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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 2008 Genetics 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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Atherosclerosis Libby P. Inflammation and atherosclerosis. Nature 2002;420:868
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Risk Factors for CAD Cigarette Hypertension LDL-cholesterol (apo B)
HDL-cholesterol Diabetes Age Atherosclerosis Circulation 2000;101:
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Risk Factors and risk of MI
Women Men Smoking Diabetes Hypertension Abd. Obesity Psychol index Fruits/Veg Exercise (-) Alcohol (-) Apo B / Apo AI Yusuf S et al. INTERHEART Lancet 2004;364:
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Apo B / AI Ratio (Chol/HDL-C)
Yusuf S et al. INTERHEART Lancet 2004;364:
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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:
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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).
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H O Cholesterol O Cholesteryl Ester LCAT
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Triglycerides Lipoprotein Lipase
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Phospholipids Choline Phosphate Glycerol Acyl Chains (Fatty acids) CH3
O=P-O CH2-CH-CH2 O=C C=O R2 CH3-N-CH3 CH3 R1 Choline Phosphate Glycerol Acyl Chains (Fatty acids)
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Apolipoprotein Phospholipid Triglyceride Cholesterol Cholesteryl ester
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Lipoproteins 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)
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Density (g/ml) Diameter (nm) 0.95- 1.006- 1.02- 1.06- 1.10- 1.20- 5 10
VLDL 1.006- IDL CHYLOMICRON RENNANTS 1.02- Density (g/ml) LDL 1.06- HDL2 1.10- HDL3 1.20- 5 10 20 40 60 80 1000 Diameter (nm)
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Lipoprotein Metabolism
FFA Liver HL LPL Exogenous Pathway Chylo Remnant Chylomicron Peripheral Cells Free Cholesterol ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol Intestine HL Steroidogenic Cells LCAT Nascent HDL HDL3 HDL2 LDL Liver ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol CETP PLTP Tg Endogenous Pathway CE Liver 3 VLDL LPL HL IDL FFA
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Human Biochemical Genetics 2008 Genetics 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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x Lipoprotein Lipase FFA Liver HL LPL Exogenous Pathway Peripheral
Chylo Remnant Chylomicron Peripheral Cells Free Cholesterol ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol Intestine HL Steroidogenic Cells LCAT Nascent HDL HDL3 HDL2 LDL Liver ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol CETP PLTP Tg Endogenous Pathway CE Liver 3 HL VLDL LPL IDL FFA
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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, subjects Wittrup HH et al. Circulation 1999;99:2901
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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 years, in women years. Respond to statins (+resins) (+ezetimibe)
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Lipoprotein Metabolism LDL-R
FFA Liver HL LPL Exogenous Pathway Chylo Remnant Chylomicron Peripheral Cells Free Cholesterol ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol Intestine X HL Steroidogenic Cells LCAT Nascent HDL HDL3 HDL2 LDL Liver X ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol CETP PLTP Tg Endogenous Pathway CE Liver 3 VLDL LPL HL IDL FFA
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Cholesterol Hepatic Cell VLDL-R LRP LDL-R IDL VLDL ApoB ApoE ApoB ApoE
Endosome VLDL-R LRP ApoB LDL-R LDL Cholesterol HMG CoA Red ACAT Cholesteryl esters Fatty acids sER Lipoprotein assembly and secretion Bile acids VLDL Hepatic Cell
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Lipoprotein Metabolism FH HMZ
FFA Liver HL LPL Exogenous Pathway Chylo Remnant Chylomicron Peripheral Cells Free Cholesterol ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol Intestine X HL Steroidogenic Cells LCAT Nascent HDL HDL3 HDL2 LDL Liver X ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol CETP PLTP Tg Endogenous Pathway CE Liver 3 VLDL LPL HL IDL FFA
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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 (1p ) (Autosomal Recessive Hypercholesterolemia) LDL-R internalization defect LDL Overproduction Defects (1q21)(Familial Combined Hyperlipidemia)
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Molecular Causes of Familial Hypercholesterolemia (FH)
ApoB: Familial defective Apo B LDL-R: Primary familial hypercholesterolemia ARH: Autosomal recessive familial Hypercholesterolemia PCSK9: Proprotein convertase subtilisin/kexin type 9
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LDL-R Mutations in FH
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LDL-R Pathway Animation
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SIMVASTATIN: MAJOR VASCULAR EVENTS
HPS Heart Protection Study SIMVASTATIN: MAJOR VASCULAR EVENTS Vascular event Statin (n=10,269) Placebo (n=10,267) Risk ratio and 95% CI Total CHD 914 1,234 Total stroke 456 613 Revascularisation 926 1,185 The study provides definite evidence that cholesterol-lowering with a statin reduces the risk not just of heart attacks but also of strokes and of both coronary and non-coronary revascularisation procedures (as well as the risk of being hospitalised for worsening angina). As for the effects of non-compliance on the estimated lipid reductions (see above), these reductions in major vascular events of about one-quarter in intention-to-treat analyses with two-thirds compliance would translate into reductions in vascular disease risk of at least one-third with full compliance to 40mg daily simvastatin. ANY OF ABOVE 2,042 2,606 24% SE 2.6 reduction (19.9%) (25.4%) (2P< ) 0.4 0.6 0.8 1.0 1.2 1.4 Statin better Statin worse
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Cholesterol treatment Trialists (Lancet 2005;366:1267)
Proportional reduction in event rate Reduction in LDL-C (mmol/L)
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LDL Apheresis + Atorvastatin Mean LDL-C (mmol/L) Mean LDL-C (mg/dL)
500 Apheresis 400 300 Mean LDL-C (mmol/L) Mean LDL-C (mg/dL) 200 + Atorvastatin 100 1992 1993 1994 1995 1996 1997 1998 1999 Time (years) Genest J. NEJM 1999;341:490
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Case 3 Type III HLP (dysbetalipoproteinemia)
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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X X Lipoprotein Metabolism Type III Apo E2/2 Apo E2/2 FFA Liver HL LPL
Exogenous Pathway Chylo Remnant X Chylomicron Apo E2/2 Peripheral Cells Free Cholesterol ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol Intestine HL Steroidogenic Cells LCAT Nascent HDL HDL3 HDL2 LDL Liver ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol CETP PLTP Tg Endogenous Pathway CE Liver 3 HL VLDL LPL X IDL Apo E2/2 FFA
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