Personalized Lipidoogy: How Genomic is Changing the Management of Dyslipidemia
Michael Davidson M.D. FACC, FNLA Professor, Director of Preventive Cardiology The University of Chicago Pritzker School of Medicine A Treasure Trove of Information for Lipoprotein Biology
Dietary fat, cholesterol Liver Bile salts, cholesterol GCKR MLXILP B48 LDLR E CYP7A Lipogenesis MEV-MMAB PNLIP ABCG5 C HMGCR CEL ABCG8 LRP1 NPC1L1 Remnant SCABR1 Cholesterol LDLR LPA Intestine Lipolysis B100 Phospholipid Protein Cholesteryl B100 ester (CE) (PL) B48 E Triglycerides C A I (TG) LP (a) VLDL B100 B100 A I All A I A V TG Nascent E CE LIPC A IV LCAT HDL CETP E LDL Chylomicron HDL PLTP IDL Fatty Cholesterol, Fatty Lipolysis acids PL Lipolysis acids LPL
LPL CD36 ABCA 1 LIPG CD36 LDLR ABCG1 PCSK9 Inhibition transporters Glycosylation ANGPTL3 GALNT2 CELSR2-PCRC1-SORT1 Degradation TRIB1 Peripheral tissues NCAN-CLIP2-PBX4
Adapted from Lusis AJ, et al. Nat Genet. 2008;40:129-130. Genome Wide Association Study (GWAS) in >100,000 Individuals of European Ancestry
• In 2010, 95 loci across the human genome were reported to harbor common variants associated with plasma lipid traits
LDL-C (newly identified loci in red) HDL-C Triglycerides
ABCG5/8 HFE SORT1 ABCA1 HNF4A PDE3A
ABO HMGCR ST3GAL4 ABCA8 IRS1 PGS1 GCKR
ANGPTL3 HNF1A TIMD4 KLF14 PLTP ANGPTL3 IRS1
APOA HPR TOP1 ANGPTL4 LACTB PPP1R3B ANKRD55 JMJD1C
APOB TRIB1 APOA LCAT SBNO1 APOA LIPC
APOE IRF2BP2 APOB LILRA/B SCARB1 APOB LPL
BRAP LDLR APOE LIPC SLC39A8 APOE LRP1
LDLRAP1 ARL15 LIPG STARD3 MLXIPL
LPA C6orf106 LPA TRIB1 CAPN3 MSL2L1
CETP MAFB CETP LPL TRPS1 CETP NAT2
CILP2 MOSC1 CITED2 LRP1 TTC39B CILP2 PINX1
CYP7A1 NPC1L1 CMIP LRP4 UBASH3B COBLL1 PLA2G6
DNAH11 OSBPL7 COBLL1 UBE2L3 CTF1 PLTP
FADS PCSK9 MC4R ZNF648 CYP26A1 TIMD4
FRK PLEC1 FADS MLXIPL ZNF664 FADS TRIB1
GPAM PPP1R3B GALNT2 MMAB TYW1B
ZNF664 Total Cholesterol
ERGIC3 EVI5 RAB3GAP1 RAF1 SPTY2D1
Note, the loci shown may have different traits associated with them, and therefore may appear in more than one category for LDL-C, HDL-C, Triglycerides, and Total Cholesterol. Teslovich TM, et al. Nature. 2010;466:707-713. Magnitude of Effects of SNP’s on LDL, HDL and TG Levels 61 year old cardiologist with a strong FH of premature CHD APOA5 Causal for both Hypertriglyceridemia and Premature Cardiovascular Disease
APOA5 Association with Lipid levels in APOA5 Association in Patients with Patients with HTG Coronary Heart Disease
50K participants in 27 studies 21K cases, 35K controls in 39 studies
6 41 year old male, father died at age 31 with documented MI
41 year old male with strong FH of premature CHD on statins since age 12 Advanced Lipid Profile CT Angiography Established and Emerging Plasma Biomarkers for Predicting CV Risk
Lipids/Lipoproteins1,2 Inflammation2,3 Altered Thrombosis2
• LDL-C • High-sensitivity • Fibrinogen • TG C-reactive protein • Homocysteine (hs-CRP) • Non-HDL-C • D-dimer • Lipoprotein-associated • Tissue-type plasminogen • HDL-C phospholipase A2 activator/plasminogen • Lipoprotein remnants • Leukocyte adhesion activator inhibitor • Lipoprotein (a) (Lp[a]) molecule (ICAM-1) • Apolipoproteins (Apo AI, B) • Serum amyloid A • LDL-P (concentration • Interleukin-6 and size) • Interleukin-18 • Small Dense LDL-C
