genetics of lipoprotein disorders
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Genetics of Lipoprotein Disorders. Jacques Genest MD Cardiovascular Genetics Laboratory McGill University Health Center. Epidemiology and Lipoprotein Metabolism Genetics of Lipoprotein Disorders Disorders of HDL; Diagnosis and Treatment. - PowerPoint PPT PresentationTRANSCRIPT
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Genetics of Lipoprotein Disorders
Jacques Genest MD
Cardiovascular Genetics Laboratory
McGill University Health Center
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Human Biochemical Genetics 2008Genetics of Lipoprotein Disorders
Epidemiology and Lipoprotein Metabolism
Genetics of Lipoprotein Disorders
Disorders of HDL; Diagnosis and Treatment
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Epidemiology of Cardiovascular Diseases
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Libby P. Inflammation and atherosclerosis. Nature 2002;420:868
Atherosclerosis
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Risk Factors for CAD
Cigarette Hypertension LDL-cholesterol (apo B) HDL-cholesterol Diabetes Age Atherosclerosis
Circulation 2000;101:111-116
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Risk Factors and risk of MI
Smoking
Diabetes
Hypertension
Abd. Obesity
Psychol index
Fruits/Veg
Exercise (-)
Alcohol (-)
Apo B / Apo AI
WomenMen
Yusuf S et al. INTERHEART Lancet 2004;364:937-952
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Apo B / AI Ratio (Chol/HDL-C)
Yusuf S et al. INTERHEART Lancet 2004;364:937-952
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Risk of MI and apo B / AI Ratio
Overall
Western Europe
Central Europe
Middle East
Africa
South Asia
China / HK
SE Asia
ANZ
South America
North America
Yusuf S et al. INTERHEART Lancet 2004;364:937-952
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Genetics and CAD
Genetics of CAD are complex. Family Hx of premature CAD increases
risk > 2.0 fold <55 for father; <65 for mother Corrected for other RF
Lloyd-Jones D et al. Lancet 2004;291:2204
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Global Mortality 2020
• 1. Ischemic Heart Disease• 2. Cerebrovascular Disease• 3. COPD • 4. Diarrheal Diseases• 5. Lung Cancer• 6. Accidents • 7. Tuberculosis (without HIV)• 8. Perinatal Disorders • 9. Lower Resp Infections
• 10. Suicide
Lancet 1997;9061
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Disability-Adjusted Life Years, 2020
• 1. Ischemic Heart Disease• 2. Unipolar Major depression• 3. Road-Traffic accidents• 4. Cerebrovascular Disease• 5. COPD• 6. Lower Resp Infections • 7. Tuberculosis• 8. War Injuries• 9. Diarrheal Diseases
• 10. HIV
Lancet 1997;349:1498
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Lipoprotein Metabolism
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Within intestinal cells (and other body cells) some of the absorbed cholesterol is esterified to fatty acids, forming cholesteryl esters. (R = fatty acid chain)
The enzyme that catalyzes cholesterol esterification in plasma is LCAT (Lecithin:Cholesterol Acyl Transferase) and intra-
cellularly, ACAT (Acyl CoA: Cholesterol Acyl Transferase).
R C O
O
C holesteryl E ster
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HO
Cholesterol
O
Cholesteryl Ester
LCAT
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H 2C
HC
H 2C
O
O
O
C R 1
O
C
C R 3
OR 2
O
O C R 3
OH 2C
HC
H 2C
O
O
OH
C R 1
O
C R 2
OH 2O
triac ylg lycero l 1 ,2 -d iac ylg lyce ro l fa tty ac id
Lipoprotein Lipase
Triglycerides
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Phospholipids
CH2
O
O=P-O
O
CH2-CH-CH2
O O
O=C C=O
R2
CH3-N-CH3
CH2
CH3
R1
Choline
Phosphate
Glycerol
Acyl Chains(Fatty acids)
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Phospholipid
Cholesteryl ester
Apolipoprotein
Triglyceride
Cholesterol
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Lipoproteins differ in their contents of proteins and lipids. They are classified based on density.
