genetic factors of coronary artery disease risk anthony a. killeen, m.d., ph.d. dept. of pathology...
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Genetic Factors of Coronary Artery Disease Risk
Anthony A. Killeen, M.D., Ph.D.
Dept. of Pathology
University of Michigan
Copyright 2001 Anthony A. Killeen 2
Outline
Familial Hypercholesterolemia
Familial Defective Apo B
Lipoprotein (a)
Apolipoprotein E
HDL/Apo AI
Mutations affecting triglyceride levels
Miscellaneous
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CAD Impact
Leading cause of death in U.S.
1.5 M heart attacks annually
0.5 M deaths
$50 -100 B annually
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CAD Risk Factors
Hyperlipidemia
Hypertension
Cigarette smoking
Diabetes mellitus
Infectious agents ? / inflammation
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Heritability of Lipid Levels
Triglycerides: 30-40%
LDL-C, HDL-C: 50-60%
Lipoprotein (a): >90%
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Familial Hypercholesterolemia (1)
Mutations in LDL-R
Autosomal codominant; 1 per million affected Inability to remove cholesterol from circulationCholesterol levels 700-1200 mg/dlSevere CAD in early lifeCutaneous and tendinous xanthomas, arcus
corneae
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Familial Hypercholesterolemia (2)
1 in 500 heterozygous5-10% of patients with MI under 55
Cholesterol levels 350-500 mg/dl
CAD by 6th decade
Tendon xanthomas, arcus corneae
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Genetics of FH
Mutations in the LDL-R gene
>150 mutations reported
In some populations, 1 or 2 mutations are commonNorth Karelia (Finland), Quebec French
Canadians
Classification of mutation is by effect
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Familial Defective ApoB (FDB)
Apo B is the major apolipoprotein of LDL
apoB3500 (Arg3500Gln) is the most frequent mutation Impaired binding to the LDL-R Mutation is identical by descent in nearly all cases
1:500-1:700 carry mutation
LDL-C levels vary, overlap FH levels
Clinical features similar to FH
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Lipoprotein (a)
Disulfide bond joins apo B in LDL to apo(a)
Apo(a) has >80% sequence homology with plasminogen – blocks activation?
Polymorphic (>30 alleles) due to variable numbers of repetitive kringle units
Plasma levels of Lp(a) inversely related to size of protein
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Lp(a) and CAD
Elevated levels of CAD (>30 mg/dl) are a risk factor
Risk is greatest in subjects with high LDL-C or LDL-C:HDL-C >2.8
Present NCEP do not recommend routine measurement of Lp(a)
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Genetics of Lp(a)
Locus is on 6q2.6-q2.7
Over 30 alleles exist
Variable number of kringle 4 repeats
Larger alleles associated with lower levels of Lp(a)
90% of population variation in plasma levels is determined by the locus
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Apolipoprotein EPolymorphic apolipoproteinE2, E3, E4 are most frequentVariation at codons 112 and 158
Present in chylomicrons, VLDL, IDL
Polymorphism association with CAD risk and Alzheimer Disease risk
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ApoE and CAD Risk
TC 10% higher in subjects with E4
TC 10% lower in subjects with E2
Type III hyperlipidemia in 1-2% of E2 homozygotes
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Type III Hyperlipidemia
1 in 1,000 - 1 in 5,000Cholesterol and TG elevatedCholesterol: 300-600 mg/dlTG: 400-800 mg/dl
Striated xanthomas, orange pigmentation of palmar/planter creasesOrange-yellow tuberoeruptive xanthomas on elbows, knees, buttocks
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Type III Hyperlipidemia (2)
CAD develops in middle aged, occasionally younger ages
Lipid abnormalities very responsive to diet/exercise
Laboratory features Increased IDL, “broad beta” band Homozygosity for E2 variant
Rare dominant apoE alleles
apoE2 shows only 1% of binding affinity to B/E receptor
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High Density Lipoprotein
Levels <35 mg/dl related to CAD risk
Levels >65 mg/dl confer protection
Low levelsGenetic factorsCigarette smoking, anabolic steroids, beta
blockers, polyunsaturated fats
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Metabolism of HDL
Synthesized in liver/intestine as a discoidal precursor
LCAT converts free cholesterol into estersMaturation into HDL3 then HDL2 More mature particles are sphericalWomen have higher HDL2 than men
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Protective Role of HDL
Reverse cholesterol transport
Protection against oxidation of LDL
Enhanced removal of remnant particles
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Genetic Disorders of HDL
Apo AI mutationsClass I: defective synthesis
Increased CAD riskClass II: truncated forms
Variable CAD riskClass III:LCAT deficiency
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Apo AI Milano
Arg173Cys
Found in a large Italian pedigree
Increased HDL catabolism
Not associated with CAD risk, maybe longevity!