1. National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Circulation. 2002(25);106:3143-3421. 2. Ridker PM, et al. Circulation. 2004;109(25 suppl 1):IV6-IV19.Ridker 3. Garza CA, et al. Mayo Clin Proc. 2007;82(2):159-165. ApoB Lipoproteins are Causal for Atheroclerosis Rationale for therapeutic lowering of Apo B lipoproteins: decrease the probability of inflammatory response to retention
Apo B lipoprotein particles Blood Monocytes bind to adhesion molecules
Smooth muscle
Modification Inflammatory response Macrophage
Foam cell
Tabas I et al. Circulation. 2007;116(16):1832–1844. Williams KJ et al. Arterioscler Thromb Vasc Biol. 1995;15(5):551–561. Williams KJ et al. Arterioscler Thromb Vasc Biol. 2005;25(8):1536–1540. Hoshiga M et al. Circ Res. 1995;77(6):1129–1135. Merrilees MJ et al. J Vasc Res. 1993;30(5):293–302. Nakata A et al. Circulation.1996;94(11):2778–2786. Steinberg D et al. N Engl J Med. 1989;320(14):915–924. Viewing a patient’s lipid profile through the eyes of lipidologist
VLDL3: Most dense VLDL subclass. IDL: An Atherogenic Pattern A: intermediate in Predominance of VLDL catabolism. B large, buoyant LDL Atherogenic B Total VLDL: “ B
Pattern B: B Predominance IDL Remnants B of dense LDL. B Buoyant LDL “” B TG-RICH LIPOPROTEINS LDL-R B B Dense LDL B HDL2: B B Subclasses of B B larger, buoyant B A B HDL. B Lp(a): Consists of LDL plus a protein called HDL2 A apo(a). “ A HDL3 HDL3: A Subclasses of A Total HDL smaller, dense DECREASINGDENSITY HDL. “ INCREASING SIZE
B = All Lipoproteins containing an ApoB100 marker for non-HDL (1:1 Ratio) A = All Lipoproteins containing an ApoAI &/or AII, marker for HDL Non-HDL-C: Cholesterol Carried by All Apolipoprotein (Apo) B Lipoproteins Triglyceride Cholesterol
All atherogenic lipoproteins
HDL LDL IDL VLDL Chylomicron remnant
Apo AI Apo B Apo B Apo B Apo B48
non-HDL
Non-HDL-C = Total-C − HDL-C High hepatic TG production in patients with diabetes results in elevated triglyceride-rich lipoprotein cholesterol (TRL-c) , small LDL-C and LDL particles
ApoA5 Very Small LPL Large VLDL LDL ApoB ApoE ApoB TG Production TRL-c LDL-C Non-HDL-C Low Renal clearance High TG
HL HDL sHDL CETP
CE TG TG
HL LPL LPL/HL Very Large Remnants Small Small VLDL slow LDL LDL ApoB ApoB ApoC-III ApoB ApoE ApoC-III ApoB ApoE ApoC-III ApoC-III
Triglyceride-rich lipoprotein-C LDL-C Non-HDL-C Cholesterol Triglycerides The greater the level of triglycerides the more VLDL-C and less LDL-C within non- HDL-C associated with Increasing CV Risk
(VLDL-C)
Varbo A, et al. J Am Coll Cardiol. 2013;61:427-436. Lipoprotein Cholesterol Levels and IHD Copenhagen Studies (n = 73,513): Risk of Ischemic Heart Disease By Lipoprotein Cholesterol Levels
Varbo et al. JACC 2013;61:427-436. Lipoprotein Genotypes and IHD
Copenhagen Studies: Causal vs Observational Risk Estimates
HRs for 1 mmol/l or a 1 ratio unit increase or decrease in plasma lipoprotein levels Varbo et al. JACC 2013;61:427-436. TG Cholesterol ApoA5 ApoC-III HL Triglycerides ApoB ApoE HDL sHDL Renal CETP HDL-C clearance
CE TG TG LPL LPL/HL HL (slow) TG TG Small production high Very small VLDL Remnants LDL LDL VLDL and remnant LDL-C cholesterol Non-HDL-C + OM3-CA (EPA, DHA) TG low LPL