Chylomicron (largest; lowest in density due to high lipid/protein ratio; highest % weight triacylglycerols)
VLDL (very low density lipoprotein; 2nd highest in triacylglycerols as % of weight)
IDL (intermediate density lipoprotein)
LDL (low density lipoprotein, highest in cholesteryl esters as % of weight)
HDL (high density lipoprotein; highest in density due to high protein/lipid ratio)
Lipoproteins
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CHYLOMICRONRENNANTS
VLDL
IDL
LDL
HDL2
HDL3
0.95-
1.006-
1.02-
1.06-
1.10-
1.20-
Den
sity
(g
/ml)
Diameter (nm)
5 10 20 40 60 80 1000
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Intestine
Liver
Lipoprotein Metabolism
EndogenousPathway
FFA
VLDL
ApoA-I, A-IIApoC-I, C-II, C-IIIPhospholipidsFree cholesterol
ApoA-I, A-IIApoC-I, C-II, C-IIIPhospholipidsFree cholesterol
NascentHDL
PeripheralCells
FFA
FreeCholesterol
HL
Liver
LCAT
HL SteroidogenicCells
ExogenousPathwayChylomicron
ChyloRemnant
HDL2 LDL
IDL
LPL
LPL
CETPPLTP
CE
Tg
HDL3
3Liver
HL
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Human Biochemical Genetics 2008Genetics of Lipoprotein Disorders
Epidemiology and Lipoprotein Metabolism
Genetics of Lipoprotein Disorders
Disorders of HDL; Diagnosis and Treatment
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Case 1
• 34 yo Man• Admitted to ED with
abdominal pain• Plasma lactescent• Triglycerides 154
mmol/L
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Intestine
Liver
Lipoprotein Lipase
EndogenousPathway
FFA
VLDL
ApoA-I, A-IIApoC-I, C-II, C-IIIPhospholipidsFree cholesterol
ApoA-I, A-IIApoC-I, C-II, C-IIIPhospholipidsFree cholesterol
NascentHDL
PeripheralCells
FFA
FreeCholesterol
HL
Liver
LCAT
HL SteroidogenicCells
ExogenousPathwayChylomicron
ChyloRemnant
HDL2 LDL
IDL
LPL
LPL
CETPPLTP
CE
Tg
HDL3
3Liver
HL
x
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Lipoprotein Lipase Deficiency(Type I)
• Chylomicrons:• Intestinal lipoprotein,
containing mostly triglycerides.
• Rapidly degraded by lipoprotein lipase in vasculature
• Deficiency produces Type I Hyperlipidemia
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Type I Hyperlipoproteinemia(Familial Hyperchylomicronemia)
• Autosomal recessive transmission.• Third most frequent cause of pancreatitis• Dietary fats, alcohol, estrogens can cause
massive (>100 mmol/L) hypertriglyceridemia• Gene frequency ~1:80 in Lac St-Jean• Heterozygotes present with delayed postprandial
triglyceride clearance• Possibly at increased risk of CAD
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Lipoprotein Lipase Gene 8q
LPL gene 8q22
Asp9Asn Glu188Gly Ans291Ser Ser447Ter
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Lipoprotein Lipase Gene and CAD
LPL Meta-analysis 29 studies, 20 903 subjects
Wittrup HH et al. Circulation 1999;99:2901
Trig HDL-C OR for CAD (95% CI)
Gly188Glu +78% -0.25 mmol/L 4.9 (1.2-19.6)
Asp9Asn +20% -0.08 mmol/L 1.4 (0.8-2.4)
Asn291Ser +31% -0.12 mmol/L 1.2 (0.9-1.5)
Ser447Ter -8% +0.04 mmol/L 0.8 (0.7-1.0)
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Case 2
• Familial Hypercholesterolemia
• Heterozygous• Frequency 1:500 (up
to 1:80 in Lac St-Jean)• LDL-Receptor gene
defect• LDL-C 2x ULN
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Familial Hypercholesterolemia
• Most frequent genetic disorder associated with premature CAD (3-5%) of patients.
