Genetic determinants of lipids: concordance and discordance ......Loss-of-Function PCSK9 Mutations...
Transcript of Genetic determinants of lipids: concordance and discordance ......Loss-of-Function PCSK9 Mutations...
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Genetic determinants of lipids: concordance and discordance with CV risk
Current Opinion in Lipidology 2011, 22:113–122
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LDL Receptor Function and Life Cycle
For illustration purposes only
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The Role of PCSK-9 in the Regulation of LDL Receptor
ExpressionFor illustration purposes only
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Loss-of-Function PCSK9 Mutations in AA Are Associated with Low LDL-C and Low
Prevalence of CHD Events
Adapted from Cohen JC. N Engl J Med 2006;354:1264-72 ARIC=Atherosclerosis Risk in the Community
30
20
10
0
0 50 100 150 200 250 300
No Nonsense Mutation
(N = 3278)
50th
Percentile
Fre
quen
cy
(%)
Mean 138 mg/dL
0 50 100 150 200 250 300
30
20
10
0Plasma LDL Cholesterol in Black
Subjects (mg/dL)
PCSK9142x or PCSK9679X
(N=85) Mean 100 mg/dL(-28%)
9.7%
PCSK9142x or PCSK9679X
No Yes
12
8
4
01.2%
Cor
onar
y H
eart
Dis
ease
(%
)
88% reduction in the risk of CHD events during 15-year follow-up
88%
![Page 5: Genetic determinants of lipids: concordance and discordance ......Loss-of-Function PCSK9 Mutations in AA Are Associated with Low LDL-C and Low Prevalence of CHD Events Adapted from](https://reader035.fdocuments.in/reader035/viewer/2022070213/610dc730357fab798662011b/html5/thumbnails/5.jpg)
Male
SBP 150
Col/HDL 5
Smoker
Diabetic
http://qrisk.org
JBS3
Lifetime cardiovascular risk
The lower the better
or
The earlier the better
15 yrs
5 yrs
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Impact of Alirocumabon LDL Receptor Expression
66
For illustration purposes only
![Page 7: Genetic determinants of lipids: concordance and discordance ......Loss-of-Function PCSK9 Mutations in AA Are Associated with Low LDL-C and Low Prevalence of CHD Events Adapted from](https://reader035.fdocuments.in/reader035/viewer/2022070213/610dc730357fab798662011b/html5/thumbnails/7.jpg)
McKenney JM et al. J Am Coll Cardiol. 2012;59:2344–2353
![Page 8: Genetic determinants of lipids: concordance and discordance ......Loss-of-Function PCSK9 Mutations in AA Are Associated with Low LDL-C and Low Prevalence of CHD Events Adapted from](https://reader035.fdocuments.in/reader035/viewer/2022070213/610dc730357fab798662011b/html5/thumbnails/8.jpg)
8Lancet Published Online October 3, 2013http://dx.doi.org/10.1016/ S0140-6736(13)61914-5
![Page 9: Genetic determinants of lipids: concordance and discordance ......Loss-of-Function PCSK9 Mutations in AA Are Associated with Low LDL-C and Low Prevalence of CHD Events Adapted from](https://reader035.fdocuments.in/reader035/viewer/2022070213/610dc730357fab798662011b/html5/thumbnails/9.jpg)
9Lancet Published Online October 3, 2013http://dx.doi.org/10.1016/ S0140-6736(13)61914-5
![Page 10: Genetic determinants of lipids: concordance and discordance ......Loss-of-Function PCSK9 Mutations in AA Are Associated with Low LDL-C and Low Prevalence of CHD Events Adapted from](https://reader035.fdocuments.in/reader035/viewer/2022070213/610dc730357fab798662011b/html5/thumbnails/10.jpg)
FACTORES DE RIESGO Y PREVENCIÓN
¿Qué hemos aprendido? • HTA
– Reducción de ictus / IAM
– Independiente del fármaco / Suelo / Efecto J
• Dislipemia– Reduccion ictus / IAM– LDL en la diana ¡¡¡ Estatinas!!!
– HDL?– Otros tratamientos para LDL
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CGH 2011
![Page 12: Genetic determinants of lipids: concordance and discordance ......Loss-of-Function PCSK9 Mutations in AA Are Associated with Low LDL-C and Low Prevalence of CHD Events Adapted from](https://reader035.fdocuments.in/reader035/viewer/2022070213/610dc730357fab798662011b/html5/thumbnails/12.jpg)
Statin Use and Reduced Cancer-Related Mortality
N Engl J Med 2012; 367:1792-1802
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Doy you solemnly
swear to prescribe
statins,
all statins
and nothing but
statins
2013 cholesterol
guidelines
Yes,
I do?
Court
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¿hipercolesterolemia o
hipoestatinemia?
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Atorvastatin increases expression of NPC1L1 & PCSK9 in hyperlipidemic men
Journal of Lipid ResearchMarch 2011 vol. 52 no. 3 558-565
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Estudio SHARP (Study of Heart and Renal Protection )
The effects of lowering LDLcholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of
Heartand Renal Protection): a randomizedplacebo-controlled trial .
Lancet 2011; 377: 2181–92
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SHARP: Diseño
Lancet 2011; 377: 2181–92
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0 1 2 3 4 5 Años de seguimiento
0
5
10
15
20
25
Por
cent
aje
deev
ento
s(%
)
Ratio de riesgo 0.83 (0.74 – 0.94)
Logrank 2P=0.0022
Placebo
Eze/simv
SHARP: Principales eventos isqu émicos
Lancet 2011; 377: 2181–92
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