VLDL Remnants Large LDL Small LDL (-25.77*) (-19.85*) (+10.04*) (-7.75*) VLDL and remnant LDL-C cholesterol Non-HDL-C *Least-squares mean difference relative to olive oil. Apo, apolipoprotein; CE, cholesterol ester; CETP, cholesterol ester transfer protein; DHA, docosahexanoic acid; EPA, eicosapentanoic acid; HDL, high-density lipoprotein; HL, hepatic lipase; LDL, low-density lipoprotein; LPL, lipoprotein lipase; TG, triglyceride; VLDL, very-low-density lipoprotein. Meta-regression Demonstrates that VLDL-C Lowering is Highly Correlated with a Reduction in the Hazard Ratio for a Major CV Event Each 8.9 mg/dL reduction in VLDL-C (equivalent to 0.5 mmol/L for TG) in the fibrate outcome trials is associated with a reduction of 26% in the hazard for a CV event 1.0 Y = -0.02955*X + 1.113; r = -0.93, P = 0.006 Y = -0.02955*X + 1.113; r = -0.93, P = 0.006
s ACCORD t BIP
n 0.9 FIELD
e
v
E
V 0.8
C VA-HIT
r
o
f
R 0.7 SIHD
H HHS
0.6 0 5 10 15 20 VLDL-C Reduction (mg/dL)
Calculated from: Nordestgaard BG, Varbo A. Lancet. 2014;384:626-635. Maki KC, et al. J Clin Lipidol. 2012;6:413-426. SIHD is Carlson LA, Rosenhamer G. Acta Med Scand. 1988;223:405-418. The importance of understanding the causal role of TRL-c vs LDL-c
• Elevated TRL-c explains the superiority of non-HDL-c over LDL-c as a predictor of CV risk • Focusing only on LDL-c rather than both LDL-c and TRL- c (ie non-HDL-c) misses a potential opportunity to further lower CV events with therapy • The primacy of LDL-c over non-HDL-c as a target of therapy raises inappropriate concerns regarding the increase in LDL-c with triglyceride lipoprotein lowering therapies • Since TRL-c is at least as atherogenic as LDL-c, non- HDL-c should be the preferred target of therapy
22 STRENGTH (Epanova) vs. REDUCE-IT (Vascepa) Outcomes Trials
Clinical factors STRENGTH REDUCE-IT Number of patients ~13,000 ~8000 Inclusion criteria TG ≥200 mg/dL, <500 mg/dL TG ≥200 mg/dL, <500 mg/dL HDL-C <40 mg/dL (men) (started with TG ≥150 mg/dL) HDL-C <45 mg/dL (women)
≥4 weeks on statin ≥4 weeks on statin Established CVD or at high Established CVD or at high risk for development CVD risk for development of CVD Primary endpoint MACE MACE Dosing regimen 4 g/d 4 g/d Placebo Corn oil Mineral oil Relations of LDL Particles and LDL Cholesterol to Levels of HDL Cholesterol and Triglycerides
Framingham Offspring Study
1800 180 1800 180 LDL Particles LDL Particles 1600 160 1600 160
1400 140 1400 140
1200 120 1200 LDL Cholesterol 120 LDL Cholesterol
1000 100 1000 100
LDL Particles LDL (nmol/L) LDL Cholesterol Cholesterol LDL (mg/dL) 20 40 60 80 100 0 100 200 300 400 HDL Cholesterol (mg/dL) Triglycerides (mg/dL)
1Otvos JD. J Lab Medicine 2002;26(11/12):555-556 When LDL-C and LDL-P are discordant risk follows LDL-P Population Distributions of LDL-C, non-HDL-C, Apo B, and LDL-P in the Framingham Offspring Study
LDL-C Non-HDL-C LDL-P ApoB Percentile (mg/dL) (mg/dL) (nmol/LL) (mg/dL) AHA/ADC Cutpoints 1 2 70 83 720 54 5 78 94 850 62 AACC 2 10 88 104 940 69 Cutpoints 20 100 119 1100 78 The medical decision 30 111 132 1220 85 cutpoints should be set so that the apo B and 40 120 143 1330 91 LDL-P cutpoints are 50 130 153 1440 97 equivalent to those for 60 139 163 1540 103 LDL-C in terms of population percentiles. 70 149 175 1670 110 80 160 187 1820 118 90 176 205 2020 130 95 191 224 2210 140
