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Apolipoprotein A-I Mutations and Cardiovascular Disease Ernst J Apolipoprotein A-I Mutations and Cardiovascular Disease Ernst J. Schaefer, MD Distinguished University Professor Human Nutrition Research Center on Aging at Tufts University, Tufts University School of Medicine, Boston, MA & Chief Medical Officer, Boston Heart Diagnostics, Framingham, MA May 26th, 2015 ISA 2015, Amsterdam, the Netherlands Decreased HDL-C and ApoA-I Framingham Offspring Study • Hypertriglyceridemia • Obesity • Diabetes • Male gender • Sedentary lifestyle • Smoking Schaefer EJ, Lamon-Fava S, Ordovas JM, Cohn SD, Schaefer MM, Castelli WP, Wilson PWF J Lipid Res. 35:871-882, 1994. Human Apolipoprotein (Apo) Metabolism Synthetic Sites Catabolic Sites FFA Chylomicron LPL, HL, LCAT Chylomicron 5 hours ApoB-48 Remnant Liver other Apos 4 ApoB-48, ApoE 6 Lipids Lipids 1 8 Kidney Intestine HDL 12 mg/kg/d ApoA-I 3 other Apos Scavenger Liver Lipids Cells 9 2 VLDL 12 mg//kg/d LDL ApoB-100 ApoB-100 Peripheral other Apos LPL, HL, 5 Lipids 3.5 days Cells Lipids LCAT 7 FFA 4 hours Schaefer & Levy New Engl J Med 1985; 312:1300, Cohn JS et al J Clin Invest 1990: 85:804, Schaefer EJ. Am J Clin Nutr. 2002;75:191 Lipoprotein Disorders in Families with Premature CHD • Familial Lipoprotein (a) Excess: 19% • Familial Dyslipidemia (High TG, Low HDL): 15% • Familial Combined Hyperlipidemia: 14% (high LDL-C &TG, usually low HDL-C) • Familial Hypoalphalipoproteinemia: 4% • Familial Hypercholesterolemia: 1% Genest JJ, Martin-Munley S, McNamara JR, Ordovas JM, Jenner J, Myers R, Wilson PW, Schaefer EJ. Circulation 85:2025-2033, 1992. (use of 10th and 90th percentile cutpoints from Framingham ApoA-I-Containing HDL Subpopulation Profiles of a Control and a CHD Patient pre pre [nm] 17.0 9.51 8.16 7.10 4.66 Asztalos et al. Arterioscler Thromb Vasc Biol. 2003;23:847-852; 2004; 24:2181-2187, 2005; 25:2185-2191, HATS Trial, Framingham Offspring Study, and the Veterans Affairs HDL Intervention Trial Differences in HDL Particles in Male CHD Cases vs Controls in the Framingham Offspring Study Apo A-I Concentration % Difference Controls (n=1277) Cases (n=169) 17 mg/dl - 39%* (16% of total) 40 mg/dl - 9% (37% of total) 38 mg/dl + 29%* (36% of total) 12 mg/dl + 16%* (11% of total) “For each 1 mg/dl apoA-I increase in alpha 1 HDL - 26% reduction in CHD risk Asztalos BF, Cupples LA, Demissie S, Horvath KV, Cox CE, Batista MC, Schaefer EJ. Arterioscler Thromb Vasc Biol 2004; 24:2181-2187. Differences in HDL Particles in Female CHD Cases vs Controls Apo A-I Concentration % Difference Controls (n=126) Cases (n=256) 27 mg/dl - 49%* (17% of total) 51 mg/dl - 25% (33% of total) 41 mg/dl - 8% (26% of total) 17 mg/dl + 41%* (11% of total) * P< 0.05 versus controls Lamon-Fava S et al Arterioscler Thromb Vasc Biol 2008;28:575-9. HDL Particles and Recurrent CHD Events in VA HIT (1097 without vs 398 with recurrent events) Apo A-I Concentration % Difference Recurrent Dis. 9.1 mg/dl - 12%** (54% of normal) 31.9 mg/dl - 7% (80% of normal) 40.5 mg/dl - 3%* (107% of normal) 12.1mg/dl + 