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, MD, PhD, FESC, SFASA, FRSH , LDL

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Genes and CVD Pharmacogenetics Gene therapy

CETP polymorphisms

WOSCOPS the B2B2 has a 30% reduced risk of a CV event compared with B1B1
Kolovou et al reported a positive association between B1 and postprandial hyperlipemia

Barzilai, et al reported that exceptional longevity is associated with ~ 3-fold increased frequency of VV genotype Soerensen et al found that is associated with longevity in oldest-old (ages 92-93) Danes population.

Freeman DJ, et al. Eur Heart J. Kolovou G, et al. Open Cardiovasc Med J. 2010;4:14-19, 2003;24(20):1833-1842 Kolovou G, et al. Am J Med Sci. 2006;331(1):10-16, Barzilai N, et al. JAMA. 2003;290(15):2030-2040, Soerensen M, et al. Age (Dordr). 2012

100 first-degree relatives of pts with CAD (asymptomatic, non-smoking, lipidlowering therapy-nave) were compared to matched controls without family history.

In this population of healthy, low-risk subjects with a family history of CAD, the AGT M235T variant was the most significant predictor of CAC

Joshi PH, et al. The M235T single nucleotide polymorphism in the angiotensinogen gene is associated with coronary artery calcium in patients with a family history of coronary artery disease. Atherosclerosis. 2013 Feb;226(2):433-9.

D allele of ACE gene


More frequent in some cohorts of European centenarians, including France, UK and Italy compared with their younger ethnically matched referents. Petranovi et al reported that the DD genotype was 2X more frequent in 80+ cohort compared with the general population of Croatia. Fiuza-Luces et al reported no differences in the allelic or genotypic frequencies between controls and centenarians in a Spanish population.

Schachter F, et al. Nat Genet. 1994; Galinsky D, et al. Atherosclerosis. 1997; Seripa D, et al. J Gerontol A BiolSci Med Sci. 2006; Petranovi M, et al. Age (Dordr). 2012; Fiuza-Luces C, et al. J Renin Angiotensin Aldosterone Syst. 2011

Table 3. ACE I/D allele frequency in Control (n=105), Nonagenarian (n=190) and Centenarian (n=12) groups

Age

ACE I/D alleles

I
<80 41.0%

D
59.0%

Total
100.0%

90
99

37.6%
62.5%

62.4%
37.5%

100.0%
100.0%

p = 0.045 Centenarian vs Control groups, p = 0.016 Nonagenarian vs Centenarian groups

Kolovou G, Kolovou V, Vasiliadis I, Giannakopoulou V, Mihas C, Bilianou H, Kollia A, Papadopoulou E, Marvaki A, Goumas G, Kalogeropoulos P, Limperi S, Katsiki N, Mavrogeni S. The Frequency of 4 Common Gene Polymorphisms in Nonagenarians, Centenarians, and Average Life Span Individuals. Angiology. 2013 Feb 6.

Table

3.

Cox

proportional-hazards

model

for

overall

mortality (>2000 pts from MASS II study)

Age

p=0.00 Previous MI p=0.02 rs2383206 p=0.02

Luciana Gioli-Pereira, et al. Higher incidence of death in multi-vessel coronary artery disease patients associated with polymorphisms in chromosome 9p21. BMC Cardiovasc Disord. 2012; 12: 61.

Gene polymorphisms (APOE, NOS3, LIPC) may be risk factors for cardiac adverse events after primary CABG

Eifert, et al. J Cardiothorac Surg. 2009.

Relative risk of clinical outcomes (a second PTCA, MI, CABG, CV death) according to LIPC gene genotypes
CAD subjects with clinical outcomes n. (%) CC carriers 6 (13%) CAD subjects without clinical outcomes n. (%) 9 (60%) OR (95% CI) 1

LIPC status

GG + GC carriers

39 (87%)

6 (40%)

7.6 (1.0 57.2)*

LIPC= polymorphisms of Apo E, Apo AI, Apo CIII, Apo B, LPL and HL

Baroni, et al. BMC Med Genet,2003

Independent effects of -219 G>T and 2/3/4 polymorphisms of apo E gene on CHD: The Southampton Atherosclerosis Study
Frequency 1 vessel 2 vessel 3 vessel Odds ratio (95% CI) Adjusted odds ratio (95% CI)
a

