MASTER CLASSES Polimorfismi protrombotici: prospettive future … · 2016. 12. 13. · MASTER...
18
MASTER CLASSES Polimorfismi protrombotici: prospettive future nella pratica clinica. Le trombosi arteriose Licia Iacoviello, MD, PhD Deprtment of Epidemiology and Thrombosis IRCCS Istituto Neurologico Mediterraneo-NEUROMED Pozzilli (IS) XXIV Congresso Nazionale SISET 9/12 Novembre 2016
Transcript of MASTER CLASSES Polimorfismi protrombotici: prospettive future … · 2016. 12. 13. · MASTER...
MASTER CLASSESPolimorfismi protrombotici prospettive
future nella pratica clinicaLe trombosi arteriose
Licia Iacoviello MD PhD
Deprtment of Epidemiology and Thrombosis
IRCCS Istituto Neurologico Mediterraneo-NEUROMED
Pozzilli (IS)
XXIV Congresso Nazionale SISET 912 Novembre 2016
La notte in cui tutte le vacche sono nerehellip
bull 1980-2000 Big randomised clinical trials
ndash Evidence-based medicine to make clinical decisions based on the average individual in the general population
bull 2000rsquos Sequencing of the human genome
ndash Personalised medicine
Family history of thrombosis
Family and twin studies have established that family history of thrombosis increases
the risk of arterial thrombosis
bull Rissanen AM Br Heart J 1979
bull Soslashrensen TI N Engl J Med1988
bull Marenberg ME et al N Engl J Med 1994
bull Roncaglioni MC Circulation 1992
Heritability
bull Heritability of thrombosis is 61 plusmn16 (Plt00001) -Spanish extended pedigrees (GAIT study) Similar in venous and arterial thrombosis
bull Heritability of CHD is 57 (95 CI 45ndash69) in M and 38 (26ndash50) in F - Swedish twins
bull Heritability of clot formation structure and lysis is 30 ndash English twins (EuroCLOT study)
N Engl J Med 1998 33879-85
0
50
100
150
RR RQ QQ
Fa
cto
r V
II a
cti
vit
y (
)
00
02
04
06
08
10
RR RQ QQ
Od
ds
Ra
tio
s (
95
C
I)
(038-133)
(001-091)
Odds ratios for cardiovascular disease comparing (PlA1A2+PlA2A2) genotypes with PlA1A1 genotype as reference group
Lower risk among PlA2 carriers Higher risk among PlA2 carriers
Study designProspective studies
Garcia-Ribes18
Abbate20
Corral 22
GrandrsquoMaison25
Laule27
Weiss4
Kekomaki21
Marian5
Carter6
Osborn7
Carter9
Hermann10
Hermann10
Samani11
Mamotte12
Scaglione13
Joven19
Senti26
Kekomaki21
Pastinen28
Subtotal
Population controls
CasesControls
100100
3873
101101
99100
977972
7168
4144
104164
101114
66167
156216
191176
428523
242235
367570
9898
250250
116136
6882
151151
10721505
Disease of case
CHD
CHD
IHD
CAD
CAD
MI or unstable angina
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Degree ofadjustment
++
Raw data
+
++
+
++
Raw data
Raw data
++
Raw data
Bray23
Aleksic24
Ridker 8
259257
439544
374704Recurrent MI or cardiovascular deathCHD
Myocardial infarction
++
+
++
++
+
+
+
Raw data
+
++
Raw data
Raw data
+
Ardissino34 200200 Myocardial infarction +
Boncler31 5580 IHD Raw data
Moshfegh32 17789 Myocardial infarction +
Hooper33 110185 Myocardial infarction +
05 1 15 2 25 3 35
Subtotal 53055209
Subtotal
TOTAL
Carter14
Anderson29
Anderson29
Gardemann15
Durante-Mangoni16
Zotz17
Other controls
6790
225276
549170
10611191
4371
12491
20691889
84468603
CAD in NIDDM
Myocardial infarction
CAD
Myocardial infarction
Myocardial infarction
Myocardial infarction
++
++
++
Raw data
Raw data
++
100 (087 to 116)
114 (105 to 125)
111 (094 to 132)
Bottiger34 998340 CAD ++
110 (103 to 118)
Platelet GP IIIa Polymorphism and coronary risk a meta- analysis
Di Castelnuovo A Iacoviello L Thromb Haemost 2001
Meta-analyses of the effect of the PAI-1 4G5G polymorphism on the risk for myocardial infarction and the mean difference in PAI-1 activity e meta-regression of natural logarithm of
the MI-related OR for the PAI-1 4G variant on PAI-1 activity
Nikolopoulos GK et al Clin Chem Lab Med 2014
Chromosome map of genes reported to be causal for susceptible to and associated with coronary artery disease and myocardial infarction in the literature
gt240 000 individuals
50 genetic risk variants for CAD
Common 50 in gt50 of the population and 25 in gt75 of the population
Average OR=+18 (from 2 to 90)
Noncoding DNA sequences
3550 mechanisms independent of known risk factors
Acting Primarily Through Unknown Pathways
Discovery of the PCSK9 variant located on 1p323 has already led to the
development of a new therapeutic agent complementary to statins
CARDIoGRAMplusC4DDiscovery of Multiple Novel Genetic Risk Variants for CAD
All of the genetic variants seem to act through atherosclerosisLipids LDL HDL triglycerides hypertension Inflammation
Thrombosis ABO blood groups A and B encode for a protein (α-1-3-N-acetylgalactoseaminyltransferase associated prolonged von Willebrandplasma half life leading to thrombosis and with increased risk formyocardial infarction
Plasminogen
CARDIoGRAMplusC4DDiscovery of Multiple Novel Genetic Risk Variants for CAD
Do genetic variants increase risk prediction and classification
Prospective Studies Assessing CVD Risk Prediction Using Multiple Genetic Markers and Risk-Prediction Metrics
Di Angelantonio E Circ Cardiovasc Genet 2012
Perk J Atherosclerosis 2012
CVD prevention in clinical practice2012 European Guidelines (ESCEACPR)
Mendelian Randomization A Novel Approach to Assess Safety and Efficacy of Genetic Variants and Their Potential as Drug Targets
RCT is performed in a predetermined adequate sample size usually for a duration of 3 to 5 years
Mendelian randomization random assignment long-life effect no confounding
Loss-of-function mutation in PCSK9 LDL-C reduction by 28CAD reduction 88
Monoclonal antibody inhibiting PCSK9 confirms the results of Mendelian randomization
SNP in the endothelial lipase gene (LIPG Asn396Ser) No effect on MI risk 14 SNPs associated solely with increased HDL-C No effect on MI risk 13 SNPs associated solely with increased LDL-C Reduce AMI risk
Roberts R Circ Res 2014
CLOPIDOGREL PHARMACOGENETICS a matter for controversy
March 12 2010 FDA ldquoboxed warningrdquo on Clopidogrel
1 Antiplatelet effect of clopidogrel depends primarily on its activation by the cytochrome P450 (CYP) system
2 Patients with decreased CYP2C19 function because of genetic polymorphisms metabolize clopidogrel poorly and have higher rates of cardiovascular events after acute coronary syndrome and percutaneous coronary interventions (PCIs) than patients with normal CYP2C19 function
3 Tests are available to identify patients with genetic polymorphisms
4 Alternative treatment strategies should be considered in poor metabolizers of the drug
bull Inhibition of ADP-induced platelet aggregation by clopidogrel rangesfrom lt10 to 100
bull residual platelet reactivity after clopidogrel is associated with anincreased risk of cardiac cerebrovascular and peripheral arterial events
bull CYP2C192 polymorphism is associated with an increased risk of majoradverse CV events
bull A systematic review and critical assessment of 11 discordant meta-analyses on reduced-function CYP2C19 genotype and risk of adverseclinical outcomes in clopidogrel users concludes that personalizedantiplatelet management based on genotyping is not supported by thecurrently available evidence (Osnabrugge RL et al Gen Med 2015)
CLOPIDOGREL PHARMACOGENETICS a matter for controversy
Circulation 2010122537-557Originally published August 2 2010
The recent US Food and Drug Administration (FDA) ldquoboxed warningrdquo on clopidogrelraises important questions for practitioners and patientsThe warning addresses the need for pharmacogenomic testing to identify patientsrsquoaltered clopidogrel metabolism and thus their risk for a suboptimal clinical response toclopidogrelAlthough there is an expanding database on genetic polymorphisms that may affectclopidogrel metabolism and thus clinical outcomes there are no evidence-based dataupon which to develop specific recommendations on the role of genetic testing inroutine care nor strategies proven to improve the safetyefficacy of specificpharmacologic approaches
TAKE HOME MESSAGES
bull I risultati della genetica nella predizione del rischiocardiovascolare sono stati finora deludenti
bull Nessun test genetico ad oggi egrave utile per la predizione delrischio cardiovascolare
bull La concentrazione sui modelli di predizione ha fattoperdere di vista altre importanti potenzialitagrave degli studi digenetica
bull Lrsquoepigenetica ci sveleragrave ancora molto sulla reale funzionedel genoma
La notte in cui tutte le vacche sono nerehellip
bull 1980-2000 Big randomised clinical trials
ndash Evidence-based medicine to make clinical decisions based on the average individual in the general population
bull 2000rsquos Sequencing of the human genome
ndash Personalised medicine
Family history of thrombosis
Family and twin studies have established that family history of thrombosis increases
the risk of arterial thrombosis
bull Rissanen AM Br Heart J 1979
bull Soslashrensen TI N Engl J Med1988
bull Marenberg ME et al N Engl J Med 1994
bull Roncaglioni MC Circulation 1992
Heritability
bull Heritability of thrombosis is 61 plusmn16 (Plt00001) -Spanish extended pedigrees (GAIT study) Similar in venous and arterial thrombosis
bull Heritability of CHD is 57 (95 CI 45ndash69) in M and 38 (26ndash50) in F - Swedish twins
bull Heritability of clot formation structure and lysis is 30 ndash English twins (EuroCLOT study)
N Engl J Med 1998 33879-85
0
50
100
150
RR RQ QQ
Fa
cto
r V
II a
cti
vit
y (
)
00
02
04
06
08
10
RR RQ QQ
Od
ds
Ra
tio
s (
95
C
I)
(038-133)
(001-091)
Odds ratios for cardiovascular disease comparing (PlA1A2+PlA2A2) genotypes with PlA1A1 genotype as reference group
Lower risk among PlA2 carriers Higher risk among PlA2 carriers
Study designProspective studies
Garcia-Ribes18
Abbate20
