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Genetics of Lipoprotein Disorders Jacques Genest MD Cardiovascular Genetics Laboratory McGill University Health Center.

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Presentation on theme: "Genetics of Lipoprotein Disorders Jacques Genest MD Cardiovascular Genetics Laboratory McGill University Health Center."— Presentation transcript:

1 Genetics of Lipoprotein Disorders Jacques Genest MD Cardiovascular Genetics Laboratory McGill University Health Center

2 Human Biochemical Genetics 2008 Genetics of Lipoprotein Disorders  Epidemiology and Lipoprotein Metabolism  Genetics of Lipoprotein Disorders  Disorders of HDL; Diagnosis and Treatment

3 Epidemiology of Cardiovascular Diseases

4 Libby P. Inflammation and atherosclerosis. Nature 2002;420:868 Atherosclerosis

5 Risk Factors for CAD  Cigarette  Hypertension  LDL-cholesterol (apo B)  HDL-cholesterol  Diabetes  Age  Atherosclerosis Circulation 2000;101:

6 Risk Factors and risk of MI Smoking Diabetes Hypertension Abd. Obesity Psychol index Fruits/Veg Exercise (-) Alcohol (-) Apo B / Apo AI Women Men Yusuf S et al. INTERHEART Lancet 2004;364:

7 Apo B / AI Ratio (Chol/HDL-C) Yusuf S et al. INTERHEART Lancet 2004;364:

8 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:

9 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

10 Global Mortality 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

11 Disability-Adjusted Life Years, 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

12 Lipoprotein Metabolism

13 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).

14 HO Cholesterol O Cholesteryl Ester LCAT

15 Lipoprotein Lipase Triglycerides

16 Phospholipids CH 2 O O=P - O O CH 2 - CH - CH 2 OO O=C C=O R2 CH 3 -N-CH 3 CH 2 CH 3 R1 Choline Phosphate Glycerol Acyl Chains (Fatty acids)

17 Phospholipid Cholesteryl ester Apolipoprotein Triglyceride Cholesterol

18 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

19 CHYLOMICRON RENNANTS VLDL IDL LDL HDL 2 HDL Density (g/ml) Diameter (nm)

20 Intestine Liver Lipoprotein Metabolism Endogenous Pathway FFA VLDL ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol Nascent HDL Peripheral Cells FFA Free Cholesterol HL Liver LCAT HL Steroidogenic Cells Exogenous Pathway Chylomicron Chylo Remnant HDL2 LDL IDL LPL CETP PLTP CE Tg HDL3 3 Liver HL

21 Human Biochemical Genetics 2008 Genetics of Lipoprotein Disorders  Epidemiology and Lipoprotein Metabolism  Genetics of Lipoprotein Disorders  Disorders of HDL; Diagnosis and Treatment

22 Case 1 34 yo Man Admitted to ED with abdominal pain Plasma lactescent Triglycerides 154 mmol/L

23 Intestine Liver Lipoprotein Lipase Endogenous Pathway FFA VLDL ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol Nascent HDL Peripheral Cells FFA Free Cholesterol HL Liver LCAT HL Steroidogenic Cells Exogenous Pathway Chylomicron Chylo Remnant HDL2 LDL IDL LPL CETP PLTP CE Tg HDL3 3 Liver HL x

24 Lipoprotein Lipase Deficiency (Type I) Chylomicrons: Intestinal lipoprotein, containing mostly triglycerides. Rapidly degraded by lipoprotein lipase in vasculature Deficiency produces Type I Hyperlipidemia

25 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

26 Lipoprotein Lipase Gene 8q LPL gene 8q22 Asp9AsnGlu188GlyAns291SerSer447Ter

27 Lipoprotein Lipase Gene and CAD LPL Meta-analysis 29 studies, subjects Wittrup HH et al. Circulation 1999;99:2901

28 Case 2 Familial Hypercholesterolemia Heterozygous Frequency 1:500 (up to 1:80 in Lac St-Jean) LDL-Receptor gene defect LDL-C 2x ULN

29 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)

30 Intestine Liver Lipoprotein Metabolism LDL-R Endogenous Pathway FFA VLDL ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol Nascent HDL Peripheral Cells FFA Free Cholesterol HL Liver LCAT HL Steroidogenic Cells Exogenous Pathway Chylomicron Chylo Remnant HDL2 LDL IDL LPL CETP PLTP CE Tg HDL3 3 Liver HL X X

31 Lipoprotein assembly and secretion Cholesterol Fatty acidsCholesteryl esters VLDL Bile acids LDL-R LDL ApoB VLDL-R LRP Endosome sER HMG CoA RedACAT VLDLIDL Hepatic Cell ApoB ApoE ApoB ApoE

32 Intestine Liver Lipoprotein Metabolism FH HMZ Endogenous Pathway FFA VLDL ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol Nascent HDL Peripheral Cells FFA Free Cholesterol HL Liver LCAT HL Steroidogenic Cells Exogenous Pathway Chylomicron Chylo Remnant HDL2 LDL IDL LPL CETP PLTP CE Tg HDL3 3 Liver HL X X

33 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)

34 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

35 LDL-R Mutations in FH

36 LDL-R Pathway Animation

37 SIMVASTATIN: MAJOR VASCULAR EVENTS Vascular event Total CHD 914 1,234 Total stroke Revascularisation 926 1,185 ANY OF ABOVE 2,042 2,606 (19.9%) (25.4%) 24% SE 2.6 reduction (2P< ) Risk ratio and 95% CI Statin (n=10,269) Statin (n=10,269) Placebo (n=10,267) Placebo (n=10,267) Statin better Statin worse HPS Heart Protection Study

38 Cholesterol treatment Trialists (Lancet 2005;366:1267) Reduction in LDL-C (mmol/L) Proportional reduction in event rate

39 Mean LDL-C (mmol/L) Time (years) + Atorvastatin Apheresis Mean LDL-C (mg/dL) LDL Apheresis Genest J. NEJM 1999;341:490

40 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

41 Type III Hyperlipoproteinemia Type III HLP Dysbetalipoproteinemia, Remnant disease Apo E 2/2 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 E 4/4 associated with Alzheimer’s disease age of onset

42 Intestine Liver Lipoprotein Metabolism Type III Endogenous Pathway FFA VLDL ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol ApoA-I, A-II ApoC-I, C-II, C-III Phospholipids Free cholesterol Nascent HDL Peripheral Cells FFA Free Cholesterol HL Liver LCAT HL Steroidogenic Cells Exogenous Pathway Chylomicron Chylo Remnant HDL2 LDL IDL LPL CETP PLTP CE Tg HDL3 3 Liver HL Apo E2/2 X X


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