4 allele 3 allele 2 allele Total T allele G allele Total T-4 haplotype

0.128 0.791 0.081 1 0.448 0.552 1 0.094

0.141 0.787 0.072 1 0.451 0.549 1 0.098

0.164 0.774 0.062 1 0.527 0.473 1 0.133

1.328 (1.026, 1.358 (1.020, 1.717), P = 0.031 1.808), P = 0.036

1.230 (0.952, 1.214 (1.091, 1.589), P = 0.114 1.610), P = 0.176


1.488 (1.133, 1.404 (1.073, 1.954), P = 0.039 1.838), P = 0.015 1.199 (1.032, 1.424), P = 0.016

T-3 haplotype

0.352

0.353

0.390

T-2 haplotype
G-4 haplotype

0.002
0.035

0.001
0.044

0.004
0.033

Shu Yu,et al. ur J Hum Gen, 2003

Allele, n (%) epsilon2 CAD patients MI (+)


MI () All

epsilon3

epsilon4

Total

3 (1.2)
18 (6.3) 21 (3.9)

218 (87.9)
240 (83.9) 458 (85.8) 392 (81.7)

27 (10.9)
28 ( 9.8) 55 (10.3) 49 (10.2)

248
286 534 480

Healthy subjects 39 (8.1)

Kolovou, et al. Curr Med Res Opin. 2002;18:118-24

Earlier CHD

Intermediate CHD

Later CHD

Healthy

N
2/2

73
0

321
0.6

108 0 10.2
1.9 68.5 18.5 0.9

103 0 8.7
2.9 65.0 22.3* 1.0

2/3
2/4 3/3 3/4 4/4

4.1
0 83.6 11.0 1.4

6.9
1.6 74.5 15.6 0.9

Pearson Chi-Square, p=0.606 among all pt groups and healthy Pearson Chi-Square, p=0.028 between Earlier CHD and Healthy groups carrying the apo 3/4 genotype. Kolovou, et al. Angiology, 2005

The role of common variants of CETP gene in left main CAD


Controls CETP genotypes (n=97) I405V II IV VV TaqIB B1B1 B1B2 B2B2 (n=241) (n=133) MPCAD LMCAD

40 (42%) 52 (54%) 4 (4%)

111 (46%) 105 (44%) 25 (10%) (P=0.08) 81 (34%) 128 (53%) 32 (13%) (P=0.001)

51 (38%) 66 (50%) 16 (12%) (P=0.12) 45 (34%) 74 (56%) 14 (10%) (P=0.001)

22 (23%) 45 (47%) 29 (30%)

Kolovou G, Vasiliadis I, Kolovou V, Karakosta A, Mavrogeni S, Papadopoulou E, Papamentzelopoulos S, Giannakopoulou V, Marvaki A, Degiannis D, Bilianou H. Lipids Health

Distribution of CYP8A1 genotype (CC, CA, AA) and allele frequencies (A and C)
Controls CYP8A1 genotype (n=103) (n=151) LMCAD P

CC
CA AA Allele frequencies C allele frequency A allele frequency

43 (34%)
44 (46%) 16 (50%)

84 (66%)
51 (54%) 16 (50%) 0.08*

0.63 0.37

0.73

0.016*
0.27
E Bousoula, V Kolovou, I Vasiliadis, A Karakosta, T Xanthos, EO Johnson, P Skandalakis, G Kolovou. Angiology, 2012

Survival curves for time-to-death from the four defined endpoints.

Regieli J J et al. Eur Heart J 2008;29:2792-2799


Published on behalf of the European Society of Cardiology. All rights reserved. The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Haplotype prevalence estimations and 95% confidence intervals (left) and effects on mortality endpoints (right).

Regieli J J et al. Eur Heart J 2008;29:2792-2799

Table 2. Distribution of CETP I405V (II, IV, VV) and TaqIB (B1B1, B1B2, B2B2) genotypes.
CETP polymorphisms I405V II IV VV TaqIB B1B1 B1B2 B2B2 41 (33) 64 (52) 19 (15) 100(65-134) 112(85-137) 101(31-172) 6.6(4.6-8.6) 6.5(5.7-7.3) 5.0(3.7-6.3) 58 (47) 50 (40) 16 (13) 81(57-105) 122(87-155) 147(172-222) 6.1(4.6-7.6) 6.3(5.4-7.2) 7.1(5.7-8.6) No of pts (%) GS (95% CI) DJS (95% CI)

GS: Gensini Score, DJS: Duke, Pearson Chi-Square, p=0.046 among all I405V genotypes; *p=0.032 (unpaired t-test) between GS of II and IV genotypes

