1. Genetic Factors of Coronary Artery Disease Risk
4/16/2017
Genetic Factors of Coronary Artery Disease Risk
Anthony A. Killeen, M.D., Ph.D.
Dept. of Pathology
University of Michigan

2. Copyright 2001 Anthony A. Killeen
4/16/2017
Outline
Familial Hypercholesterolemia
Familial Defective Apo B
Lipoprotein (a)
Apolipoprotein E
HDL/Apo AI
Mutations affecting triglyceride levels
Miscellaneous
Copyright 2001 Anthony A. Killeen

3. Copyright 2001 Anthony A. Killeen
4/16/2017
CAD Impact
Leading cause of death in U.S.
1.5 M heart attacks annually
0.5 M deaths
$ B annually
Copyright 2001 Anthony A. Killeen

4. Copyright 2001 Anthony A. Killeen
4/16/2017
CAD Risk Factors
Hyperlipidemia
Hypertension
Cigarette smoking
Diabetes mellitus
Infectious agents ? / inflammation
Copyright 2001 Anthony A. Killeen

5. Factors Determining Lipid Levels
4/16/2017
Factors Determining Lipid Levels
Genetic
Environmental
Copyright 2001 Anthony A. Killeen

6. Heritability of Lipid Levels
4/16/2017
Heritability of Lipid Levels
Triglycerides: 30-40%
LDL-C, HDL-C: 50-60%
Lipoprotein (a): >90%
Copyright 2001 Anthony A. Killeen

7. Familial Hypercholesterolemia (1)
4/16/2017
Familial Hypercholesterolemia (1)
Mutations in LDL-R
Autosomal codominant; 1 per million affected
Inability to remove cholesterol from circulation
Cholesterol levels mg/dl
Severe CAD in early life
Cutaneous and tendinous xanthomas, arcus corneae
Copyright 2001 Anthony A. Killeen

8. Familial Hypercholesterolemia (2)
4/16/2017
Familial Hypercholesterolemia (2)
1 in 500 heterozygous
5-10% of patients with MI under 55
Cholesterol levels mg/dl
CAD by 6th decade
Tendon xanthomas, arcus corneae
Copyright 2001 Anthony A. Killeen

9. Copyright 2001 Anthony A. Killeen
4/16/2017
Genetics of FH
Mutations in the LDL-R gene
>150 mutations reported
In some populations, 1 or 2 mutations are common
North Karelia (Finland), Quebec French Canadians
Classification of mutation is by effect
Copyright 2001 Anthony A. Killeen

10. Familial Defective ApoB (FDB)
4/16/2017
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
Copyright 2001 Anthony A. Killeen

11. Copyright 2001 Anthony A. Killeen
4/16/2017
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
Copyright 2001 Anthony A. Killeen

12. Copyright 2001 Anthony A. Killeen
4/16/2017
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)
Copyright 2001 Anthony A. Killeen

13. Copyright 2001 Anthony A. Killeen
4/16/2017
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
Copyright 2001 Anthony A. Killeen

14. Copyright 2001 Anthony A. Killeen
4/16/2017
Apolipoprotein E
Polymorphic apolipoprotein
E2, E3, E4 are most frequent
Variation at codons 112 and 158
Present in chylomicrons, VLDL, IDL
Polymorphism association with CAD risk and Alzheimer Disease risk
Copyright 2001 Anthony A. Killeen

15. Copyright 2001 Anthony A. Killeen
4/16/2017
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
Copyright 2001 Anthony A. Killeen

16. Type III Hyperlipidemia
4/16/2017
Type III Hyperlipidemia
1 in 1, in 5,000
Cholesterol and TG elevated
Cholesterol: mg/dl
TG: mg/dl
Striated xanthomas, orange pigmentation of palmar/planter creases
Orange-yellow tuberoeruptive xanthomas on elbows, knees, buttocks
Copyright 2001 Anthony A. Killeen

17. Type III Hyperlipidemia (2)
4/16/2017
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
Copyright 2001 Anthony A. Killeen

18. High Density Lipoprotein
4/16/2017
High Density Lipoprotein
Levels <35 mg/dl related to CAD risk
Levels >65 mg/dl confer protection
Low levels
Genetic factors
Cigarette smoking, anabolic steroids, beta blockers, polyunsaturated fats
Copyright 2001 Anthony A. Killeen

19. Copyright 2001 Anthony A. Killeen
4/16/2017
Metabolism of HDL
Synthesized in liver/intestine as a discoidal precursor
LCAT converts free cholesterol into esters
Maturation into HDL3 then HDL2
More mature particles are spherical
Women have higher HDL2 than men
Copyright 2001 Anthony A. Killeen