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Lecithin:Cholesterol Acyl Transferase Deficiency
Risk factor for CADConverts cholesterol to cholesteryl ester in HDL and LDLApo AI is an activatorFish-eye disease (corneal opacities)Absent cholesterol esterification in HDLPreserved esterification in LDL
Complete LCAT deficiency
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Tangier Disease
Extremely rare, autosomal recessive
Very low HDL-C and apo AI Rapid turnover of HDL
Low LDL-C, elevated TG
Lipid laden macrophages are deposited in lymphoid tissue Orange tonsils
Demyelination; premature vascular disease in 50%
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ABCA1 and HDL
Molecular defect in Tangier disease is in ATP-binding cassette transporter 1
Carriers of mutations have low HDL, high TG
A common polymorphism, R219K (f=0.46), is associated with lower TG, a trend toward higher HDL, and decreased severity of CAD
R allele may account for 5% of risk of CAD
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Lipoprotein Lipase
Locus on 8. >150 mutations reported
Deficiency causes familial chylomicronemiaTG >1,000 mg/dl
Autosomal recessive, 1 in 106 affectedDiffuse abd. pain, pancreatitisEruptive xanthomas, lipemia retinalis
Deficiency of apo C-II has similar phenotype
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Familial Hypertriglyceridemia
Type IV hyperlipoproteinemia1-2% of the population
Elevated TG and VLDL-CTG 200-500 mg/dl
LDL-C, HDL-C tend to be reduced
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Familial Hypertriglyceridemia (2)
Very sensitive to alcohol, exercise, caloric intake, dietary CHO, estrogens
Often associated with obesity, hyperuricemia, and glucose intolerance
Autosomal dominant with age dependent penetrance (?)
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Familial Combined Hyperlipidemia
Elevated TC and TG with other family members also having one or both lipids elevated
Affects 1% of population. Heterogeneous disorder
Autosomal dominant with age dependent penetrance (?)
Increased risk of CAD
Increased production of apo B and VLDL
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Familial Combined Hyperlipidemia (2)
Loci implicated in different familiesapoAI-CIII-AIV LPL
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Polymorphisms in Other Genes
Cholesteryl ester transfer proteinCETP level is inversely related to HDL levelCommon polymorphisms contribute to plasma
levels and response to Pravastatin
Factor VIIHigher plasma levels of FVII have higher CAD
riskCommon polymorphisms contribute to plasma
level
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Other Genes
Angiotensin converting enzyme (ACE) I/D polymorphism - D is deletion (and deleterious)
Prothrombin G20210AFactor V LeidenGp IIb/IIIa Pl A1/A1 (A2 is higher risk)Alcohol dehydrogenase (affects beneficial effects of moderate alcohol consumption)
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Other Risk Factors
Fibrinogen, decreased fibrinolysis
Plasminogen activator inhibitor 1
Homocysteine
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Polygenic Hyperlipidemia
In most patients, CAD is not due to single gene defects
CAD risk is determined by lifestyle and genetic factors
Genetic factors in most people are individually minor effects
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Loci Implicated in Polygenic Hyperlipidemia
LDL-R
ApoB
ApoE
ApoAI-CIII-AIV
LPL
CETP
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Mutations and the Fredrickson Classification
Type I (Chylomicronemia): LPL, apo CII
Type IIa (Cholesterol): FDB, LDL-R
Type IIb (Cholesterol, TG): Unclear
Type III: apo E2 homozygosity
Type IV: (TG): Unclear
Type V: TG and chylomicrons: Unclear