Kolovou G, et al. Clin Invest Med. 2006;29:14-9

Table 3. AGT (CA)n, ACE I/D, REN (TCTG)n, NPRA (CT)n genotype odds ratios (OR) with 95% confidence interval (CI) for the presence

of CAD
Genotype AGT (CA)n SS SL LL ACE I/D II ID 0.509 1.123 0.259-1.001 0.709-1.778 1.473 0.679 0.963 0.924-2.347 0.421-1.097 0.526-1.763 OR 95% CI

DD
D allele REN (TCTG)n SS SL LL NPRA (CT)n

1.225
1.322

0.772-1.943
0.943-1.853

0.554 2.183 0.234

0.345-0.888* 1.352-3.526* 0.055-0.996*

SS
SL LL

1.263
0.679 1.369

0.599-2.666
0.361-1.276 0.654-2.868

AGT, angiotensinogen; ACE, angiotensin converting enzyme; REN, renin; NPRA, natriuretic peptide receptor A; S, short; L, long; I, insertion; D, deletion. *p<0.05

Karayannis, et al. Angiology,2010,

Random effects odds ratio (OR) estimates with the corresponding 95% CI of the allele ACE D vs. I for restenosis a) after PCIballoon, and b) after PCISTENT. The CI of pooled estimates are displayed as a horizontal line through the diamond.

Kitsios, et al. BMC Med Genet. 2009

Renin-angiotensin-aldosterone system gene polymorphisms in coronary artery bypass graft surgery patients

Table 2. Frequencies of genotypes and alleles in CABG patients and non-CAD controls for AGT M235T, AGT T174M, ACE I/D and AT1 receptor A1166C polymorphisms. CABG patients Non-CAD controls (n=154) (n=155) p value AGT M235T genotypes n (%) 95% CI n (%) 95% CI MM 34 (22) 1629 44 (28) 2236 0.05 MT 94 (61) 5369 73 (47) 3955 TT 26 (17) 1223 38 (24) 1838

G. Ragia, E. Nikolaidis, A. Tavridou, KI Arvanitidis, S. Kanoni, GV Dedoussis, G. Bougioukas, V G. Manolopoulos. J Renin-Angiotensin-Aldosterone System, 2010

Kaplan Meier curves for AGT1R polymorphisms

Franco, et al. BMC Med Genet. 2007; 8: 27.

Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease
Schunkert H, Knig IR, Kathiresan S, Reilly MP, Assimes TL, Holm H, Preuss M, Stewart AF, Barbalic M, Gieger C, Absher D, Aherrahrou Z, Allayee H, Altshuler D, Anand SS, Andersen K, Anderson JL, Ardissino D, Ball SG, Balmforth AJ, Barnes TA, Becker DM, Becker LC, Berger K, Bis JC, Boekholdt SM, Boerwinkle E, Braund PS, Brown MJ, Burnett MS, Buysschaert I; Cardiogenics, Carlquist JF, Chen L, Cichon S, Codd V, Davies RW, Dedoussis G, Dehghan A, Demissie S, Devaney JM, Diemert P, Do R, Doering A, Eifert S, Mokhtari NE, Ellis SG, Elosua R, Engert JC, Epstein SE, de Faire U, Fischer M, Folsom AR, Freyer J, Gigante B, Girelli D, Gretarsdottir S, Gudnason V, Gulcher JR, Halperin E, Hammond N, Hazen SL, Hofman A, Horne BD, Illig T, Iribarren C, Jones GT, Jukema JW, Kaiser MA, Kaplan LM, Kastelein JJ, Khaw KT, Knowles JW, Kolovou G, Kong A, Laaksonen R, Lambrechts D, Leander K, Lettre G, Li M, Lieb W, Loley C, Lotery AJ, Mannucci PM, Maouche S, Martinelli N, McKeown PP, Meisinger C, Meitinger T, Melander O, Merlini PA, Mooser V, Morgan T, Mhleisen TW, Muhlestein JB, Mnzel T, Musunuru K, Nahrstaedt J, Nelson CP, Nthen MM, Olivieri O, Patel RS, Patterson CC, Peters A, Peyvandi F, Qu L, Quyyumi AA, Rader DJ, Rallidis LS, Rice C, Rosendaal FR, Rubin D, Salomaa V, Sampietro ML, Sandhu MS, Schadt E, Schfer A, Schillert A, Schreiber S, Schrezenmeir J, Schwartz SM, Siscovick DS, Sivananthan M, Sivapalaratnam S, Smith A, Smith TB, Snoep JD, Soranzo N, Spertus JA, Stark K, Stirrups K, Stoll M, Tang WH, Tennstedt S, Thorgeirsson G, Thorleifsson G, Tomaszewski M, Uitterlinden AG, van Rij AM, Voight BF, Wareham NJ, Wells GA, Wichmann HE, Wild PS, Willenborg C, Witteman JC, Wright BJ, Ye S, Zeller T, Ziegler A, Cambien F, Goodall AH, Cupples LA, Quertermous T, Mrz W, Hengstenberg C, Blankenberg S, Ouwehand WH, Hall AS, Deloukas P, Thompson JR, Stefansson K, Roberts R, Thorsteinsdottir U, O'Donnell CJ, McPherson R, Erdmann J; CARDIoGRAM Consortium, Samani NJ.