9%* (100% of normal) “In CHD patients with low HDL those with lower α-1 HDL on trial were significantly more likely to have recurrent events.” Asztalos BF, Collins D, Cupples LA, Demissie S, Horvath KV, Bloomfield HE, Robins SJ, Schaefer EJ. Arterioscler Thromb Vasc Biol 2005; 25:2185-2191. Effects of Atorvastatin 80 mg/dl vs. Rosuvastatin 40 mg/dl on HDL Particles vs Baseline in STELLAR (n=306) Atorvastatin Rosuvastatin + 12%* + 24%* + 4% + 13* -7% - 6% - 40%* - 39%* Asztalos BF, LeMaulf F, Dallal GE, Stein E, Jones PH, Horvath KV, McTaggert F, Schaefer EJ. Am J Cardiol 2007; 99: 681-685. Effects of Simvastatin/Niacin on HDL Particles in CHD Cases in HATS (n=123) Apo A-I Concentration % Difference 9 mg/dl + 115%* 30 mg/dl + 27% 45 mg/dl - 17%* 15 mg/dl - 39%* “The increase in apoA-I in large alpha 1 HDL was significantly related (p<0.01) to lack of progression or regression of coronary artery stenosis.” Asztalos BF, Batista M, Horvath KV, Cox CE, Dallal GE, Morse JS, Brown GB, Schaefer EJ. Arterioscler Thromb Vasc Biol 2003;23:847-852. Low HDL in Population 3 candidate genes (ABCA1, APOA1, and LCAT) sequenced in subjects < 5th percentile of HDL-C vs. > 95th percentile of HDL-C. NS variants were significantly more common (12% versus 2%) in individuals with low HDL-C (n=284) than in those with high HDL-C (n=236). 9.9% ABCA1, 2.2% LCAT, and 0.2% APOA1 Cohen JC et al Science 2004; 305:869-72. Apolipoprotein A-I Variants in the General Population Sequenced APOA1 gene in 10,330 population-based participants in the Copenhagen City Heart Study. Only 0.27% of individuals in the general population were heterozygous for NS variants which were associated with substantial reductions in apoA-I (up to 39 mg/dL) and/or HDL cholesterol (up to 0.9 mmol/L). 0.41% of the population were heterozygous for variants predisposing to amyloidosis. NS variants were associated with a hazard ratio of 1.72 (CI, 1.09-2.70, p<0.01) for myocardial infarction (MI), largely driven by A164S, a variant usually not associated with low apoA-I or HDL cholesterol levels. Haase CL, Frikke-Schmidt R, Nordestgaard BG, Tybjaerg-Hansen A, PLoS Genetics 2012;8(11):e1003063 ApoA-I Mutations and Amyloidosis In hereditary amyloidosis apoA-I mutations cause its proteolysis, and the depositions of 9-11 kd N terminal fragments as fibrils in the kidney, liver, and heart, damaging these organs. All amyloidogenic apoA-I mutations cluster in residue segments 26-107 and 154 -178, and can destabilize lipid free and HDL bound apoA-I. ApoA-I Iowa (G26R) is among the best characterized of these variants. Gursky O et al. Biochemistry 2012;51:10-18. Marked HDL Deficiency HDL-C Levels < 20 mg/dL in the absence of liver disease, TG > 1000 mg/dL, or testosterone use Usually due to mutations at either the APOAI, ABCAI (Tangier disease), or LCAT gene loci They can be distinguished based on a standard lipid profile, HDL particle analysis, and corneal examination. Parameters in Marked Deficiency HDL- Direct LDL- ApoAI in Parameter C/ApoAI C/TG HDL (mg/dL) (mg/dL) Particles AI/CIII/AIV Deficiency ** 2/0 126/56 ND AI/CIII Deficiency ** 