Corral 22
GrandrsquoMaison25
Laule27
Weiss4
Kekomaki21
Marian5
Carter6
Osborn7
Carter9
Hermann10
Hermann10
Samani11
Mamotte12
Scaglione13
Joven19
Senti26
Kekomaki21
Pastinen28
Subtotal
Population controls
CasesControls
100100
3873
101101
99100
977972
7168
4144
104164
101114
66167
156216
191176
428523
242235
367570
9898
250250
116136
6882
151151
10721505
Disease of case
CHD
CHD
IHD
CAD
CAD
MI or unstable angina
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Degree ofadjustment
++
Raw data
+
++
+
++
Raw data
Raw data
++
Raw data
Bray23
Aleksic24
Ridker 8
259257
439544
374704Recurrent MI or cardiovascular deathCHD
Myocardial infarction
++
+
++
++
+
+
+
Raw data
+
++
Raw data
Raw data
+
Ardissino34 200200 Myocardial infarction +
Boncler31 5580 IHD Raw data
Moshfegh32 17789 Myocardial infarction +
Hooper33 110185 Myocardial infarction +
05 1 15 2 25 3 35
Subtotal 53055209
Subtotal
TOTAL
Carter14
Anderson29
Anderson29
Gardemann15
Durante-Mangoni16
Zotz17
Other controls
6790
225276
549170
10611191
4371
12491
20691889
84468603
CAD in NIDDM
Myocardial infarction
CAD
Myocardial infarction
Myocardial infarction
Myocardial infarction
++
++
++
Raw data
Raw data
++
100 (087 to 116)
114 (105 to 125)
111 (094 to 132)
Bottiger34 998340 CAD ++
110 (103 to 118)
Platelet GP IIIa Polymorphism and coronary risk a meta- analysis
Di Castelnuovo A Iacoviello L Thromb Haemost 2001
Meta-analyses of the effect of the PAI-1 4G5G polymorphism on the risk for myocardial infarction and the mean difference in PAI-1 activity e meta-regression of natural logarithm of
the MI-related OR for the PAI-1 4G variant on PAI-1 activity
Nikolopoulos GK et al Clin Chem Lab Med 2014
Chromosome map of genes reported to be causal for susceptible to and associated with coronary artery disease and myocardial infarction in the literature
gt240 000 individuals
50 genetic risk variants for CAD
Common 50 in gt50 of the population and 25 in gt75 of the population
Average OR=+18 (from 2 to 90)
Noncoding DNA sequences
3550 mechanisms independent of known risk factors
Acting Primarily Through Unknown Pathways
Discovery of the PCSK9 variant located on 1p323 has already led to the
development of a new therapeutic agent complementary to statins
CARDIoGRAMplusC4DDiscovery of Multiple Novel Genetic Risk Variants for CAD
All of the genetic variants seem to act through atherosclerosisLipids LDL HDL triglycerides hypertension Inflammation
Thrombosis ABO blood groups A and B encode for a protein (α-1-3-N-acetylgalactoseaminyltransferase associated prolonged von Willebrandplasma half life leading to thrombosis and with increased risk formyocardial infarction
Plasminogen
CARDIoGRAMplusC4DDiscovery of Multiple Novel Genetic Risk Variants for CAD
Do genetic variants increase risk prediction and classification
Prospective Studies Assessing CVD Risk Prediction Using Multiple Genetic Markers and Risk-Prediction Metrics
Di Angelantonio E Circ Cardiovasc Genet 2012
Perk J Atherosclerosis 2012
CVD prevention in clinical practice2012 European Guidelines (ESCEACPR)
Mendelian Randomization A Novel Approach to Assess Safety and Efficacy of Genetic Variants and Their Potential as Drug Targets
RCT is performed in a predetermined adequate sample size usually for a duration of 3 to 5 years
Mendelian randomization random assignment long-life effect no confounding
Loss-of-function mutation in PCSK9 LDL-C reduction by 28CAD reduction 88
Monoclonal antibody inhibiting PCSK9 confirms the results of Mendelian randomization
SNP in the endothelial lipase gene (LIPG Asn396Ser) No effect on MI risk 14 SNPs associated solely with increased HDL-C No effect on MI risk 13 SNPs associated solely with increased LDL-C Reduce AMI risk
Roberts R Circ Res 2014
CLOPIDOGREL PHARMACOGENETICS a matter for controversy
March 12 2010 FDA ldquoboxed warningrdquo on Clopidogrel
1 Antiplatelet effect of clopidogrel depends primarily on its activation by the cytochrome P450 (CYP) system
2 Patients with decreased CYP2C19 function because of genetic polymorphisms metabolize clopidogrel poorly and have higher rates of cardiovascular events after acute coronary syndrome and percutaneous coronary interventions (PCIs) than patients with normal CYP2C19 function
3 Tests are available to identify patients with genetic polymorphisms
4 Alternative treatment strategies should be considered in poor metabolizers of the drug
bull Inhibition of ADP-induced platelet aggregation by clopidogrel rangesfrom lt10 to 100
bull residual platelet reactivity after clopidogrel is associated with anincreased risk of cardiac cerebrovascular and peripheral arterial events
bull CYP2C192 polymorphism is associated with an increased risk of majoradverse CV events
bull A systematic review and critical assessment of 11 discordant meta-analyses on reduced-function CYP2C19 genotype and risk of adverseclinical outcomes in clopidogrel users concludes that personalizedantiplatelet management based on genotyping is not supported by thecurrently available evidence (Osnabrugge RL et al Gen Med 2015)
CLOPIDOGREL PHARMACOGENETICS a matter for controversy
Circulation 2010122537-557Originally published August 2 2010
The recent US Food and Drug Administration (FDA) ldquoboxed warningrdquo on clopidogrelraises important questions for practitioners and patientsThe warning addresses the need for pharmacogenomic testing to identify patientsrsquoaltered clopidogrel metabolism and thus their risk for a suboptimal clinical response toclopidogrelAlthough there is an expanding database on genetic polymorphisms that may affectclopidogrel metabolism and thus clinical outcomes there are no evidence-based dataupon which to develop specific recommendations on the role of genetic testing inroutine care nor strategies proven to improve the safetyefficacy of specificpharmacologic approaches
TAKE HOME MESSAGES
bull I risultati della genetica nella predizione del rischiocardiovascolare sono stati finora deludenti
bull Nessun test genetico ad oggi egrave utile per la predizione delrischio cardiovascolare
bull La concentrazione sui modelli di predizione ha fattoperdere di vista altre importanti potenzialitagrave degli studi digenetica
bull Lrsquoepigenetica ci sveleragrave ancora molto sulla reale funzionedel genoma
Family history of thrombosis
Family and twin studies have established that family history of thrombosis increases
the risk of arterial thrombosis
bull Rissanen AM Br Heart J 1979
bull Soslashrensen TI N Engl J Med1988
bull Marenberg ME et al N Engl J Med 1994
bull Roncaglioni MC Circulation 1992
Heritability
bull Heritability of thrombosis is 61 plusmn16 (Plt00001) -Spanish extended pedigrees (GAIT study) Similar in venous and arterial thrombosis
bull Heritability of CHD is 57 (95 CI 45ndash69) in M and 38 (26ndash50) in F - Swedish twins
bull Heritability of clot formation structure and lysis is 30 ndash English twins (EuroCLOT study)
N Engl J Med 1998 33879-85
0
50
100
150
RR RQ QQ
Fa
cto
r V
II a
cti
vit
y (
)
00
02
04
06
08
10
RR RQ QQ
Od
ds
Ra
tio
s (
95
C
I)
(038-133)
(001-091)
Odds ratios for cardiovascular disease comparing (PlA1A2+PlA2A2) genotypes with PlA1A1 genotype as reference group
Lower risk among PlA2 carriers Higher risk among PlA2 carriers
Study designProspective studies
Garcia-Ribes18
Abbate20
Corral 22
GrandrsquoMaison25
Laule27
Weiss4
Kekomaki21
Marian5
Carter6
Osborn7
Carter9
Hermann10
Hermann10
Samani11
Mamotte12
Scaglione13
Joven19
Senti26
Kekomaki21
Pastinen28
Subtotal
Population controls
CasesControls
100100
3873
101101
99100
977972
7168
4144
104164
101114
66167
156216
191176
428523
242235
367570
9898
250250
116136
6882
151151
10721505
Disease of case
CHD
CHD
IHD
CAD
CAD
MI or unstable angina
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Degree ofadjustment
++
Raw data
+
++
+
++
Raw data
Raw data
++
Raw data
Bray23
Aleksic24
Ridker 8
259257
439544
374704Recurrent MI or cardiovascular deathCHD
Myocardial infarction
++
+
++
++
+
+
+
Raw data
+
++
Raw data
Raw data
+
Ardissino34 200200 Myocardial infarction +
Boncler31 5580 IHD Raw data
Moshfegh32 17789 Myocardial infarction +
Hooper33 110185 Myocardial infarction +
05 1 15 2 25 3 35
Subtotal 53055209
Subtotal
TOTAL
Carter14
Anderson29
Anderson29
Gardemann15
Durante-Mangoni16
Zotz17
Other controls
6790
225276
549170
10611191
4371
12491
20691889
84468603
CAD in NIDDM
Myocardial infarction
CAD
Myocardial infarction
Myocardial infarction
Myocardial infarction
++
++
++
Raw data
Raw data
++
100 (087 to 116)
114 (105 to 125)
111 (094 to 132)
Bottiger34 998340 CAD ++
110 (103 to 118)
Platelet GP IIIa Polymorphism and coronary risk a meta- analysis
Di Castelnuovo A Iacoviello L Thromb Haemost 2001
Meta-analyses of the effect of the PAI-1 4G5G polymorphism on the risk for myocardial infarction and the mean difference in PAI-1 activity e meta-regression of natural logarithm of
the MI-related OR for the PAI-1 4G variant on PAI-1 activity
Nikolopoulos GK et al Clin Chem Lab Med 2014
Chromosome map of genes reported to be causal for susceptible to and associated with coronary artery disease and myocardial infarction in the literature
gt240 000 individuals
50 genetic risk variants for CAD
Common 50 in gt50 of the population and 25 in gt75 of the population
Average OR=+18 (from 2 to 90)
Noncoding DNA sequences
3550 mechanisms independent of known risk factors
Acting Primarily Through Unknown Pathways
Discovery of the PCSK9 variant located on 1p323 has already led to the
development of a new therapeutic agent complementary to statins
CARDIoGRAMplusC4DDiscovery of Multiple Novel Genetic Risk Variants for CAD
All of the genetic variants seem to act through atherosclerosisLipids LDL HDL triglycerides hypertension Inflammation
