • At least 7 family studies
  • Occurrence of MI or subclinical atherosclerosis
  • Linkage Chr 1, 2, 3, 13, 14, 15, 16, X
  • Lack of replication
  • Genes identified
  • MEF2A (Chr 15q26)
  • ALOX5AP
  • LTA4

11
Candidate Gene Association Analyses in CAD
  • Generally single gene/single polymorphism
  • Small cohorts
  • Inability to replicate findings in additional
    studies
  • Genetic analysis of 103 candidate genes (n1400,
    with follow-up n 806) unable to replicate
    findings (Pare et al, Am Hum Genet, 2007,
    80673-682)
  • Similar results in n811 ACS patients, 70 genes
    (Morgan et al, JAMA, 2007, 297 1551-1561

12
Why are the results of Linkage and Candidate Gene
studies so disappointing?
  • Inadequately powered
  • Phenotypic heterogeneity and imprecise definition
    of phenotypes
  • Bias (e.g. population stratification)
  • Multiple genes each contribute to small
    percentage of phenotype (lt5-10)
  • A single gene is insufficient to induce disease
  • Information from multiple polymorphisms should be
    integrated to become clinically useful
  • Multiple possible combinations of genotypes
  • Population and disease heterogeneity

13
What about Genome Wide Association Studies?
14
Genome-wide association studies
  • Previously single SNP/single cohort associations
    with little replication
  • Now large international consortium studies of
    tens of thousands of individuals and hundreds of
    thousands of SNPs
  • Technology
  • Ultra high-throughput genotyping with ability to
    analyze 500K to gt1M SNPs in each individual

15
Topol, EJ et al., JAMA, 2007 298218-221
16
Multiple GWASs confirming 9p21 in Caucasian
populations
  • McPherson et al, Science (316), June 8 2007,
    1488-91
  • Initial study, 322 cases vs 312 controls 73K
    SNPs
  • Confirmed in 5 independent Caucasian populations
    (n23,000)
  • Helgadottir et al, Science (316), June 8 2007,
    1491-3
  • Initial study, 1607 cases vs 6728 controls 306K
    SNPs
  • Replicated in
  • 665 cases and 3533 controls
  • Three other case control populations
  • Philadelphia, Atlanta, Durham, NC
  • 4587 cases, 12,767 controls
  • Wellcome Trust Case Consortium, Nature,
    447661-678, 2007
  • Samani et al, NEJM (357), Aug 2 2007, 443-53
  • PROCARDIS Consortium (Broadbent et al, Hum Mol
    Gen, 2008, 17)

17
Chromosome 9p21
  • 9p21 confined to 58K bp region
  • Risk associated with MI and CAD independent of
    known risk factors
  • 50 of individuals heterozygous for allele
  • 15-20 increased risk of CAD
  • 25 of individuals homozygous for allele
  • 30-40 increased risk of CAD
  • Odds ratio
  • Heterozygous 1.3-1.5
  • Homozygous 1.8-2.1

18
9p21 and ANRIL
  • High-risk CAD 9p21 haplotype overlaps with exons
    13-19 of ANRIL
  • Newly annotated gene, encodes large antisense
    non-coding RNA (ncRNA)
  • Identified through deletion analysis of French
    family with hereditary melanoma-neural system
    tumors
  • Expressed in atheromatous human vessels
  • Comparable cell type profiles to atherosclerotic
    arteries
  • Expressed in vascular endothelial cells,
    monocyte-derived macrophages, and coronary smooth
    muscle cells
  • Very little known about function
  • Gene class is thought to be involved in
    transcriptional control

Broadbent, et al, Human Mol Gen, 2008, 17 806-14
19
KIF6 Variant and CAD
  • CARE Cholesterol and Recurrent Events
  • WOSCOPS West of Scotland Coronary Prevention
    Study