We performed a meta-analysis of 14 genome-wide association studies of CAD comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 10 and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci were associated with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits. Nat Genet. 2011 Mar 6;43(4):333-8.

The present genomic analysis of more than 135,000 individuals revealed three major findings. First, we more than doubled the number of loci with firm association to CAD. Specifically, our study yielded 13 previously unidentified loci and confirmed 10 previously reported loci. Second, we found that only a minority of the established and new loci appear to act through traditional RFs but that the majority reside in gene regions that were not previously suspected in the pathogenesis of CAD. Third, a substantial proportion of the CAD risk variants were also strongly associated with various other human disease traits in GWAS.

Nat Genet. 2011 Mar 6;43(4):333-8.

: ;

Genes and CVD Pharmacogenetics Gene therapy

Pharmacogenetics aims to personalize medication choice and dosage to ensure that maximum clinical benefit is achieved whilst side effects are minimized. Over the past decade, our knowledge of pharmacogenetics in CV therapies has increased significantly.

Yip VL, Pirmohamed M. Expanding Role of Pharmacogenomics in the Management of Cardiovascular Disorders. Am J Cardiovasc Drugs. 2013 Apr 12.

The anticoagulant warfarin represents the most advanced application of pharmacogenetics in CV medicine. Prospective randomized clinical trials are currently underway utilizing dosing algorithms that incorporate genetic polymorphisms in cytochrome P450 (CYP)2C9 and vitamin k (VKORC1) to determine warfarin dosages.

Yip VL, Pirmohamed M. Expanding Role of Pharmacogenomics in the Management of Cardiovascular Disorders. Am J Cardiovasc Drugs. 2013 Apr 12.

Polymorphisms in CYP2C9 and VKORC1 account for approximately 40 % of the variance in warfarin dose.

Yip VL, Pirmohamed M. Expanding Role of Pharmacogenomics in the Management of Cardiovascular Disorders. Am J Cardiovasc Drugs. 2013 Apr 12.

Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY), 2944 pts

Analysis identified that carriage of the CES1 rs2244613 minor allele occurred in 33% of patients in RE-LY and was associated with lower exposure to active dabigatran.

The presence of the polymorphism associated with a lower risk of bleeding

was

Par G, et al. Genetic determinants of dabigatran plasma levels and their relation to bleeding.Circulation. 2013 Apr 2;127(13):1404-12

Response to statins has been associated with polymorphisms in CETP, APOE, APOC1 genes.
Polymorphisms in SLCO1B1 gene is associated with increased statin-induced myopathy.

Yip VL, Pirmohamed M. Expanding Role of Pharmacogenomics in the Management of Cardiovascular Disorders. Am J Cardiovasc Drugs. 2013 Apr 12.

DNAJC5B gene and pravastatin

Shiffman D, et al. Genome-wide study of gene variants associated with differential cardiovascular event reduction by pravastatin therapy. PLoS One. 2012;7(5):e38240

Heterozygotes of rs13279522 (~26% of the population) had 45% event reduction in a combined analysis of CARE, WOSCOPS and PROSPER/PHASE, while major homozygotes (~71% of the population) had 13% event reduction by pravastatin.

Shiffman D, et al. Genome-wide study of gene variants associated with differential cardiovascular event reduction by pravastatin therapy. PLoS One. 2012;7(5):e38240

PCR-RFLP I405V
TaqIB
I/I V/V I/V B1/B2
B2/B2 B1/B1

Pharmacogenetic study of cholesteryl ester transfer protein gene and simvastatin treatment in hypercholesterolaemic subjects. Anagnostopoulou K, Kolovou G, Kostakou P, Mihas C, Mikhailidis D, Cokkinos DV.