Thrombosis ABO blood groups A and B encode for a protein (α-1-3-N-acetylgalactoseaminyltransferase associated prolonged von Willebrandplasma half life leading to thrombosis and with increased risk formyocardial infarction
Plasminogen
CARDIoGRAMplusC4DDiscovery of Multiple Novel Genetic Risk Variants for CAD
Do genetic variants increase risk prediction and classification
Prospective Studies Assessing CVD Risk Prediction Using Multiple Genetic Markers and Risk-Prediction Metrics
Di Angelantonio E Circ Cardiovasc Genet 2012
Perk J Atherosclerosis 2012
CVD prevention in clinical practice2012 European Guidelines (ESCEACPR)
Mendelian Randomization A Novel Approach to Assess Safety and Efficacy of Genetic Variants and Their Potential as Drug Targets
RCT is performed in a predetermined adequate sample size usually for a duration of 3 to 5 years
Mendelian randomization random assignment long-life effect no confounding
Loss-of-function mutation in PCSK9 LDL-C reduction by 28CAD reduction 88
Monoclonal antibody inhibiting PCSK9 confirms the results of Mendelian randomization
SNP in the endothelial lipase gene (LIPG Asn396Ser) No effect on MI risk 14 SNPs associated solely with increased HDL-C No effect on MI risk 13 SNPs associated solely with increased LDL-C Reduce AMI risk
Roberts R Circ Res 2014
CLOPIDOGREL PHARMACOGENETICS a matter for controversy
March 12 2010 FDA ldquoboxed warningrdquo on Clopidogrel
1 Antiplatelet effect of clopidogrel depends primarily on its activation by the cytochrome P450 (CYP) system
2 Patients with decreased CYP2C19 function because of genetic polymorphisms metabolize clopidogrel poorly and have higher rates of cardiovascular events after acute coronary syndrome and percutaneous coronary interventions (PCIs) than patients with normal CYP2C19 function
3 Tests are available to identify patients with genetic polymorphisms
4 Alternative treatment strategies should be considered in poor metabolizers of the drug
bull Inhibition of ADP-induced platelet aggregation by clopidogrel rangesfrom lt10 to 100
bull residual platelet reactivity after clopidogrel is associated with anincreased risk of cardiac cerebrovascular and peripheral arterial events
bull CYP2C192 polymorphism is associated with an increased risk of majoradverse CV events
bull A systematic review and critical assessment of 11 discordant meta-analyses on reduced-function CYP2C19 genotype and risk of adverseclinical outcomes in clopidogrel users concludes that personalizedantiplatelet management based on genotyping is not supported by thecurrently available evidence (Osnabrugge RL et al Gen Med 2015)
CLOPIDOGREL PHARMACOGENETICS a matter for controversy
Circulation 2010122537-557Originally published August 2 2010
The recent US Food and Drug Administration (FDA) ldquoboxed warningrdquo on clopidogrelraises important questions for practitioners and patientsThe warning addresses the need for pharmacogenomic testing to identify patientsrsquoaltered clopidogrel metabolism and thus their risk for a suboptimal clinical response toclopidogrelAlthough there is an expanding database on genetic polymorphisms that may affectclopidogrel metabolism and thus clinical outcomes there are no evidence-based dataupon which to develop specific recommendations on the role of genetic testing inroutine care nor strategies proven to improve the safetyefficacy of specificpharmacologic approaches
TAKE HOME MESSAGES
bull I risultati della genetica nella predizione del rischiocardiovascolare sono stati finora deludenti
bull Nessun test genetico ad oggi egrave utile per la predizione delrischio cardiovascolare
bull La concentrazione sui modelli di predizione ha fattoperdere di vista altre importanti potenzialitagrave degli studi digenetica
bull Lrsquoepigenetica ci sveleragrave ancora molto sulla reale funzionedel genoma
Heritability
bull Heritability of thrombosis is 61 plusmn16 (Plt00001) -Spanish extended pedigrees (GAIT study) Similar in venous and arterial thrombosis
bull Heritability of CHD is 57 (95 CI 45ndash69) in M and 38 (26ndash50) in F - Swedish twins
bull Heritability of clot formation structure and lysis is 30 ndash English twins (EuroCLOT study)
N Engl J Med 1998 33879-85
0
50
100
150
RR RQ QQ
Fa
cto
r V
II a
cti
vit
y (
)
00
02
04
06
08
10
RR RQ QQ
Od
ds
Ra
tio
s (
95
C
I)
(038-133)
(001-091)
Odds ratios for cardiovascular disease comparing (PlA1A2+PlA2A2) genotypes with PlA1A1 genotype as reference group
Lower risk among PlA2 carriers Higher risk among PlA2 carriers
Study designProspective studies
Garcia-Ribes18
Abbate20
Corral 22
GrandrsquoMaison25
Laule27
Weiss4
Kekomaki21
Marian5
Carter6
Osborn7
Carter9
Hermann10
Hermann10
Samani11
Mamotte12
Scaglione13
Joven19
Senti26
Kekomaki21
Pastinen28
Subtotal
Population controls
CasesControls
100100
3873
101101
99100
977972
7168
4144
104164
101114
66167
156216
191176
428523
242235
367570
9898
250250
116136
6882
151151
10721505
Disease of case
CHD
CHD
IHD
CAD
CAD
MI or unstable angina
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Degree ofadjustment
++
Raw data
+
++
+
++
Raw data
Raw data
++
Raw data
Bray23
Aleksic24
Ridker 8
259257
439544
374704Recurrent MI or cardiovascular deathCHD
Myocardial infarction
++
+
++
++
+
+
+
Raw data
+
++
Raw data
Raw data
+
Ardissino34 200200 Myocardial infarction +
Boncler31 5580 IHD Raw data
Moshfegh32 17789 Myocardial infarction +
Hooper33 110185 Myocardial infarction +
05 1 15 2 25 3 35
Subtotal 53055209
Subtotal
TOTAL
Carter14
Anderson29
Anderson29
Gardemann15
Durante-Mangoni16
Zotz17
Other controls
6790
225276
549170
10611191
4371
12491
20691889
84468603
CAD in NIDDM
Myocardial infarction
CAD
Myocardial infarction
Myocardial infarction
Myocardial infarction
++
++
++
Raw data
Raw data
++
100 (087 to 116)
114 (105 to 125)
111 (094 to 132)
Bottiger34 998340 CAD ++
110 (103 to 118)
Platelet GP IIIa Polymorphism and coronary risk a meta- analysis
Di Castelnuovo A Iacoviello L Thromb Haemost 2001
Meta-analyses of the effect of the PAI-1 4G5G polymorphism on the risk for myocardial infarction and the mean difference in PAI-1 activity e meta-regression of natural logarithm of
the MI-related OR for the PAI-1 4G variant on PAI-1 activity
Nikolopoulos GK et al Clin Chem Lab Med 2014
Chromosome map of genes reported to be causal for susceptible to and associated with coronary artery disease and myocardial infarction in the literature
gt240 000 individuals
50 genetic risk variants for CAD
Common 50 in gt50 of the population and 25 in gt75 of the population
Average OR=+18 (from 2 to 90)
Noncoding DNA sequences
3550 mechanisms independent of known risk factors
Acting Primarily Through Unknown Pathways
Discovery of the PCSK9 variant located on 1p323 has already led to the
development of a new therapeutic agent complementary to statins
CARDIoGRAMplusC4DDiscovery of Multiple Novel Genetic Risk Variants for CAD
All of the genetic variants seem to act through atherosclerosisLipids LDL HDL triglycerides hypertension Inflammation
Thrombosis ABO blood groups A and B encode for a protein (α-1-3-N-acetylgalactoseaminyltransferase associated prolonged von Willebrandplasma half life leading to thrombosis and with increased risk formyocardial infarction
Plasminogen
CARDIoGRAMplusC4DDiscovery of Multiple Novel Genetic Risk Variants for CAD
Do genetic variants increase risk prediction and classification
Prospective Studies Assessing CVD Risk Prediction Using Multiple Genetic Markers and Risk-Prediction Metrics
Di Angelantonio E Circ Cardiovasc Genet 2012
Perk J Atherosclerosis 2012
CVD prevention in clinical practice2012 European Guidelines (ESCEACPR)
Mendelian Randomization A Novel Approach to Assess Safety and Efficacy of Genetic Variants and Their Potential as Drug Targets
RCT is performed in a predetermined adequate sample size usually for a duration of 3 to 5 years
Mendelian randomization random assignment long-life effect no confounding
Loss-of-function mutation in PCSK9 LDL-C reduction by 28CAD reduction 88
Monoclonal antibody inhibiting PCSK9 confirms the results of Mendelian randomization
SNP in the endothelial lipase gene (LIPG Asn396Ser) No effect on MI risk 14 SNPs associated solely with increased HDL-C No effect on MI risk 13 SNPs associated solely with increased LDL-C Reduce AMI risk
Roberts R Circ Res 2014
CLOPIDOGREL PHARMACOGENETICS a matter for controversy
March 12 2010 FDA ldquoboxed warningrdquo on Clopidogrel
1 Antiplatelet effect of clopidogrel depends primarily on its activation by the cytochrome P450 (CYP) system
2 Patients with decreased CYP2C19 function because of genetic polymorphisms metabolize clopidogrel poorly and have higher rates of cardiovascular events after acute coronary syndrome and percutaneous coronary interventions (PCIs) than patients with normal CYP2C19 function
3 Tests are available to identify patients with genetic polymorphisms
4 Alternative treatment strategies should be considered in poor metabolizers of the drug
bull Inhibition of ADP-induced platelet aggregation by clopidogrel rangesfrom lt10 to 100
bull residual platelet reactivity after clopidogrel is associated with anincreased risk of cardiac cerebrovascular and peripheral arterial events
bull CYP2C192 polymorphism is associated with an increased risk of majoradverse CV events
bull A systematic review and critical assessment of 11 discordant meta-analyses on reduced-function CYP2C19 genotype and risk of adverseclinical outcomes in clopidogrel users concludes that personalizedantiplatelet management based on genotyping is not supported by thecurrently available evidence (Osnabrugge RL et al Gen Med 2015)