AACC=American Association for Clinical Chemistry; ACC=American College of Cardiology; ADA=American Diabetes Association. 1. Brunzell JD, et al. Diabetes Care. 2008;31(4):811-822. 2. Contois JH, et al. Clin Chem. 2009;55(3):407-419 On-treatment CV risk: LDL-C vs LDL-P
1.00 0.99 Kaplan Meier Curves for Combined CHD/Stroke 0.98 Risk at 36 months of follow-up 097 Comparative Effectiveness Analysis of LDL-P 0.96 vs. LDL-C on CHD/stroke risk 0.95
0.94 an event an 0.93 0.92 0.91 LDL-P cohort without without 0.90 0.89 0.88 LDL-C cohort 0.87 0.86 0.85 LDL-C cohort LDL-P cohort 0.84 0.83 # Patients 705 705 0.82 # Events 237 196 Proportion of patients patients of Proportion 0.81 Log-rank p-value = 0.029 0.80
0 100 200 300 400 500 600 700 800 900 1000 1100
Time to Event (DAYS)
Toth PP et al. Atherosclerosis 2014;235:585-591 LDL Particle Number Measures as Targets of Therapy
Percentile Equivalent Concentration Biomarker Population <5th <20th <50th <80th LDL-C (mg/dL) <75 100 130 160 ApoB (mg/dL) Framingham <60 80 100 120 <850 1100 1400 1800 NMR LDL-P (nmol/L) MESA <800 1000 1300 1600 Proposed Targets of therapy Organization Very High Risk High Risk Moderate Risk American Diabetes Association / American College of Cardiology Apo B < 80 Apo B < 90 NA Foundation Consensus Statement [1] American Association for Clinical Chemistry Lipoproteins & Vascular Apo B or LDL-P Apo B or LDL -P Diseases Working Group Recommendations [2] < 20th percentile (see above) <50th percentile American Association of Clinical Endocrinologists Guidelines for Apo B < 80 Apo B < 90 NA Management of Dyslipidemia [3] Option Option Apo B or LDL-P National Lipid Association Expert Recommendations [4] Apo B < 5th Apo B <50th percentile percentile <20th percentile Canadian Cardiovascular Society Guidelines [5] Apo B < 80 NA
ESC/EAS Guidelines for the Management of Dyslipidemia [6] Apo B < 80 Apo B < 100 NA
NLA Management of Dyslipidemia [7] Apo B < 80 Option for Apo B < 90
American Association of Clinical Endocrinologists/ American College Apo B < 80 Apo B < 90 NA of Endocrinology Comprehensive Diabetes Algorithm [8] LDL-P < 1000 LDL-P < 1200 Cumulative incidence curves for risk of coronary heart disease (CHD) by small dense low-density lipoprotein-cholesterol (sdLDL-C) and large buoyant LDL-C (lbLDL-C) quartiles, adjusted for age, race, and sex.
Hoogeveen R C et al. Arterioscler Thromb Vasc Biol. 2014;34:1069-1077
Copyright © American Heart Association, Inc. All rights reserved. Cumulative incidence of cardiovascular events in subgroups with low-density lipoprotein- cholesterol (LDL-C) <100 mg/dL (<25th percentile) and small dense LDL-C (sdLDL-C) <27.8 mg/dL (<25th percentile), from proportional hazards models adjusted for age, sex, and race.
Hoogeveen R C et al. Arterioscler Thromb Vasc Biol. 2014;34:1069-1077
Copyright © American Heart Association, Inc. All rights reserved. Ference, B.A. et al. J Am Coll Cardiol. 2015; 65(15):1552–61. Effect of Random Allocation to Lower LDL-C on the Risk of Coronary Heart Disease Mediated by Polymorphisms in NPC1L1, HMGCR, or Both. A 2X2 Factorial Mendelian Randomization Study: Randomization Worked!