20
Association of KIF6 with CAD 2 Prospective
Trials of Pravastatin
  • CARE Cholesterol and Recurrent Events
  • Secondary prevention in patients with a prior MI
  • 40 mg pravastatin vs placebo
  • 87 men and 13 women
  • LDL-C 115 to 174 mg/dL at baseline
  • 2,697 participants studied
  • WOSCOPS West of Scotland Coronary Prevention
    Study
  • Primary prevention
  • 40 mg pravastatin vs placebo
  • Men aged 45 to 64
  • LDL-C 174 to 232 mg/dL at baseline
  • 1,527 participants studied

21
Risk of CAD in CARE Placebo ArmKIF6 Variant and
Traditional Risk Factors
Smoking
Diabetes
KIF6 Variant
Age 55
HDL-C lt 40
Hypertension
LDL-C 130
Adjusted Hazard Ratio
  • Magnitude of risk predicted by KIF6 variant was
  • Similar to that of traditional risk factors
  • Independent of traditional risk factors

22
Risk of CAD in WOSCOPS Placebo ArmKIF6 Variant
and Traditional Risk Factors
Diabetes
KIF6 Variant
HDL-C lt 40
LDL-C 189
Hypertension
Adjusted Risk Ratio
  • Magnitude of risk predicted by KIF6 variant was
  • Similar to that of traditional risk factors
  • Independent of traditional risk factors

Case and control patients were matched for age
and smoking all were men Median level in
placebo arm
23
KIF6 Variant is Associated with CAD 5
Prospective Studies
CARE
Untreated patients
WOSCOPS
CHS
Some treatment
ARIC
WHS
Hazard Ratio
  • KIF6 variant predicts risk of CAD
  • Up to 55 increased risk in untreated populations

Adjusted for traditional risk factors
24
Recent Developments in CV Genetics
  • 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

25
  • PROVE IT - TIMI 22 study
  • Pravastatin or Atorvastatin Evaluation and
    Infection Therapy, Thrombolysis in MI
  • Patients hospitalized within 10 days after an
    acute coronary syndrome

26
Prevention of CHD Events by Statins Carriers of
the KIF6 Variant Benefit the Most
WOSCOPS
PROVE IT
Pravastatin 40 mg
Atorvastatin 80 mg
Non-carriers
Non-carriers
Carriers
Carriers
All
All
Absolute Risk Reduction ()
3.5
10.0
6.2
0.1
0.8
5.5
  • KIF6 carriers received significant risk reduction
    from atorvastatin in PROVE IT, suggesting KIF6
    may also predict response with other statins
  • KIF6 carriers also received significantly greater
    benefit than noncarriers (p0.003 for WOSCOPS and
    0.018 for PROVE IT)

27
Statin Intensity and CHD Event ReductionAccording
to KIF6 719Arg Carrier Status
Noncarriers
KIF6 Carriers
Pravastatin
Pravastatin
P1.0
p0.001
Death or major CV events
Atorvastatin
Atorvastatin
Months of follow-up
Months of follow-up
  • 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

28
KIF6 SummaryRisk for CAD and Risk Reduction from
Statins
  • 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

29
Warfarin 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

30
Warfarin PGx Ready for Prime 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?

31
Warfarin
  • Widely prescribed anticoagulant
  • 12th most commonly prescribed drug

45 increase from 1998 to 2004
Wysowski, D. K. et al. Arch Intern Med
20071671414-1419.
32
Warfarin
  • 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 gt
    4.0
  • Most likely to occur within first few weeks of
    initiating treatment
  • Subtherapeutic INR thrombotic complications

33
Warfarin is the Most Commonly Implicated
Medication in U.S. ED Visits
Furosemide
Bactrim
Lisinopril
Levofloxacin
Glipizide
Phenytoin
Vicodin
Glyburide
Metformin
Digoxin
Clopodigrel
Aspirin
Insulin
Warfarin
0
5
10
15
20
Frequency
Budnitz et al, Ann Intern Med 2007147755-765.
34
Wide Range in Warfarin Dose Requirements
Warfarin Sensitivity
Warfarin Resistance
James AH. J Clin Path 199245704-06
35
Sources of variability in Warfarin dosing
VKORC1 25
Other 28
CYP2C9 17
Drugs 12
CYP4F2 2
Age 7
Weight 9
36
Warfarin Pharmacology
  • Racemic mixture of R- and S-enantiomers
  • S-Warfarin approx. 7-10X as potent as R-
  • Majority of in vivo activity of warfarin resides
    in S-warfarin
  • Metabolized mainly through CYP2C9
  • Targets VKORC1 (Vitamin K epoxide reductase
    complex subunit 1)
  • Interferes with recycling of Vit K in the liver
  • Reduced activation of clotting factors