CLOPIDOGREL PHARMACOGENETICS a matter for controversy
Circulation 2010122537-557Originally published August 2 2010
The recent US Food and Drug Administration (FDA) ldquoboxed warningrdquo on clopidogrelraises important questions for practitioners and patientsThe warning addresses the need for pharmacogenomic testing to identify patientsrsquoaltered clopidogrel metabolism and thus their risk for a suboptimal clinical response toclopidogrelAlthough there is an expanding database on genetic polymorphisms that may affectclopidogrel metabolism and thus clinical outcomes there are no evidence-based dataupon which to develop specific recommendations on the role of genetic testing inroutine care nor strategies proven to improve the safetyefficacy of specificpharmacologic approaches
TAKE HOME MESSAGES
bull I risultati della genetica nella predizione del rischiocardiovascolare sono stati finora deludenti
bull Nessun test genetico ad oggi egrave utile per la predizione delrischio cardiovascolare
bull La concentrazione sui modelli di predizione ha fattoperdere di vista altre importanti potenzialitagrave degli studi digenetica
bull Lrsquoepigenetica ci sveleragrave ancora molto sulla reale funzionedel genoma
N Engl J Med 1998 33879-85
0
50
100
150
RR RQ QQ
Fa
cto
r V
II a
cti
vit
y (
)
00
02
04
06
08
10
RR RQ QQ
Od
ds
Ra
tio
s (
95
C
I)
(038-133)
(001-091)
Odds ratios for cardiovascular disease comparing (PlA1A2+PlA2A2) genotypes with PlA1A1 genotype as reference group
Lower risk among PlA2 carriers Higher risk among PlA2 carriers
Study designProspective studies
Garcia-Ribes18
Abbate20
Corral 22
GrandrsquoMaison25
Laule27
Weiss4
Kekomaki21
Marian5
Carter6
Osborn7
Carter9
Hermann10
Hermann10
Samani11
Mamotte12
Scaglione13
Joven19
Senti26
Kekomaki21
Pastinen28
Subtotal
Population controls
CasesControls
100100
3873
101101
99100
977972
7168
4144
104164
101114
66167
156216
191176
428523
242235
367570
9898
250250
116136
6882
151151
10721505
Disease of case
CHD
CHD
IHD
CAD
CAD
MI or unstable angina
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Degree ofadjustment
++
Raw data
+
++
+
++
Raw data
Raw data
++
Raw data
Bray23
Aleksic24
Ridker 8
259257
439544
374704Recurrent MI or cardiovascular deathCHD
Myocardial infarction
++
+
++
++
+
+
+
Raw data
+
++
Raw data
Raw data
+
Ardissino34 200200 Myocardial infarction +
Boncler31 5580 IHD Raw data
Moshfegh32 17789 Myocardial infarction +
Hooper33 110185 Myocardial infarction +
05 1 15 2 25 3 35
Subtotal 53055209
Subtotal
TOTAL
Carter14
Anderson29
Anderson29
Gardemann15
Durante-Mangoni16
Zotz17
Other controls
6790
225276
549170
10611191
4371
12491
20691889
84468603
CAD in NIDDM
Myocardial infarction
CAD
Myocardial infarction
Myocardial infarction
Myocardial infarction
++
++
++
Raw data
Raw data
++
100 (087 to 116)
114 (105 to 125)
111 (094 to 132)
Bottiger34 998340 CAD ++
110 (103 to 118)
Platelet GP IIIa Polymorphism and coronary risk a meta- analysis
Di Castelnuovo A Iacoviello L Thromb Haemost 2001
Meta-analyses of the effect of the PAI-1 4G5G polymorphism on the risk for myocardial infarction and the mean difference in PAI-1 activity e meta-regression of natural logarithm of
the MI-related OR for the PAI-1 4G variant on PAI-1 activity
Nikolopoulos GK et al Clin Chem Lab Med 2014
Chromosome map of genes reported to be causal for susceptible to and associated with coronary artery disease and myocardial infarction in the literature
gt240 000 individuals
50 genetic risk variants for CAD
Common 50 in gt50 of the population and 25 in gt75 of the population
Average OR=+18 (from 2 to 90)
Noncoding DNA sequences
3550 mechanisms independent of known risk factors
Acting Primarily Through Unknown Pathways
Discovery of the PCSK9 variant located on 1p323 has already led to the
development of a new therapeutic agent complementary to statins
CARDIoGRAMplusC4DDiscovery of Multiple Novel Genetic Risk Variants for CAD
All of the genetic variants seem to act through atherosclerosisLipids LDL HDL triglycerides hypertension Inflammation
Thrombosis ABO blood groups A and B encode for a protein (α-1-3-N-acetylgalactoseaminyltransferase associated prolonged von Willebrandplasma half life leading to thrombosis and with increased risk formyocardial infarction
Plasminogen
CARDIoGRAMplusC4DDiscovery of Multiple Novel Genetic Risk Variants for CAD
Do genetic variants increase risk prediction and classification
Prospective Studies Assessing CVD Risk Prediction Using Multiple Genetic Markers and Risk-Prediction Metrics
Di Angelantonio E Circ Cardiovasc Genet 2012
Perk J Atherosclerosis 2012
CVD prevention in clinical practice2012 European Guidelines (ESCEACPR)
Mendelian Randomization A Novel Approach to Assess Safety and Efficacy of Genetic Variants and Their Potential as Drug Targets
RCT is performed in a predetermined adequate sample size usually for a duration of 3 to 5 years
Mendelian randomization random assignment long-life effect no confounding
Loss-of-function mutation in PCSK9 LDL-C reduction by 28CAD reduction 88
Monoclonal antibody inhibiting PCSK9 confirms the results of Mendelian randomization
SNP in the endothelial lipase gene (LIPG Asn396Ser) No effect on MI risk 14 SNPs associated solely with increased HDL-C No effect on MI risk 13 SNPs associated solely with increased LDL-C Reduce AMI risk
Roberts R Circ Res 2014
CLOPIDOGREL PHARMACOGENETICS a matter for controversy
March 12 2010 FDA ldquoboxed warningrdquo on Clopidogrel
1 Antiplatelet effect of clopidogrel depends primarily on its activation by the cytochrome P450 (CYP) system
2 Patients with decreased CYP2C19 function because of genetic polymorphisms metabolize clopidogrel poorly and have higher rates of cardiovascular events after acute coronary syndrome and percutaneous coronary interventions (PCIs) than patients with normal CYP2C19 function
3 Tests are available to identify patients with genetic polymorphisms
4 Alternative treatment strategies should be considered in poor metabolizers of the drug
bull Inhibition of ADP-induced platelet aggregation by clopidogrel rangesfrom lt10 to 100
bull residual platelet reactivity after clopidogrel is associated with anincreased risk of cardiac cerebrovascular and peripheral arterial events
bull CYP2C192 polymorphism is associated with an increased risk of majoradverse CV events
bull A systematic review and critical assessment of 11 discordant meta-analyses on reduced-function CYP2C19 genotype and risk of adverseclinical outcomes in clopidogrel users concludes that personalizedantiplatelet management based on genotyping is not supported by thecurrently available evidence (Osnabrugge RL et al Gen Med 2015)
CLOPIDOGREL PHARMACOGENETICS a matter for controversy
Circulation 2010122537-557Originally published August 2 2010
The recent US Food and Drug Administration (FDA) ldquoboxed warningrdquo on clopidogrelraises important questions for practitioners and patientsThe warning addresses the need for pharmacogenomic testing to identify patientsrsquoaltered clopidogrel metabolism and thus their risk for a suboptimal clinical response toclopidogrelAlthough there is an expanding database on genetic polymorphisms that may affectclopidogrel metabolism and thus clinical outcomes there are no evidence-based dataupon which to develop specific recommendations on the role of genetic testing inroutine care nor strategies proven to improve the safetyefficacy of specificpharmacologic approaches
TAKE HOME MESSAGES
bull I risultati della genetica nella predizione del rischiocardiovascolare sono stati finora deludenti
bull Nessun test genetico ad oggi egrave utile per la predizione delrischio cardiovascolare
bull La concentrazione sui modelli di predizione ha fattoperdere di vista altre importanti potenzialitagrave degli studi digenetica
bull Lrsquoepigenetica ci sveleragrave ancora molto sulla reale funzionedel genoma
Odds ratios for cardiovascular disease comparing (PlA1A2+PlA2A2) genotypes with PlA1A1 genotype as reference group
Lower risk among PlA2 carriers Higher risk among PlA2 carriers
Study designProspective studies
Garcia-Ribes18
Abbate20
Corral 22
GrandrsquoMaison25
Laule27
Weiss4
Kekomaki21
Marian5
Carter6
Osborn7
Carter9
Hermann10
Hermann10
Samani11
Mamotte12
Scaglione13
Joven19
Senti26
Kekomaki21
Pastinen28
Subtotal
Population controls
CasesControls
100100
3873
101101
99100
977972
7168
4144
104164
101114
66167
156216
191176
428523
242235
367570
9898
250250
116136
6882
151151
10721505
Disease of case
CHD
CHD
IHD
CAD
CAD
MI or unstable angina
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Myocardial infarction
Degree ofadjustment
++
Raw data
+
++
+
++
Raw data
Raw data
++
Raw data
Bray23
Aleksic24
Ridker 8
259257
439544
374704Recurrent MI or cardiovascular deathCHD
Myocardial infarction
++
+
++
++
+
+
+
Raw data
+
++
Raw data
Raw data
+
Ardissino34 200200 Myocardial infarction +
Boncler31 5580 IHD Raw data
Moshfegh32 17789 Myocardial infarction +
Hooper33 110185 Myocardial infarction +
05 1 15 2 25 3 35
Subtotal 53055209
Subtotal
TOTAL
Carter14
Anderson29
Anderson29
Gardemann15
Durante-Mangoni16
Zotz17
Other controls
6790
225276
549170
10611191
4371
12491
20691889
84468603
CAD in NIDDM
Myocardial infarction
CAD
Myocardial infarction
Myocardial infarction
Myocardial infarction
++
++
++
Raw data
Raw data
++
100 (087 to 116)
114 (105 to 125)
111 (094 to 132)
Bottiger34 998340 CAD ++
110 (103 to 118)
Platelet GP IIIa Polymorphism and coronary risk a meta- analysis
Di Castelnuovo A Iacoviello L Thromb Haemost 2001
Meta-analyses of the effect of the PAI-1 4G5G polymorphism on the risk for myocardial infarction and the mean difference in PAI-1 activity e meta-regression of natural logarithm of