2/0 135/62 ND AI Deficiency** 2/0 126/56 ND Tangier Disease (ABCA1)** 3/2.0 52/159 Preβ-1 Preβ-1, α-4, LCAT Deficiency 7/52 0/139 larger HDL Fish Eye Disease* 6/36 157/158 Preβ-1, α-4 Preβ-1, α-4, Controls 55/150 120/100 3,2, and 1 Premature CVD, ** prior to age 40, ** prior to age 60 , * prior to age 70 years, Schaefer EJ et al Curr. Opin. Lipidol 2010; 21:289-97. Apolipoprotein A-I Immunoblotting in Various Disorders of HDL Metabolism Schaefer EJ, Santos RD, Asztalos BF. Curr Opin Lipidol 2010;21:289-97. Arcus Juvenilis, Tendinous Xanthomas, Heterozygous Familial Hypercholesterolemia Atypical Arcus Juvenilis, Xanthomas, ApoA-I Deficiency, CVD age 39 years,homozygous nonsense codon -2 in APOAI gene. Santos R et al. J Lipid Res 2008;49: 349-357. Female with homozygous Tangier disease, developed neuropathy at age 25 years, CHD at age 45 years, died from CHD at age 58 years, at autopsy severe diffuse CAD. Her diffuse corneal opacification was best seen on slit lamp examination; ABCA1 mutation Asn to His at residue 1740 in 2nd transmembrane domain. Brousseau et al J Lipid Res 2000;41:433-441 52 year old male with diffuse corneal opacification & atypical arcus juvenilis, renal insufficiency, & anemia, LCAT mutation homozygous Met to Arg at residue 293, received LCAT enzyme replacement at NIH for 10 weeks (Dr. Remaley), stabilized renal disease & improved anemia, but shortage of enzyme, Rx stopped, and now on dialysis, Roshan et al J Clin Lipidol 2011;5:493-99. HDL Particles Before and After LCAT Enzyme Replacement in LCAT Deficient Patient Treated at NIH by Dr. Alan Remaley and Colleagues Atypical arcus juvenilis in a healthy 23 year woman and positive family history of premature CHD, compound heterozygous mutation P34L and T137M in LCAT gene, data consistent with Fish Eye Disease. Dimick et al. J Clin Lipidol 2014; 8:223-230. 22 Confidential – Boston Heart Diagnostics Familial Apolipoprotein A-I Deficiency Patients who lack AI/CIII/AIV (deletion of gene complex) have marked HDL deficiency, low TG levels, normal LDL-C levels, premature CHD (female age 43 died of CHD after bypass) (Schaefer et al Arteriosclerosis, 1982, JLR 1985, Ordovas et al JBC 1989) Patients who lack AI/CIII (DNA rearrangement) have marked HDL, low TG levels, normal LDL-C levels, premature CHD (two sisters required bypass at 29 and 30 years of age, since then have died of CHD), planar xanthomas, and normal fat absorption (Norum et al NEJM, 1982, Karathanasis PNAS 1987) Patients who lack AI only have marked HDL deficiency, normal TG levels, and premature CHD: 1) Homozygous nonsense mutation, codon 84, CHD in Japanese female in her 50s. (Matsunaga et al PNAS, 1991) 2) 4 homozygotes in kindred by Q[-2]X mutation in Canada, 3 had CHD in their 30s, one was in her 20s, no CHD. (Ng et al JCI, 1994) 3) Two brothers with severe CHD at 38 and 39 requiring bypass, tubo-eruptive and planar xanthomas, normal LDL-C and TG; Q[-2]X mutation, (Santos et al, JLR 2008) Apolipoprotein A-I Variants ApoA-I - 243 residues with repeats of amphipathic alpha helices.
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