Genetics of Lipoprotein Disorders
Jacques Genest MD
Cardiovascular Genetics Laboratory
McGill University Health Center
Human Biochemical Genetics 2008Genetics of Lipoprotein Disorders
Epidemiology and Lipoprotein Metabolism
Genetics of Lipoprotein Disorders
Disorders of HDL; Diagnosis and Treatment
Epidemiology of Cardiovascular Diseases
Libby P. Inflammation and atherosclerosis. Nature 2002;420:868
Atherosclerosis
Risk Factors for CAD
Cigarette Hypertension LDL-cholesterol (apo B) HDL-cholesterol Diabetes Age Atherosclerosis
Circulation 2000;101:111-116
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
Apo B / AI Ratio (Chol/HDL-C)
Yusuf S et al. INTERHEART Lancet 2004;364:937-952
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
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
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
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
Lipoprotein Metabolism
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
HO
Cholesterol
O
Cholesteryl Ester
LCAT
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
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)
Phospholipid
Cholesteryl ester
Apolipoprotein
Triglyceride
Cholesterol
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
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
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
Human Biochemical Genetics 2008Genetics of Lipoprotein Disorders
Epidemiology and Lipoprotein Metabolism
Genetics of Lipoprotein Disorders
Disorders of HDL; Diagnosis and Treatment
Case 1
• 34 yo Man• Admitted to ED with
abdominal pain• Plasma lactescent• Triglycerides 154
mmol/L
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
Lipoprotein Lipase Deficiency(Type I)
• Chylomicrons:• Intestinal lipoprotein,
containing mostly triglycerides.
• Rapidly degraded by lipoprotein lipase in vasculature
• Deficiency produces Type I Hyperlipidemia
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
Lipoprotein Lipase Gene 8q
LPL gene 8q22
Asp9Asn Glu188Gly Ans291Ser Ser447Ter
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)
Case 2
• Familial Hypercholesterolemia
• Heterozygous• Frequency 1:500 (up
to 1:80 in Lac St-Jean)• LDL-Receptor gene
defect• LDL-C 2x ULN
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)
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
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
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
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)
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
LDL-R Mutations in FH
LDL-R Pathway Animation
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
Cholesterol treatment Trialists(Lancet 2005;366:1267)
Reduction in LDL-C (mmol/L)
Pro
po
rtio
nal
red
uct
ion
in
eve
nt
rate
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
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
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
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
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