the MI-related OR for the PAI-1 4G variant on PAI-1 activity
Nikolopoulos GK et al Clin Chem Lab Med 2014
Chromosome map of genes reported to be causal for susceptible to and associated with coronary artery disease and myocardial infarction in the literature
gt240 000 individuals
50 genetic risk variants for CAD
Common 50 in gt50 of the population and 25 in gt75 of the population
Average OR=+18 (from 2 to 90)
Noncoding DNA sequences
3550 mechanisms independent of known risk factors
Acting Primarily Through Unknown Pathways
Discovery of the PCSK9 variant located on 1p323 has already led to the
development of a new therapeutic agent complementary to statins
CARDIoGRAMplusC4DDiscovery of Multiple Novel Genetic Risk Variants for CAD
All of the genetic variants seem to act through atherosclerosisLipids LDL HDL triglycerides hypertension Inflammation
Thrombosis ABO blood groups A and B encode for a protein (α-1-3-N-acetylgalactoseaminyltransferase associated prolonged von Willebrandplasma half life leading to thrombosis and with increased risk formyocardial infarction
Plasminogen
CARDIoGRAMplusC4DDiscovery of Multiple Novel Genetic Risk Variants for CAD
Do genetic variants increase risk prediction and classification
Prospective Studies Assessing CVD Risk Prediction Using Multiple Genetic Markers and Risk-Prediction Metrics
Di Angelantonio E Circ Cardiovasc Genet 2012
Perk J Atherosclerosis 2012
CVD prevention in clinical practice2012 European Guidelines (ESCEACPR)
Mendelian Randomization A Novel Approach to Assess Safety and Efficacy of Genetic Variants and Their Potential as Drug Targets
RCT is performed in a predetermined adequate sample size usually for a duration of 3 to 5 years
Mendelian randomization random assignment long-life effect no confounding
Loss-of-function mutation in PCSK9 LDL-C reduction by 28CAD reduction 88
Monoclonal antibody inhibiting PCSK9 confirms the results of Mendelian randomization
SNP in the endothelial lipase gene (LIPG Asn396Ser) No effect on MI risk 14 SNPs associated solely with increased HDL-C No effect on MI risk 13 SNPs associated solely with increased LDL-C Reduce AMI risk
Roberts R Circ Res 2014
CLOPIDOGREL PHARMACOGENETICS a matter for controversy
March 12 2010 FDA ldquoboxed warningrdquo on Clopidogrel
1 Antiplatelet effect of clopidogrel depends primarily on its activation by the cytochrome P450 (CYP) system
2 Patients with decreased CYP2C19 function because of genetic polymorphisms metabolize clopidogrel poorly and have higher rates of cardiovascular events after acute coronary syndrome and percutaneous coronary interventions (PCIs) than patients with normal CYP2C19 function
3 Tests are available to identify patients with genetic polymorphisms
4 Alternative treatment strategies should be considered in poor metabolizers of the drug
bull Inhibition of ADP-induced platelet aggregation by clopidogrel rangesfrom lt10 to 100
bull residual platelet reactivity after clopidogrel is associated with anincreased risk of cardiac cerebrovascular and peripheral arterial events
bull CYP2C192 polymorphism is associated with an increased risk of majoradverse CV events
bull A systematic review and critical assessment of 11 discordant meta-analyses on reduced-function CYP2C19 genotype and risk of adverseclinical outcomes in clopidogrel users concludes that personalizedantiplatelet management based on genotyping is not supported by thecurrently available evidence (Osnabrugge RL et al Gen Med 2015)
CLOPIDOGREL PHARMACOGENETICS a matter for controversy
Circulation 2010122537-557Originally published August 2 2010
The recent US Food and Drug Administration (FDA) ldquoboxed warningrdquo on clopidogrelraises important questions for practitioners and patientsThe warning addresses the need for pharmacogenomic testing to identify patientsrsquoaltered clopidogrel metabolism and thus their risk for a suboptimal clinical response toclopidogrelAlthough there is an expanding database on genetic polymorphisms that may affectclopidogrel metabolism and thus clinical outcomes there are no evidence-based dataupon which to develop specific recommendations on the role of genetic testing inroutine care nor strategies proven to improve the safetyefficacy of specificpharmacologic approaches
TAKE HOME MESSAGES
bull I risultati della genetica nella predizione del rischiocardiovascolare sono stati finora deludenti
bull Nessun test genetico ad oggi egrave utile per la predizione delrischio cardiovascolare
bull La concentrazione sui modelli di predizione ha fattoperdere di vista altre importanti potenzialitagrave degli studi digenetica
bull Lrsquoepigenetica ci sveleragrave ancora molto sulla reale funzionedel genoma
Meta-analyses of the effect of the PAI-1 4G5G polymorphism on the risk for myocardial infarction and the mean difference in PAI-1 activity e meta-regression of natural logarithm of
the MI-related OR for the PAI-1 4G variant on PAI-1 activity
Nikolopoulos GK et al Clin Chem Lab Med 2014
Chromosome map of genes reported to be causal for susceptible to and associated with coronary artery disease and myocardial infarction in the literature
gt240 000 individuals
50 genetic risk variants for CAD
Common 50 in gt50 of the population and 25 in gt75 of the population
Average OR=+18 (from 2 to 90)
Noncoding DNA sequences
3550 mechanisms independent of known risk factors
Acting Primarily Through Unknown Pathways
Discovery of the PCSK9 variant located on 1p323 has already led to the
development of a new therapeutic agent complementary to statins
CARDIoGRAMplusC4DDiscovery of Multiple Novel Genetic Risk Variants for CAD
All of the genetic variants seem to act through atherosclerosisLipids LDL HDL triglycerides hypertension Inflammation
Thrombosis ABO blood groups A and B encode for a protein (α-1-3-N-acetylgalactoseaminyltransferase associated prolonged von Willebrandplasma half life leading to thrombosis and with increased risk formyocardial infarction
Plasminogen
CARDIoGRAMplusC4DDiscovery of Multiple Novel Genetic Risk Variants for CAD
Do genetic variants increase risk prediction and classification
Prospective Studies Assessing CVD Risk Prediction Using Multiple Genetic Markers and Risk-Prediction Metrics
Di Angelantonio E Circ Cardiovasc Genet 2012
Perk J Atherosclerosis 2012
CVD prevention in clinical practice2012 European Guidelines (ESCEACPR)
Mendelian Randomization A Novel Approach to Assess Safety and Efficacy of Genetic Variants and Their Potential as Drug Targets
RCT is performed in a predetermined adequate sample size usually for a duration of 3 to 5 years
Mendelian randomization random assignment long-life effect no confounding
Loss-of-function mutation in PCSK9 LDL-C reduction by 28CAD reduction 88
Monoclonal antibody inhibiting PCSK9 confirms the results of Mendelian randomization
SNP in the endothelial lipase gene (LIPG Asn396Ser) No effect on MI risk 14 SNPs associated solely with increased HDL-C No effect on MI risk 13 SNPs associated solely with increased LDL-C Reduce AMI risk
Roberts R Circ Res 2014
CLOPIDOGREL PHARMACOGENETICS a matter for controversy
March 12 2010 FDA ldquoboxed warningrdquo on Clopidogrel
1 Antiplatelet effect of clopidogrel depends primarily on its activation by the cytochrome P450 (CYP) system
2 Patients with decreased CYP2C19 function because of genetic polymorphisms metabolize clopidogrel poorly and have higher rates of cardiovascular events after acute coronary syndrome and percutaneous coronary interventions (PCIs) than patients with normal CYP2C19 function
3 Tests are available to identify patients with genetic polymorphisms
4 Alternative treatment strategies should be considered in poor metabolizers of the drug
bull Inhibition of ADP-induced platelet aggregation by clopidogrel rangesfrom lt10 to 100
bull residual platelet reactivity after clopidogrel is associated with anincreased risk of cardiac cerebrovascular and peripheral arterial events
bull CYP2C192 polymorphism is associated with an increased risk of majoradverse CV events
bull A systematic review and critical assessment of 11 discordant meta-analyses on reduced-function CYP2C19 genotype and risk of adverseclinical outcomes in clopidogrel users concludes that personalizedantiplatelet management based on genotyping is not supported by thecurrently available evidence (Osnabrugge RL et al Gen Med 2015)
CLOPIDOGREL PHARMACOGENETICS a matter for controversy
Circulation 2010122537-557Originally published August 2 2010
The recent US Food and Drug Administration (FDA) ldquoboxed warningrdquo on clopidogrelraises important questions for practitioners and patientsThe warning addresses the need for pharmacogenomic testing to identify patientsrsquoaltered clopidogrel metabolism and thus their risk for a suboptimal clinical response toclopidogrelAlthough there is an expanding database on genetic polymorphisms that may affectclopidogrel metabolism and thus clinical outcomes there are no evidence-based dataupon which to develop specific recommendations on the role of genetic testing inroutine care nor strategies proven to improve the safetyefficacy of specificpharmacologic approaches
TAKE HOME MESSAGES
bull I risultati della genetica nella predizione del rischiocardiovascolare sono stati finora deludenti
bull Nessun test genetico ad oggi egrave utile per la predizione delrischio cardiovascolare
bull La concentrazione sui modelli di predizione ha fattoperdere di vista altre importanti potenzialitagrave degli studi digenetica
bull Lrsquoepigenetica ci sveleragrave ancora molto sulla reale funzionedel genoma