20. Copyright 2001 Anthony A. Killeen
4/16/2017
Protective Role of HDL
Reverse cholesterol transport
Protection against oxidation of LDL
Enhanced removal of remnant particles
Copyright 2001 Anthony A. Killeen

21. Genetic Disorders of HDL
4/16/2017
Genetic Disorders of HDL
Apo AI mutations
Class I: defective synthesis
Increased CAD risk
Class II: truncated forms
Variable CAD risk
Class III:LCAT deficiency
Copyright 2001 Anthony A. Killeen

22. Copyright 2001 Anthony A. Killeen
4/16/2017
Apo AI Milano
Arg173Cys
Found in a large Italian pedigree
Increased HDL catabolism
Not associated with CAD risk, maybe longevity!
Copyright 2001 Anthony A. Killeen

23. Lecithin:Cholesterol Acyl Transferase Deficiency
4/16/2017
Lecithin:Cholesterol Acyl Transferase Deficiency
Risk factor for CAD
Converts cholesterol to cholesteryl ester in HDL and LDL
Apo AI is an activator
Fish-eye disease (corneal opacities)
Absent cholesterol esterification in HDL
Preserved esterification in LDL
Complete LCAT deficiency
Copyright 2001 Anthony A. Killeen

24. Copyright 2001 Anthony A. Killeen
4/16/2017
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%
Copyright 2001 Anthony A. Killeen

25. Copyright 2001 Anthony A. Killeen
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
Copyright 2001 Anthony A. Killeen

26. Copyright 2001 Anthony A. Killeen
4/16/2017
Lipoprotein Lipase
Locus on 8. >150 mutations reported
Deficiency causes familial chylomicronemia
TG >1,000 mg/dl
Autosomal recessive, 1 in 106 affected
Diffuse abd. pain, pancreatitis
Eruptive xanthomas, lipemia retinalis
Deficiency of apo C-II has similar phenotype
Copyright 2001 Anthony A. Killeen

27. Familial Hypertriglyceridemia
4/16/2017
Familial Hypertriglyceridemia
Type IV hyperlipoproteinemia
1-2% of the population
Elevated TG and VLDL-C
TG mg/dl
LDL-C, HDL-C tend to be reduced
Copyright 2001 Anthony A. Killeen

28. Familial Hypertriglyceridemia (2)
4/16/2017
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 (?)
Copyright 2001 Anthony A. Killeen

29. Familial Combined Hyperlipidemia
4/16/2017
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
Copyright 2001 Anthony A. Killeen

30. Familial Combined Hyperlipidemia (2)
4/16/2017
Familial Combined Hyperlipidemia (2)
Loci implicated in different families
apoAI-CIII-AIV
LPL
Copyright 2001 Anthony A. Killeen

31. Polymorphisms in Other Genes
4/16/2017
Polymorphisms in Other Genes
Cholesteryl ester transfer protein
CETP level is inversely related to HDL level
Common polymorphisms contribute to plasma levels and response to Pravastatin
Factor VII
Higher plasma levels of FVII have higher CAD risk
Common polymorphisms contribute to plasma level
Copyright 2001 Anthony A. Killeen

32. Copyright 2001 Anthony A. Killeen
Other Genes
Angiotensin converting enzyme (ACE)
I/D polymorphism - D is deletion (and deleterious)
Prothrombin G20210A
Factor V Leiden
Gp IIb/IIIa Pl A1/A1 (A2 is higher risk)
Alcohol dehydrogenase (affects beneficial effects of moderate alcohol consumption)
Copyright 2001 Anthony A. Killeen

33. Copyright 2001 Anthony A. Killeen
Other Risk Factors
Fibrinogen, decreased fibrinolysis
Plasminogen activator inhibitor 1
Homocysteine
Copyright 2001 Anthony A. Killeen

34. Polygenic Hyperlipidemia
4/16/2017
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
Copyright 2001 Anthony A. Killeen

35. Loci Implicated in Polygenic Hyperlipidemia
LDL-R
ApoB
ApoE
ApoAI-CIII-AIV
LPL
CETP
Copyright 2001 Anthony A. Killeen

36. Mutations and the Fredrickson Classification
4/16/2017
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
Copyright 2001 Anthony A. Killeen

37. Future Goals for Diagnostics
Identification of other risk genes
Specific therapeutics based on genotype?
Development of a personal CAD risk profile?
Substantial improvement in technology (chips?)
Re-imbursement, privacy, discrimination issues
Meaningful outcomes
Copyright 2001 Anthony A. Killeen