. Ference, B.A. et al. J Am Coll Cardiol. 2015; 65(15):1552–61. IMPROVE-IT: Ezetimibe vs Statin Benefit
Change in LDL-C vs Clinical Benefit
Events (%) Events Reduction in Rate of Major Vascular Vascular Major of Rate in Reduction
0.5 (19.3) 1.0 (38.6) 1.5 (57.9) 2.0 (77.2) Reduction in LDL Cholesterol: mmol/L (mg/dL) Lifelong genetically low LDL confers much greater CV risk reduction than short-term drug treatment
Ference, B.A. et al. J Am Coll Cardiol. 2015; 65(15):1552–61. Of 15 variants that alter HDL-C, 6 also affect MI risk Of 15 variants that alter HDL-C, 6 also affect MI risk Of 15 variants that alter HDL-C, 6 also affect MI risk
All 6 are ‘HDL-C Plus’ (alter HDL-C & at least one other lipid fraction) HDL Metabolism
Bile Mature HDL-C SR-BI A-I
CE CE LCAT FC FC Liver SR-BI HL, EL FC E A-I Nascent HDL-C LDL-C
Receptor CETP
CE B VLDL/LDL-C
Cuchel et al. Arterioscler Thromb Vasc Biol. 2003;23:1710-12. Copyright © 2003 American Heart Association, Inc. HDL Metabolism with SRBI Blocked
Bile Mature HDL-C SR-BI A-I
CE CE LCAT FC FC Liver SR-BI HL, EL FC E A-I Nascent HDL-C LDL-C
Receptor CETP
CE B VLDL/LDL-C
Cuchel et al. Arterioscler Thromb Vasc Biol. 2003;23:1710-12. Copyright © 2003 American Heart Association, Inc. 62 yo male with preclinical atherosclerosis Cholesterol Efflux Capacity and ASCVD Events: Dallas Heart Study
10% Low efflux 8% Q1 ASCVD Events: MI 6% Q2 Stroke PCI/CABG CV death Q3 4% Q4 n=132 Log rank p=0.002 High 2% efflux
0% 0 1 2 3 4 5 6 7 8 9 Rohatgi et al. NEJM 2014;371:2383-92. Years Lp(a)-related CV risk in Patients on Statins
Baseline 4th Quartile Achieved Odds Ratio Odds Ratio Study Name N Lp(a) mg/dL LDL-C (95% CI) P-Value (95% CI) Weight AIM HIGH – Niacin group 1427 ~>50 65.2 1.90 (1.33-2.72) 0.001 10.8%
LIPID-Pravastatin group 7863 >73.7 112.5 1.23 (1.09-1.40) <0.001 58.7%
JUPITER-Rosuva group 3877 ~>21 55 1.71 (0.99-2.95) 0.06 29.4%
54.9 OVERALL 13167 89.1 1.61 100% (weighted value) (weighted value) (weighted value)
0.5 1 1.5 2 2.5 3 Hazard Ratio (95% CI) for CV Events
Baseline LDL-C in those with Lp(a) levels > 4th quartile compared to the lowest quartile
Tsimikas S. JACC 2017;69:692-711 Genomic study vs CVOT Greater CV Benefit with Longer Exposure Similar CV Benefits for Anti-PCSK9 mAb to Statins REVEAL Trial Design for Efficacy of Anacetrapib
Anacetrapib 100 mg 30,000 patients aged Atorvastatin to >50 with occlusive achieve LDL-C arterial disease target
Placebo
Sites in North America, Europe, and Asia 4-year follow-up Primary End Point Planned completion in 2017 Coronary death, myocardial infarction, or coronary revascularization
Available at: www.revealtrial.org. CETP Genotypes – Meta-Analysis Association with CETP Phenotype and Lipid Levels
Thompson A, et al. JAMA 2008;299:2777. CETP Genotypes – Meta-Analysis Odds Ratios for Coronary Disease vs Odds Ratios for HDL-C
0.95 (0.92-0.99)
0.94 (0.89-1.00)
0.95 (0.91-1.00)
Thompson A, et al. JAMA 2008;299:2777. The HPS3/TIMI55–REVEAL Collaborative Group* N Engl J Med 2017; 377:1217-1227 The HPS3/TIMI55–REVEAL Collaborative Group* N Engl J Med 2017; 377:1217-1227 Validation of the Lipid Hypothesis and Lower is Better
• IMPROVE-IT proves LDL-C of 54mg/dl on ezetimibe plus statins has lower MACE vs 70mg/dl on statins alone • FOUIER trial confirms lowering LDL-C with anti-PCSK9 mAb • Odyssey Outcomes reduce MACE similar to statins with second anti- and lower is better PCSK9 mAb • AHA/ACC Guidelines remove • AHA/ACC reverses goals • REVERAL trial positive further Previous guidelines validating another MOA for LDL- and re-establishes C reduction goals GWAS studies confirm all polymorphisms with lower LDL- c levels have lower CV risk
2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 Overwhelming Evidence Supports the Causality of LDL-C Rader, NEJM 2000; 343: 1181. JUPITER Dual Target Analysis: ApoB:ApoA<0.5, hsCRP<2 mg/L
0.08 Placebo
HR 1.0 (referent) 0.06 ApoB:ApoA > 0.5 and / or
hsCRP > 2 mg/L 0.04 HR 0.62 (0.49-
Cumulative IncidenceCumulative 0.81)
ApoB:ApoA < 0.5 0.02 and hsCRP < 2 mg/L
HR 0.34 (0.21- 0.00 0 1 2 3 4 0.53)
Follow-up (years) Number at Risk P < 0.0001 Rosuvastatin 7,716 7,699 7,678 6,040 3,608 1,812 1,254 913 508 145 Placebo 7,832 7,806 7,777 6,114 3,656 1,863 1,263 905 507 168 Seite 56 Role of inflammation in atherosclerosis ? - A fierce debate started in the 19th century - Both observed cellular inflammatory changes in the atherosclerotic vessel walls
Carl von Rokitansky Rudolf Virchow „Inflammation accompanies „Inflammation initiates atherosclerosis“ atherosclerosis“
Rolitansky; Virchow R. Der ateromatöse Prozess A manual of pathologic anatomy. 1852 der Arterien. Wien Med Wschr 1856 Seite 57 Canakinumab: Dose-response effects of at 4 months for C-reactive protein (CRP), interleukin-6 (IL-6), and fibrinogen in placebo-subtracted analyses.