Chromosome map of genes reported to be causal for susceptible to and associated with coronary artery disease and myocardial infarction in the literature
gt240 000 individuals
50 genetic risk variants for CAD
Common 50 in gt50 of the population and 25 in gt75 of the population
Average OR=+18 (from 2 to 90)
Noncoding DNA sequences
3550 mechanisms independent of known risk factors
Acting Primarily Through Unknown Pathways
Discovery of the PCSK9 variant located on 1p323 has already led to the
development of a new therapeutic agent complementary to statins
CARDIoGRAMplusC4DDiscovery of Multiple Novel Genetic Risk Variants for CAD
All of the genetic variants seem to act through atherosclerosisLipids LDL HDL triglycerides hypertension Inflammation
Thrombosis ABO blood groups A and B encode for a protein (α-1-3-N-acetylgalactoseaminyltransferase associated prolonged von Willebrandplasma half life leading to thrombosis and with increased risk formyocardial infarction
Plasminogen
CARDIoGRAMplusC4DDiscovery of Multiple Novel Genetic Risk Variants for CAD
Do genetic variants increase risk prediction and classification
Prospective Studies Assessing CVD Risk Prediction Using Multiple Genetic Markers and Risk-Prediction Metrics
Di Angelantonio E Circ Cardiovasc Genet 2012
Perk J Atherosclerosis 2012
CVD prevention in clinical practice2012 European Guidelines (ESCEACPR)
Mendelian Randomization A Novel Approach to Assess Safety and Efficacy of Genetic Variants and Their Potential as Drug Targets
RCT is performed in a predetermined adequate sample size usually for a duration of 3 to 5 years
Mendelian randomization random assignment long-life effect no confounding
Loss-of-function mutation in PCSK9 LDL-C reduction by 28CAD reduction 88
Monoclonal antibody inhibiting PCSK9 confirms the results of Mendelian randomization
SNP in the endothelial lipase gene (LIPG Asn396Ser) No effect on MI risk 14 SNPs associated solely with increased HDL-C No effect on MI risk 13 SNPs associated solely with increased LDL-C Reduce AMI risk
Roberts R Circ Res 2014
CLOPIDOGREL PHARMACOGENETICS a matter for controversy
March 12 2010 FDA ldquoboxed warningrdquo on Clopidogrel
1 Antiplatelet effect of clopidogrel depends primarily on its activation by the cytochrome P450 (CYP) system
2 Patients with decreased CYP2C19 function because of genetic polymorphisms metabolize clopidogrel poorly and have higher rates of cardiovascular events after acute coronary syndrome and percutaneous coronary interventions (PCIs) than patients with normal CYP2C19 function
3 Tests are available to identify patients with genetic polymorphisms
4 Alternative treatment strategies should be considered in poor metabolizers of the drug
bull Inhibition of ADP-induced platelet aggregation by clopidogrel rangesfrom lt10 to 100
bull residual platelet reactivity after clopidogrel is associated with anincreased risk of cardiac cerebrovascular and peripheral arterial events
bull CYP2C192 polymorphism is associated with an increased risk of majoradverse CV events
bull A systematic review and critical assessment of 11 discordant meta-analyses on reduced-function CYP2C19 genotype and risk of adverseclinical outcomes in clopidogrel users concludes that personalizedantiplatelet management based on genotyping is not supported by thecurrently available evidence (Osnabrugge RL et al Gen Med 2015)
CLOPIDOGREL PHARMACOGENETICS a matter for controversy
Circulation 2010122537-557Originally published August 2 2010
The recent US Food and Drug Administration (FDA) ldquoboxed warningrdquo on clopidogrelraises important questions for practitioners and patientsThe warning addresses the need for pharmacogenomic testing to identify patientsrsquoaltered clopidogrel metabolism and thus their risk for a suboptimal clinical response toclopidogrelAlthough there is an expanding database on genetic polymorphisms that may affectclopidogrel metabolism and thus clinical outcomes there are no evidence-based dataupon which to develop specific recommendations on the role of genetic testing inroutine care nor strategies proven to improve the safetyefficacy of specificpharmacologic approaches
TAKE HOME MESSAGES
bull I risultati della genetica nella predizione del rischiocardiovascolare sono stati finora deludenti
bull Nessun test genetico ad oggi egrave utile per la predizione delrischio cardiovascolare
bull La concentrazione sui modelli di predizione ha fattoperdere di vista altre importanti potenzialitagrave degli studi digenetica
bull Lrsquoepigenetica ci sveleragrave ancora molto sulla reale funzionedel genoma
gt240 000 individuals
50 genetic risk variants for CAD
Common 50 in gt50 of the population and 25 in gt75 of the population
Average OR=+18 (from 2 to 90)
Noncoding DNA sequences
3550 mechanisms independent of known risk factors
Acting Primarily Through Unknown Pathways
Discovery of the PCSK9 variant located on 1p323 has already led to the
development of a new therapeutic agent complementary to statins
CARDIoGRAMplusC4DDiscovery of Multiple Novel Genetic Risk Variants for CAD
All of the genetic variants seem to act through atherosclerosisLipids LDL HDL triglycerides hypertension Inflammation
Thrombosis ABO blood groups A and B encode for a protein (α-1-3-N-acetylgalactoseaminyltransferase associated prolonged von Willebrandplasma half life leading to thrombosis and with increased risk formyocardial infarction
Plasminogen
CARDIoGRAMplusC4DDiscovery of Multiple Novel Genetic Risk Variants for CAD
Do genetic variants increase risk prediction and classification
Prospective Studies Assessing CVD Risk Prediction Using Multiple Genetic Markers and Risk-Prediction Metrics
Di Angelantonio E Circ Cardiovasc Genet 2012
Perk J Atherosclerosis 2012
CVD prevention in clinical practice2012 European Guidelines (ESCEACPR)
Mendelian Randomization A Novel Approach to Assess Safety and Efficacy of Genetic Variants and Their Potential as Drug Targets
RCT is performed in a predetermined adequate sample size usually for a duration of 3 to 5 years
Mendelian randomization random assignment long-life effect no confounding
Loss-of-function mutation in PCSK9 LDL-C reduction by 28CAD reduction 88
Monoclonal antibody inhibiting PCSK9 confirms the results of Mendelian randomization
SNP in the endothelial lipase gene (LIPG Asn396Ser) No effect on MI risk 14 SNPs associated solely with increased HDL-C No effect on MI risk 13 SNPs associated solely with increased LDL-C Reduce AMI risk
Roberts R Circ Res 2014
CLOPIDOGREL PHARMACOGENETICS a matter for controversy
March 12 2010 FDA ldquoboxed warningrdquo on Clopidogrel
1 Antiplatelet effect of clopidogrel depends primarily on its activation by the cytochrome P450 (CYP) system
2 Patients with decreased CYP2C19 function because of genetic polymorphisms metabolize clopidogrel poorly and have higher rates of cardiovascular events after acute coronary syndrome and percutaneous coronary interventions (PCIs) than patients with normal CYP2C19 function
3 Tests are available to identify patients with genetic polymorphisms
4 Alternative treatment strategies should be considered in poor metabolizers of the drug
bull Inhibition of ADP-induced platelet aggregation by clopidogrel rangesfrom lt10 to 100
bull residual platelet reactivity after clopidogrel is associated with anincreased risk of cardiac cerebrovascular and peripheral arterial events
bull CYP2C192 polymorphism is associated with an increased risk of majoradverse CV events
bull A systematic review and critical assessment of 11 discordant meta-analyses on reduced-function CYP2C19 genotype and risk of adverseclinical outcomes in clopidogrel users concludes that personalizedantiplatelet management based on genotyping is not supported by thecurrently available evidence (Osnabrugge RL et al Gen Med 2015)
CLOPIDOGREL PHARMACOGENETICS a matter for controversy
Circulation 2010122537-557Originally published August 2 2010
The recent US Food and Drug Administration (FDA) ldquoboxed warningrdquo on clopidogrelraises important questions for practitioners and patientsThe warning addresses the need for pharmacogenomic testing to identify patientsrsquoaltered clopidogrel metabolism and thus their risk for a suboptimal clinical response toclopidogrelAlthough there is an expanding database on genetic polymorphisms that may affectclopidogrel metabolism and thus clinical outcomes there are no evidence-based dataupon which to develop specific recommendations on the role of genetic testing inroutine care nor strategies proven to improve the safetyefficacy of specificpharmacologic approaches
TAKE HOME MESSAGES
bull I risultati della genetica nella predizione del rischiocardiovascolare sono stati finora deludenti
bull Nessun test genetico ad oggi egrave utile per la predizione delrischio cardiovascolare
bull La concentrazione sui modelli di predizione ha fattoperdere di vista altre importanti potenzialitagrave degli studi digenetica
bull Lrsquoepigenetica ci sveleragrave ancora molto sulla reale funzionedel genoma
All of the genetic variants seem to act through atherosclerosisLipids LDL HDL triglycerides hypertension Inflammation
Thrombosis ABO blood groups A and B encode for a protein (α-1-3-N-acetylgalactoseaminyltransferase associated prolonged von Willebrandplasma half life leading to thrombosis and with increased risk formyocardial infarction
Plasminogen
CARDIoGRAMplusC4DDiscovery of Multiple Novel Genetic Risk Variants for CAD
Do genetic variants increase risk prediction and classification
Prospective Studies Assessing CVD Risk Prediction Using Multiple Genetic Markers and Risk-Prediction Metrics
Di Angelantonio E Circ Cardiovasc Genet 2012
Perk J Atherosclerosis 2012
