genetic factors of coronary artery disease risk anthony a. killeen, m.d., ph.d. dept. of pathology...

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


CAD Impact

Leading cause of death in U.S.

1.5 M heart attacks annually

0.5 M deaths

$50 -100 B annually


CAD Risk Factors

Hyperlipidemia

Hypertension

Cigarette smoking

Diabetes mellitus

Infectious agents ? / inflammation


Factors Determining Lipid Levels

Genetic

Environmental


Heritability of Lipid Levels

Triglycerides: 30-40%

LDL-C, HDL-C: 50-60%

Lipoprotein (a): >90%


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


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


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


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


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


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)


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


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


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


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


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


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


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


Protective Role of HDL

Reverse cholesterol transport

Protection against oxidation of LDL

Enhanced removal of remnant particles


Genetic Disorders of HDL

Apo AI mutationsClass I: defective synthesis

Increased CAD riskClass II: truncated forms

Variable CAD riskClass III:LCAT deficiency


Apo AI Milano

Arg173Cys

Found in a large Italian pedigree

Increased HDL catabolism

Not associated with CAD risk, maybe longevity!


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


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%


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


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


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


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 (?)


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


Familial Combined Hyperlipidemia (2)

Loci implicated in different familiesapoAI-CIII-AIV LPL


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


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)


Other Risk Factors

Fibrinogen, decreased fibrinolysis

Plasminogen activator inhibitor 1

Homocysteine


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


Loci Implicated in Polygenic Hyperlipidemia

LDL-R

ApoB

ApoE

ApoAI-CIII-AIV

LPL

CETP


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


Future Goals for Diagnostics

Identification of other risk genesSpecific therapeutics based on genotype?

Development of a personal CAD risk profile?Substantial improvement in technology (chips?)Re-imbursement, privacy, discrimination issuesMeaningful outcomes

genetic factors of coronary artery disease risk anthony a. killeen, m.d., ph.d. dept. of pathology...

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