Ridker P et al. Circulation 2012;126:2739-2748 Seite 58 Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS)
Stable CAD (post MI) N = 10,061 Residual Inflammatory Risk 39 Countries (hsCRP > 2 mg/L) April 2011 - June 2017 1490 Primary Events
Randomized Randomized Randomized Randomized Canakinumab 50 mg Canakinumab 150 mg Canakinumab 300 mg Placebo SC q 3 months SC q 3 months SC q 3 months SC q 3 months
Primary Endpoint: Nonfatal MI, Nonfatal Stroke, Cardiovascular Death (MACE)
Secondary Endpoint: MACE plus Unstable Angina Requiring Urgent Revascularization (MACE+)
Patients were excluded from CANTOS if they had nephrotic syndrome or eGFR < 30ml/min/1.73m2.
Ridker PM et al. N Engl J Med. 2017;377:1119-31 Seite 59 CANTOS: Primary Cardiovascular Endpoints
Placebo SC q 3 months Canakinumab 150/300 mg SC q 3 months
MACE MACE - Plus
HR 0.85 HR 0.83 95%CI 0.76-0.96 95%CI 0.74-0.92
P = 0.007 P = 0.0006
Cumulative Incidence(%) Cumulative Cumulative Incidence(%) Cumulative
0 1 2 3 4 5 Follow-up Years Follow-up Years
35 - 40% reductions in hsCRP and IL-6 No change in LDLC
Ridker PM et al. N Engl J Med. 2017;377:1119-31 CANTOS validated that inflammation plus CKD leads to a high CV mortality rate and normalizing CRP (< 2mg/dl) results in substantial CV Benefits Testing for concordance
Implications for Lower LDL-C concentration compounds Observational epidemiology LDL-C lowering Genetic epidemiology Statin trials .8 .9 1 1.1 1.2 1.3
Lower circulating Lp-PLA2 activity Observational epidemiology Darapladib Genetic epidemiology X .8 .9 1 1.1 1.2 1.3 1.4
Higher circulating lipoprotein(a)
Observational epidemiology Various Genetic epidemiology
.8 .9 1 1.1 1.2 1.3 1.4
Circulating interleukin-6 receptor
Observational epidemiology ? ? Genetic epidemiology IL-6 inhibitors
LSC, Lancet 2010 .8 .9 1 1.1 1.2 1.3 1.4 ERFC, JAMA 2009 Odds ratio (95% CI) IL6R Genetics Consortium, Lancet 2012 Clarke, NEJM 2009 Genomics will Change the Treatment Paradigm to Primordial Prevention Michael’s genetic CV risk Polygenic Risk Score Accurately Predicts Future Risk of Cardiovascular Disease
FavorableIntermediateUnfavorable
100 lifestyle lifestyle lifestyle Artery
- 80
60
40
Calcification Score Calcification 20
Standardized Coronary Standardized 015 22 3132 29 4732 52 64 Low Intermediate High Genetic Risk Genomic Risk Score: Individuals with the highest burden of genetic risk derived the largest relative and absolute clinical benefit with statin therapy INTERVENTIONAL LIPIDOLOGIST