CVD prevention in clinical practice2012 European Guidelines (ESCEACPR)
Mendelian Randomization A Novel Approach to Assess Safety and Efficacy of Genetic Variants and Their Potential as Drug Targets
RCT is performed in a predetermined adequate sample size usually for a duration of 3 to 5 years
Mendelian randomization random assignment long-life effect no confounding
Loss-of-function mutation in PCSK9 LDL-C reduction by 28CAD reduction 88
Monoclonal antibody inhibiting PCSK9 confirms the results of Mendelian randomization
SNP in the endothelial lipase gene (LIPG Asn396Ser) No effect on MI risk 14 SNPs associated solely with increased HDL-C No effect on MI risk 13 SNPs associated solely with increased LDL-C Reduce AMI risk
Roberts R Circ Res 2014
CLOPIDOGREL PHARMACOGENETICS a matter for controversy
March 12 2010 FDA ldquoboxed warningrdquo on Clopidogrel
1 Antiplatelet effect of clopidogrel depends primarily on its activation by the cytochrome P450 (CYP) system
2 Patients with decreased CYP2C19 function because of genetic polymorphisms metabolize clopidogrel poorly and have higher rates of cardiovascular events after acute coronary syndrome and percutaneous coronary interventions (PCIs) than patients with normal CYP2C19 function
3 Tests are available to identify patients with genetic polymorphisms
4 Alternative treatment strategies should be considered in poor metabolizers of the drug
bull Inhibition of ADP-induced platelet aggregation by clopidogrel rangesfrom lt10 to 100
bull residual platelet reactivity after clopidogrel is associated with anincreased risk of cardiac cerebrovascular and peripheral arterial events
bull CYP2C192 polymorphism is associated with an increased risk of majoradverse CV events
bull A systematic review and critical assessment of 11 discordant meta-analyses on reduced-function CYP2C19 genotype and risk of adverseclinical outcomes in clopidogrel users concludes that personalizedantiplatelet management based on genotyping is not supported by thecurrently available evidence (Osnabrugge RL et al Gen Med 2015)
CLOPIDOGREL PHARMACOGENETICS a matter for controversy
Circulation 2010122537-557Originally published August 2 2010
The recent US Food and Drug Administration (FDA) ldquoboxed warningrdquo on clopidogrelraises important questions for practitioners and patientsThe warning addresses the need for pharmacogenomic testing to identify patientsrsquoaltered clopidogrel metabolism and thus their risk for a suboptimal clinical response toclopidogrelAlthough there is an expanding database on genetic polymorphisms that may affectclopidogrel metabolism and thus clinical outcomes there are no evidence-based dataupon which to develop specific recommendations on the role of genetic testing inroutine care nor strategies proven to improve the safetyefficacy of specificpharmacologic approaches
TAKE HOME MESSAGES
bull I risultati della genetica nella predizione del rischiocardiovascolare sono stati finora deludenti
bull Nessun test genetico ad oggi egrave utile per la predizione delrischio cardiovascolare
bull La concentrazione sui modelli di predizione ha fattoperdere di vista altre importanti potenzialitagrave degli studi digenetica
bull Lrsquoepigenetica ci sveleragrave ancora molto sulla reale funzionedel genoma
Do genetic variants increase risk prediction and classification
Prospective Studies Assessing CVD Risk Prediction Using Multiple Genetic Markers and Risk-Prediction Metrics
Di Angelantonio E Circ Cardiovasc Genet 2012
Perk J Atherosclerosis 2012
CVD prevention in clinical practice2012 European Guidelines (ESCEACPR)
Mendelian Randomization A Novel Approach to Assess Safety and Efficacy of Genetic Variants and Their Potential as Drug Targets
RCT is performed in a predetermined adequate sample size usually for a duration of 3 to 5 years
Mendelian randomization random assignment long-life effect no confounding
Loss-of-function mutation in PCSK9 LDL-C reduction by 28CAD reduction 88
Monoclonal antibody inhibiting PCSK9 confirms the results of Mendelian randomization
SNP in the endothelial lipase gene (LIPG Asn396Ser) No effect on MI risk 14 SNPs associated solely with increased HDL-C No effect on MI risk 13 SNPs associated solely with increased LDL-C Reduce AMI risk
Roberts R Circ Res 2014
CLOPIDOGREL PHARMACOGENETICS a matter for controversy
March 12 2010 FDA ldquoboxed warningrdquo on Clopidogrel
1 Antiplatelet effect of clopidogrel depends primarily on its activation by the cytochrome P450 (CYP) system
2 Patients with decreased CYP2C19 function because of genetic polymorphisms metabolize clopidogrel poorly and have higher rates of cardiovascular events after acute coronary syndrome and percutaneous coronary interventions (PCIs) than patients with normal CYP2C19 function
3 Tests are available to identify patients with genetic polymorphisms
4 Alternative treatment strategies should be considered in poor metabolizers of the drug
bull Inhibition of ADP-induced platelet aggregation by clopidogrel rangesfrom lt10 to 100
bull residual platelet reactivity after clopidogrel is associated with anincreased risk of cardiac cerebrovascular and peripheral arterial events
bull CYP2C192 polymorphism is associated with an increased risk of majoradverse CV events
bull A systematic review and critical assessment of 11 discordant meta-analyses on reduced-function CYP2C19 genotype and risk of adverseclinical outcomes in clopidogrel users concludes that personalizedantiplatelet management based on genotyping is not supported by thecurrently available evidence (Osnabrugge RL et al Gen Med 2015)
CLOPIDOGREL PHARMACOGENETICS a matter for controversy
Circulation 2010122537-557Originally published August 2 2010
The recent US Food and Drug Administration (FDA) ldquoboxed warningrdquo on clopidogrelraises important questions for practitioners and patientsThe warning addresses the need for pharmacogenomic testing to identify patientsrsquoaltered clopidogrel metabolism and thus their risk for a suboptimal clinical response toclopidogrelAlthough there is an expanding database on genetic polymorphisms that may affectclopidogrel metabolism and thus clinical outcomes there are no evidence-based dataupon which to develop specific recommendations on the role of genetic testing inroutine care nor strategies proven to improve the safetyefficacy of specificpharmacologic approaches
TAKE HOME MESSAGES
bull I risultati della genetica nella predizione del rischiocardiovascolare sono stati finora deludenti
bull Nessun test genetico ad oggi egrave utile per la predizione delrischio cardiovascolare
bull La concentrazione sui modelli di predizione ha fattoperdere di vista altre importanti potenzialitagrave degli studi digenetica
bull Lrsquoepigenetica ci sveleragrave ancora molto sulla reale funzionedel genoma
Perk J Atherosclerosis 2012
CVD prevention in clinical practice2012 European Guidelines (ESCEACPR)
Mendelian Randomization A Novel Approach to Assess Safety and Efficacy of Genetic Variants and Their Potential as Drug Targets
RCT is performed in a predetermined adequate sample size usually for a duration of 3 to 5 years
Mendelian randomization random assignment long-life effect no confounding
Loss-of-function mutation in PCSK9 LDL-C reduction by 28CAD reduction 88
Monoclonal antibody inhibiting PCSK9 confirms the results of Mendelian randomization
SNP in the endothelial lipase gene (LIPG Asn396Ser) No effect on MI risk 14 SNPs associated solely with increased HDL-C No effect on MI risk 13 SNPs associated solely with increased LDL-C Reduce AMI risk
Roberts R Circ Res 2014
CLOPIDOGREL PHARMACOGENETICS a matter for controversy
March 12 2010 FDA ldquoboxed warningrdquo on Clopidogrel
1 Antiplatelet effect of clopidogrel depends primarily on its activation by the cytochrome P450 (CYP) system
2 Patients with decreased CYP2C19 function because of genetic polymorphisms metabolize clopidogrel poorly and have higher rates of cardiovascular events after acute coronary syndrome and percutaneous coronary interventions (PCIs) than patients with normal CYP2C19 function
3 Tests are available to identify patients with genetic polymorphisms
4 Alternative treatment strategies should be considered in poor metabolizers of the drug
bull Inhibition of ADP-induced platelet aggregation by clopidogrel rangesfrom lt10 to 100
bull residual platelet reactivity after clopidogrel is associated with anincreased risk of cardiac cerebrovascular and peripheral arterial events
bull CYP2C192 polymorphism is associated with an increased risk of majoradverse CV events
bull A systematic review and critical assessment of 11 discordant meta-analyses on reduced-function CYP2C19 genotype and risk of adverseclinical outcomes in clopidogrel users concludes that personalizedantiplatelet management based on genotyping is not supported by thecurrently available evidence (Osnabrugge RL et al Gen Med 2015)
CLOPIDOGREL PHARMACOGENETICS a matter for controversy
Circulation 2010122537-557Originally published August 2 2010
The recent US Food and Drug Administration (FDA) ldquoboxed warningrdquo on clopidogrelraises important questions for practitioners and patientsThe warning addresses the need for pharmacogenomic testing to identify patientsrsquoaltered clopidogrel metabolism and thus their risk for a suboptimal clinical response toclopidogrelAlthough there is an expanding database on genetic polymorphisms that may affectclopidogrel metabolism and thus clinical outcomes there are no evidence-based dataupon which to develop specific recommendations on the role of genetic testing inroutine care nor strategies proven to improve the safetyefficacy of specificpharmacologic approaches