METHODS: Hypercholesterolaemic pts (n = 180) attending the lipid clinic were genotyped and their response to simvastatin was evaluated. RESULTS: Sequence variations in the CETP gene influenced the effect of lipidlowering treatment. Specifically, the I allele of the I405V polymorphism was associated with a greater reduction in TG (p = 0.04) and a significant increase in HDL cholesterol (p = 0.05) after treatment compared with the V allele. CONCLUSIONS: The authors' findings suggest that CETP I405V polymorphism modifies the effect of simvastatin on TG reduction and HDL-C elevation; the carriers of the I allele responded better to treatment. These findings need to be confirmed in larger studies

Expert Opin Pharmacother. 2007

I405V

300

250

p=0.04
-22%

200

150

-16%

Baseline I405 V405

100

50

0 TC TG LDL HDL

TaqIB

300 250 200 150 100 50 0 TC TG LDL HDL

NS
Before B1 B2

Cholesteryl Ester Transfer Protein Gene and Effectiveness of Lipid Lowering of Atorvastatin
Atorvastatin users (n=212) , TaqIB and I405V

In whole population, B1B1 allele decreased TGs in a lesser degree compared to B1B2 or B2B2 genotypes (21%, 28% or 29%. In Low HDL group the B2 carriers had greater decrease of TC and TGs compared to B1 carriers. In High HDL group, LDL showed greater % decrease in subjects with II genotype compared to those with IV genotype

Kolovou G, et al. OCMJ, 2010

: ;

Genes and CVD Pharmacogenetics Gene therapy

PCSK9 inhibitor

(Ig) G2 PCSK9 LDLR. .

LDLR

LDLR

/ LDLR

PCSK9

LDL

Golgi

, , , 2012, . INFOHEALTH

TNT: PCSK9

1613 pts with stable CHD (ATV10mg vs ATV 80mg) Follow up 5ys
PCSK9 levels predict CV events in patients treated with low-dose of ATV

Huijgen R. J Am Coll Cardiol. 2012 May 15;59(20):1778-84

PCSK9 inhibitor
Multicentre, randomised, placebo-controlled phase II trial, 77 hFH: statin EZE PCSK9 50mg, 200mg, or 300mg/4 weeks, or 150mg/2 weeks LDL 29% for 150 mg/4 weeks 32% for 200 mg/4 weeks 43% for 300 mg/4 weeks 68% for 150 mg/2 weeks
Stein EA, et al. Lancet. 2012 Jul 7;380(9836):29-36.

Mipomersen: Mechanism of Action


DNA
Transcription

mRNA
Translation

Disease-Associated Protein
Traditional Drug

Transcription

No Translation

Antisense Drug
(Oligonucleotide)

No Disease-Associated Proteins Produced


Crooke R, et al. Adapted from: Crooke ST, ed. Antisense drug technology: principles, strategies and applications. 2nd ed. Boca Raton, FL: CRC Press, 2007:601-639.

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Mipomersen: Apo B-100 as a Target


Cholesterol

VLDL Mipomersen Apo B Triglyceride

Apo B-100 is an important structural and functional component of lipoproteins Blocking Apo B-100 production blocks VLDL and LDL production

VLDL

IDL

Apo A

LDL1
LDL2 LDL3
45

Lp(a)

45

45

Apo B inhibitor
Double-blind, placebo-controlled, mipomersen, in pts with statin intolerant, for 28 weeks 33 pts sc 200 mg/weekly mipomersen or placebo LDL: 47%, apoB 46%: Lp(a) 27%
19% mipomersen and 17% placebo discontinued Liver transaminase increases 3 in mipomersen 33%

Visser , et al. Eur Heart J. 2012 May;33(9):1142-9

MTP inhibitor, Lomitapide

LDL 46%

ACAT2

MTP

NPC1L1

Apo B48
ABCG5 ABCG8

, , , 2012, . INFOHEALTH

Georgios Hatzigeorgiou Vasiliki Giannakopoulou Ioannis Vasiliadis Nikos Kontoras Constantinos Mihas Antzi Karakosta Olga Diakoumakou Vana Kolovou Sofia Diamantopoulou Dionysia Manolopoulou Sophie Mavrogeni

Dimitris Mikhailidis Panos Deloukas Eleni Bilianou Niki Katsiski Georgios Dedoussis Evaggelos Manolopoulos Christina Marvaki Constantinos Demopoulos Smaragdi Antonopoulou