• LDL-receptor defects underlie the majority of cases
• Defective apolipoprotein B (ligand for the LDL-R) • Third genetic locus identified• CAD develops in men 35-55 years, in women 45-
65 years.• Respond to statins (+resins) (+ezetimibe)
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Intestine
Liver
Lipoprotein Metabolism LDL-R
EndogenousPathway
FFA
VLDL
ApoA-I, A-IIApoC-I, C-II, C-IIIPhospholipidsFree cholesterol
ApoA-I, A-IIApoC-I, C-II, C-IIIPhospholipidsFree cholesterol
NascentHDL
PeripheralCells
FFA
FreeCholesterol
HL
Liver
LCAT
HL SteroidogenicCells
ExogenousPathwayChylomicron
ChyloRemnant
HDL2 LDL
IDL
LPL
LPL
CETPPLTP
CE
Tg
HDL3
3Liver
HL
X
X
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Lipoprotein assembly and secretion
Cholesterol
Fatty acids Cholesteryl esters
VLDL
Bile acids
LDL-R LDL
ApoBVLDL-RLRP
Endosome
sER
HMG CoA Red ACAT
VLDL IDL
Hepatic Cell
ApoB
ApoEApoB
ApoE
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Intestine
Liver
Lipoprotein Metabolism FH HMZ
EndogenousPathway
FFA
VLDL
ApoA-I, A-IIApoC-I, C-II, C-IIIPhospholipidsFree cholesterol
ApoA-I, A-IIApoC-I, C-II, C-IIIPhospholipidsFree cholesterol
NascentHDL
PeripheralCells
FFA
FreeCholesterol
HL
Liver
LCAT
HL SteroidogenicCells
ExogenousPathwayChylomicron
ChyloRemnant
HDL2 LDL
IDL
LPL
LPL
CETPPLTP
CE
Tg
HDL3
3Liver
HL
X
X
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Familial Hypercholesterolemia
LDL-R gene (19p13) (Familial Hypercholesterolemia) LDL-Receptor Defects
Apo B gene (2q23) (Familial Defective apo B) Apolipoprotein B Mutations
PCSK9 (proprotein convertase subtilisin/kexin type 9) (1p32) Autosomal Dominant Hypercholesterolemia
ARH gene (1p35-36.1) (Autosomal Recessive Hypercholesterolemia) LDL-R internalization defect
LDL Overproduction Defects (1q21)(Familial Combined Hyperlipidemia)
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Molecular Causes of Familial Hypercholesterolemia (FH)
LDL-R: Primary familial hypercholesterolemia
ARH:Autosomal recessive familial Hypercholesterolemia
PCSK9:Proprotein convertase subtilisin/kexin type 9
ApoB:Familial defective Apo B
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LDL-R Mutations in FH
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LDL-R Pathway Animation
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SIMVASTATIN: MAJOR VASCULAR EVENTSSIMVASTATIN: MAJOR VASCULAR EVENTS
Vascular eventVascular event
Total CHDTotal CHD 914914 1,2341,234
Total strokeTotal stroke 456456 613613
RevascularisationRevascularisation 926926 1,1851,185
ANY OF ABOVEANY OF ABOVE 2,0422,042 2,6062,606(19.9%)(19.9%) (25.4%)(25.4%)
24% SE 2.6 reduction24% SE 2.6 reduction(2P<0.00001)(2P<0.00001)
0.40.4 0.60.6 0.80.8 1.01.0 1.21.2 1.41.4
Risk ratio and 95% CIRisk ratio and 95% CIStatin(n=10,269)
Statin(n=10,269)
Placebo(n=10,267)
Placebo(n=10,267)
Statin betterStatin better Statin worseStatin worse
HPS Heart Protection Study
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Cholesterol treatment Trialists(Lancet 2005;366:1267)
Reduction in LDL-C (mmol/L)
Pro
po
rtio
nal
red
uct
ion
in
eve
nt
rate
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Mea
n L
DL
-C (
mm
ol/
L)
Time (years)
+ Atorvastatin
Apheresis19
92
1993
1994
1995
1996
1997
1998
400
300
200
100
Mea
n L
DL
-C (
mg
/dL
)500
1999
LDL Apheresis
Genest J. NEJM 1999;341:490
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Case 3 Type III HLP(dysbetalipoproteinemia)
• Type III HLP• Rare• Tuberous xanthomas
and palmar xanthomas• Diagnosis is made on
clinical grounds,• Lipoprotein ultra-
centrifugation• Apo E phenotype or
genotype
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Type III Hyperlipoproteinemia
• Type III HLP• Dysbetalipoproteinemia, Remnant disease
• Apo E2/2 genotype + one other “hit” (unknown for the most part)
• Responsive to diet and drug therapy• Accumulation of remnant lipoproteins because
of abnormal uptake by the liver
• Apo E4/4 associated with Alzheimer’s disease age of onset
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Intestine
Liver
Lipoprotein Metabolism Type III
EndogenousPathway
FFA
VLDL
ApoA-I, A-IIApoC-I, C-II, C-IIIPhospholipidsFree cholesterol
ApoA-I, A-IIApoC-I, C-II, C-IIIPhospholipidsFree cholesterol
NascentHDL
PeripheralCells
FFA
FreeCholesterol
HL
Liver
LCAT
HL SteroidogenicCells
ExogenousPathwayChylomicron
ChyloRemnant
HDL2 LDL
IDL
LPL
LPL
CETPPLTP
CE
Tg
HDL3
3Liver
HL
Apo E2/2
Apo E2/2
X
X