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

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

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 $50 -100 B annually Copyright 2001 Anthony A. Killeen

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

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

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

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 700-1200 mg/dl Severe CAD in early life Cutaneous and tendinous xanthomas, arcus corneae Copyright 2001 Anthony A. Killeen

Familial Hypercholesterolemia (2) 4/16/2017 Familial Hypercholesterolemia (2) 1 in 500 heterozygous 5-10% of patients with MI under 55 Cholesterol levels 350-500 mg/dl CAD by 6th decade Tendon xanthomas, arcus corneae Copyright 2001 Anthony A. Killeen

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

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

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

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

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

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

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

Type III Hyperlipidemia 4/16/2017 Type III Hyperlipidemia 1 in 1,000 - 1 in 5,000 Cholesterol and TG elevated Cholesterol: 300-600 mg/dl TG: 400-800 mg/dl Striated xanthomas, orange pigmentation of palmar/planter creases Orange-yellow tuberoeruptive xanthomas on elbows, knees, buttocks Copyright 2001 Anthony A. Killeen

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

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

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

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

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

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

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

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

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

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

Familial Hypertriglyceridemia 4/16/2017 Familial Hypertriglyceridemia Type IV hyperlipoproteinemia 1-2% of the population Elevated TG and VLDL-C TG 200-500 mg/dl LDL-C, HDL-C tend to be reduced Copyright 2001 Anthony A. Killeen

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

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

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

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

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

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

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

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

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

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