37
Pharmacodynamics
Pharmacokinetics
(hepatocyte)
(hepatocyte)
S-Warfarin
R-Warfarin
S-Warfarin
R-Warfarin
CYP2C19 CYP3A4 CYP1A1 CYP1A2 CYP2C8 CYP2C9
CYP2C9
VKOR
inactive
4-hydroxywarfarin
6-hydroxywarfarin
Vitamin K (oxidized)
Vitamin K (reduced)
6-hydroxywarfarin
7-hydroxywarfarin
7-hydroxywarfarin
8-hydroxywarfarin
GGCX
10-hydroxywarfarin
Inactive Vitamin K- dependent clotting factors
Active Vitamin K- dependent clotting factors
Elimination
38
Warfarin PGx
  • CYP2C9
  • CYP2C92 variant
  • Arg144Cys
  • 30 decrease in enzymatic activity
  • CYP2C93 variant
  • Ile359Leu
  • 70-95 decreased enzymatic activity
  • VKORC1
  • Promoter SNP -1639GgtA
  • 44 decrease in promoter activity

39
Allele Frequencies
40
Genotype-guided Warfarin Dosing
McClain, et al., Gen Med, 2008, 10(2)
89-98 www.warfarindosing.org
41
Can Pharmacogenomics Assist Warfarin Dosing?
Warfarin Dosing
Initiation
Stabilization
PGx- Informed (CYP2C9 only)
185 Patients
Algorithm Guided (Ageno et al, 2000)
Caraco, Clin Pharm Ther, 2008
42
CYP2C9 Genotype-guided Warfarin Prescribing
Efficacy and Safety
Time to First Therapeutic INR
Plt0.001
1.0
0.8
PGx-informed
Controls
0.6
Proportion of patients with INRgt2
0.4
0.2
Time to therapeutic INR 2.73 days earlier
0.0
0
5
10
15
20
25
Days
Caraco, Clin Pharm Ther, 2008
43
CYP2C9 Genotype-guided Warfarin Prescribing
Efficacy and Safety
Time to First Stable Anticoagulation
1.0
Plt0.001
0.8
PGx-informed
Controls
0.6
Proportion of patients at stable anticoagulation
0.4
Time to stable anticoagulation 18 days
earlier (227 vs 4021 days)
0.2
0.0
0
25
50
75
100
125
Days
Caraco, Clin Pharm Ther, 2008
44
CYP2C9 Genotype-guided Warfarin Prescribing
Efficacy and Safety
  • Time spent in the therapeutic range was higher
  • (80.4 vs. 63.4)
  • Bleeding incidence was lower (3.2 vs. 12.5)
  • Patients with 1 or 2 variant alleles required 77
    and 52 of dose used by 1/1, respectively

Caraco, Clin Pharm Ther, 2008
45
Using genotyping results to make Warfarin dosing
decisions
  • No clinically validated algorithm
  • A work in progress
  • Several large multi-center studies being
    undertaken to address this question
  • www.warfarindosing.org

46
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47
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48
Warfarin PGx Summary
  • Some studies suggest that warfarin PGx testing is
    beneficial
  • Reduced time to stable INR
  • Reduced adverse events
  • Large multi-center studies currently underway
  • Clinical outcomes
  • Validated dosing algorithms
  • New technology allowing for more rapid results
  • Genetic variants explain 40-45 of variability in
    response to warfarin
  • Important to realize the impact of the compound
    effects of
  • polymorphisms in CYP2C9 AND VKORC1
  • Drug-drug interactions, co-morbidities, age, BMI

49
Recent Developments in CV Genetics
  • 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

50
Thank You!!
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