Genetics of Lipoprotein Disorders

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


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)


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


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


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


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



NascentHDL

PeripheralCells

FFA

FreeCholesterol

HL

Liver

LCAT



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



NascentHDL

PeripheralCells

FFA

FreeCholesterol

HL

Liver

LCAT



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



NascentHDL

PeripheralCells

FFA

FreeCholesterol

HL

Liver

LCAT



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



NascentHDL

PeripheralCells

FFA

FreeCholesterol

HL

Liver

LCAT



ChyloRemnant

HDL2 LDL

IDL

LPL

LPL

CETPPLTP

CE

Tg

HDL3

3Liver

HL

Apo E2/2

Apo E2/2

X

X

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Genetics of Lipoprotein Disorders