TAKE HOME MESSAGES
bull I risultati della genetica nella predizione del rischiocardiovascolare sono stati finora deludenti
bull Nessun test genetico ad oggi egrave utile per la predizione delrischio cardiovascolare
bull La concentrazione sui modelli di predizione ha fattoperdere di vista altre importanti potenzialitagrave degli studi digenetica
bull Lrsquoepigenetica ci sveleragrave ancora molto sulla reale funzionedel genoma
Mendelian Randomization A Novel Approach to Assess Safety and Efficacy of Genetic Variants and Their Potential as Drug Targets
RCT is performed in a predetermined adequate sample size usually for a duration of 3 to 5 years
Mendelian randomization random assignment long-life effect no confounding
Loss-of-function mutation in PCSK9 LDL-C reduction by 28CAD reduction 88
Monoclonal antibody inhibiting PCSK9 confirms the results of Mendelian randomization
SNP in the endothelial lipase gene (LIPG Asn396Ser) No effect on MI risk 14 SNPs associated solely with increased HDL-C No effect on MI risk 13 SNPs associated solely with increased LDL-C Reduce AMI risk
Roberts R Circ Res 2014
CLOPIDOGREL PHARMACOGENETICS a matter for controversy
March 12 2010 FDA ldquoboxed warningrdquo on Clopidogrel
1 Antiplatelet effect of clopidogrel depends primarily on its activation by the cytochrome P450 (CYP) system
2 Patients with decreased CYP2C19 function because of genetic polymorphisms metabolize clopidogrel poorly and have higher rates of cardiovascular events after acute coronary syndrome and percutaneous coronary interventions (PCIs) than patients with normal CYP2C19 function
3 Tests are available to identify patients with genetic polymorphisms
4 Alternative treatment strategies should be considered in poor metabolizers of the drug
bull Inhibition of ADP-induced platelet aggregation by clopidogrel rangesfrom lt10 to 100
bull residual platelet reactivity after clopidogrel is associated with anincreased risk of cardiac cerebrovascular and peripheral arterial events
bull CYP2C192 polymorphism is associated with an increased risk of majoradverse CV events
bull A systematic review and critical assessment of 11 discordant meta-analyses on reduced-function CYP2C19 genotype and risk of adverseclinical outcomes in clopidogrel users concludes that personalizedantiplatelet management based on genotyping is not supported by thecurrently available evidence (Osnabrugge RL et al Gen Med 2015)
CLOPIDOGREL PHARMACOGENETICS a matter for controversy
Circulation 2010122537-557Originally published August 2 2010
The recent US Food and Drug Administration (FDA) ldquoboxed warningrdquo on clopidogrelraises important questions for practitioners and patientsThe warning addresses the need for pharmacogenomic testing to identify patientsrsquoaltered clopidogrel metabolism and thus their risk for a suboptimal clinical response toclopidogrelAlthough there is an expanding database on genetic polymorphisms that may affectclopidogrel metabolism and thus clinical outcomes there are no evidence-based dataupon which to develop specific recommendations on the role of genetic testing inroutine care nor strategies proven to improve the safetyefficacy of specificpharmacologic approaches
TAKE HOME MESSAGES
bull I risultati della genetica nella predizione del rischiocardiovascolare sono stati finora deludenti
bull Nessun test genetico ad oggi egrave utile per la predizione delrischio cardiovascolare
bull La concentrazione sui modelli di predizione ha fattoperdere di vista altre importanti potenzialitagrave degli studi digenetica
bull Lrsquoepigenetica ci sveleragrave ancora molto sulla reale funzionedel genoma
CLOPIDOGREL PHARMACOGENETICS a matter for controversy
March 12 2010 FDA ldquoboxed warningrdquo on Clopidogrel
1 Antiplatelet effect of clopidogrel depends primarily on its activation by the cytochrome P450 (CYP) system
2 Patients with decreased CYP2C19 function because of genetic polymorphisms metabolize clopidogrel poorly and have higher rates of cardiovascular events after acute coronary syndrome and percutaneous coronary interventions (PCIs) than patients with normal CYP2C19 function
3 Tests are available to identify patients with genetic polymorphisms
4 Alternative treatment strategies should be considered in poor metabolizers of the drug
bull Inhibition of ADP-induced platelet aggregation by clopidogrel rangesfrom lt10 to 100
bull residual platelet reactivity after clopidogrel is associated with anincreased risk of cardiac cerebrovascular and peripheral arterial events
bull CYP2C192 polymorphism is associated with an increased risk of majoradverse CV events
bull A systematic review and critical assessment of 11 discordant meta-analyses on reduced-function CYP2C19 genotype and risk of adverseclinical outcomes in clopidogrel users concludes that personalizedantiplatelet management based on genotyping is not supported by thecurrently available evidence (Osnabrugge RL et al Gen Med 2015)
CLOPIDOGREL PHARMACOGENETICS a matter for controversy
Circulation 2010122537-557Originally published August 2 2010
The recent US Food and Drug Administration (FDA) ldquoboxed warningrdquo on clopidogrelraises important questions for practitioners and patientsThe warning addresses the need for pharmacogenomic testing to identify patientsrsquoaltered clopidogrel metabolism and thus their risk for a suboptimal clinical response toclopidogrelAlthough there is an expanding database on genetic polymorphisms that may affectclopidogrel metabolism and thus clinical outcomes there are no evidence-based dataupon which to develop specific recommendations on the role of genetic testing inroutine care nor strategies proven to improve the safetyefficacy of specificpharmacologic approaches
TAKE HOME MESSAGES
bull I risultati della genetica nella predizione del rischiocardiovascolare sono stati finora deludenti
bull Nessun test genetico ad oggi egrave utile per la predizione delrischio cardiovascolare
bull La concentrazione sui modelli di predizione ha fattoperdere di vista altre importanti potenzialitagrave degli studi digenetica
bull Lrsquoepigenetica ci sveleragrave ancora molto sulla reale funzionedel genoma
bull Inhibition of ADP-induced platelet aggregation by clopidogrel rangesfrom lt10 to 100
bull residual platelet reactivity after clopidogrel is associated with anincreased risk of cardiac cerebrovascular and peripheral arterial events
bull CYP2C192 polymorphism is associated with an increased risk of majoradverse CV events
bull A systematic review and critical assessment of 11 discordant meta-analyses on reduced-function CYP2C19 genotype and risk of adverseclinical outcomes in clopidogrel users concludes that personalizedantiplatelet management based on genotyping is not supported by thecurrently available evidence (Osnabrugge RL et al Gen Med 2015)
CLOPIDOGREL PHARMACOGENETICS a matter for controversy
Circulation 2010122537-557Originally published August 2 2010
The recent US Food and Drug Administration (FDA) ldquoboxed warningrdquo on clopidogrelraises important questions for practitioners and patientsThe warning addresses the need for pharmacogenomic testing to identify patientsrsquoaltered clopidogrel metabolism and thus their risk for a suboptimal clinical response toclopidogrelAlthough there is an expanding database on genetic polymorphisms that may affectclopidogrel metabolism and thus clinical outcomes there are no evidence-based dataupon which to develop specific recommendations on the role of genetic testing inroutine care nor strategies proven to improve the safetyefficacy of specificpharmacologic approaches
TAKE HOME MESSAGES
bull I risultati della genetica nella predizione del rischiocardiovascolare sono stati finora deludenti
bull Nessun test genetico ad oggi egrave utile per la predizione delrischio cardiovascolare
bull La concentrazione sui modelli di predizione ha fattoperdere di vista altre importanti potenzialitagrave degli studi digenetica
bull Lrsquoepigenetica ci sveleragrave ancora molto sulla reale funzionedel genoma
Circulation 2010122537-557Originally published August 2 2010
The recent US Food and Drug Administration (FDA) ldquoboxed warningrdquo on clopidogrelraises important questions for practitioners and patientsThe warning addresses the need for pharmacogenomic testing to identify patientsrsquoaltered clopidogrel metabolism and thus their risk for a suboptimal clinical response toclopidogrelAlthough there is an expanding database on genetic polymorphisms that may affectclopidogrel metabolism and thus clinical outcomes there are no evidence-based dataupon which to develop specific recommendations on the role of genetic testing inroutine care nor strategies proven to improve the safetyefficacy of specificpharmacologic approaches
TAKE HOME MESSAGES
bull I risultati della genetica nella predizione del rischiocardiovascolare sono stati finora deludenti
bull Nessun test genetico ad oggi egrave utile per la predizione delrischio cardiovascolare
bull La concentrazione sui modelli di predizione ha fattoperdere di vista altre importanti potenzialitagrave degli studi digenetica
bull Lrsquoepigenetica ci sveleragrave ancora molto sulla reale funzionedel genoma
TAKE HOME MESSAGES
bull I risultati della genetica nella predizione del rischiocardiovascolare sono stati finora deludenti
bull Nessun test genetico ad oggi egrave utile per la predizione delrischio cardiovascolare
bull La concentrazione sui modelli di predizione ha fattoperdere di vista altre importanti potenzialitagrave degli studi digenetica
bull Lrsquoepigenetica ci sveleragrave ancora molto sulla reale funzionedel genoma
