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Prof. Dr. H. SchunkertMedizinische Klinik IIUK S-H Campus Lübeck
Genome-wide association formyocardial infarction
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Clinical Demands for Genetic Testing
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Myocardial infarction
Genes
Genes GenesGenesGenes
Calcification/ Remodeling/ Plaque formation
Hyperlipidemia?
Genes
Genes GenesGenesGenes
environment environmentenvironment environmentenvironment
Hypertension smoking
Hypercoagulation
Inflammation/ Endothelial dysfunction
Diab. mell.
Clin Res Cardiol. 2007;96:1-7
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Which genes are responsible?
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Genome-wide Map- Microsatellites
1 3 4 5 1514131211109876
16 20 211817 2219
2
Resolution:n=400
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MI locus 14q32
Nat Genet 2002;30:210-214
point LOD 3.9p= 0.00015
genome wide LODp< 0.05
1
2
3
4
0 20 40 60 80 100 120
D1
4S
74
2
D1
4S
12
8
D1
4S
60
8
D1
4S
59
9
D1
4S
58
7
D1
4S
58
8
GA
TA
13
9A
07
D1
4S
61
7
D1
4S
59
2
D1
4S
60
6
D1
4S
14
3
D1
4S
97
9
D1
4S
10
19
D1
4S
26
7
D1
4S
14
26
D1
4S
98
5
D1
4S
10
51
D1
4S
29
2
D1
4S
10
07
LOD
cM
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linkage-Scans for atherosclerosisgenetic hot spots for CAD
Clin Res Cardiol 2007; 96:1–7
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2007
2006
2005
2000
1992candidate gene-polymorphisms
genome-widelinkage analysis
10k-SNP Chip
LO
D
black box : myocardial infarction
500k-SNP Chip
1000k-SNP Chip
the key: a chip!
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Genome-wide Map- SNPs1 3 4 5 1514131211109876
16 20 211817 2219
2
resolution:N=1.000.000
12
3
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rs1333049
Better Coverage
Chromosome 9p21.3
Gene
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genome scan - 500,000s SNPs
identification ofpositive regions
replication
2.000 affected individuals 2.000 healthy individuals
122
GWAs – Strategy I
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GWAs – Strategy II
2000 cases3200 controls
1988 cases3000 controls
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NEJM 2007; 357: 443-453
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Association of locus on chromosome 9p21.3 with CAD
STUDY CASES/CONTROLS RISK ALLELE FREQUENCY
ODDS RATIO PER COPY OF RISK ALLELE
P-VALUE
WTCCC 1926/2938 0.53 1.37 (1.26 –1.48) 1.8x10 -14
German MI FS 875/1644 0.52 1.33 (1.18 -1.51) 6.8x10 -6
Combined 2801/4582 0.53 1.36 (1.27 -1.46) 2.9x10 -19
rs599839
NEJM 2007; 357: 443-453
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Structure of the chromosome 9 CAD-associated locus
T2DM SignalT2DM Signal
NEJM 2007; 357: 443-453
-Lo
g p
-val
ue
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Association of locus on chromosome 9p21.3 with CAD
McPherson R et al. Science 2007;316:1488-1491
Most replicated locus for CAD risk to date
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Association of locus on chromosome 9p21.3 with CAD
Helgadottir A et al. Science 2007; 316:1491-1493
Most replicated locus for CAD risk to date
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RS_ID BP_pos Chr p-trendLeft Main WTCCC_CAD German MI MAFRS2133188 219202148 1 1,8E-02 4,7E-04 7,7E-03 0,149132RS12543112 125776973 8 4,9E-02 1,9E-03 1,3E-03 0,421187RS10757264 22009732 9 9,4E-05 1,9E-07 5,6E-03 0,47855RS10757272 22078260 9 2,2E-07 4,8E-12 1,0E-06 0,495403RS10965212 22013795 9 2,1E-06 9,5E-10 3,2E-03 0,473873RS10965215 22019445 9 2,8E-06 5,1E-10 3,6E-04 0,470378RS1292136 22014351 9 2,6E-07 4,9E-09 3,2E-03 0,491228RS1333048 22115347 9 1,3E-05 1,3E-13 2,0E-06 0,487127RS2891168 22088619 9 1,2E-07 5,9E-13 4,0E-07 0,497433RS4977574 22088574 9 1,8E-07 4,3E-13 4,3E-07 0,498978RS523096 22009129 9 5,8E-05 1,4E-06 2,5E-03 0,444217RS564398 22019547 9 8,6E-06 1,8E-08 1,5E-03 0,417605RS643319 22007836 9 9,4E-06 3,1E-08 2,0E-03 0,485174RS7865618 22021005 9 3,6E-06 1,3E-09 2,3E-03 0,425869RS9632884 22062301 9 1,1E-05 3,8E-13 2,2E-06 0,495298RS7945815 26496312 11 4,0E-02 3,7E-01 4,9E-03 0,35559
SNPs with triple replication across 3 GWAs
13 out of 16 SNPs with triple replication are located at 9p21 !
(Circulation Suppl 2007)
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Replicated association between chromosome 9p21.3 and MI risk
(in revision)p=7.78x10-33 (OR 1.31 [ 1.25,1.37])
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Broadbend et al (Procardis) Hum Mol Gen 2008 (in press)
Replicated association between chromosome 9p21.3 and MI risk
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Broadbend et al (Procardis) Hum Mol Gen 2008 (in press)
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Replicated association between chromosome 9p21.3 and MI risk
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Broadbend et al (Procardis) Hum Mol Gen 2008 (in press)
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Replicated association between chromosome 9p21.3 and MI risk
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Helgadottir et al (deCode) Nat Genet 2008 (in press)
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Helgadottir et al (deCode) Nat Genet 2008 (in press)
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Replicated association between chromosome 9p21.3 and MI risk
in Korea
Shen et al ATVB 2008;28; in press
n=294 n=611
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rs13
3304
9
rs78
6561
8
rs12
9213
6
rs70
4485
9
HaplotypeT GGT
A CAC
Haplotype analysis of the chromosome 9 CAD-associated locus
WTCCC Study: Odds ratio1.48 (1.34-1.64) per copy of the ACAC haplotype
German MI Study: Odds ratio1.34 (1.12-1.59) per copy of the ACAC haplotype
NEJM 2007; 357: 443-453
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rs13
3304
9
rs78
6561
8
rs12
9213
6
rs70
4485
9
Haplotype analysis of the chromosome 9 CAD-associated locus
rs7865618.Haplotypic background
StudyTTA TTG ACA
GerMIFS II 0.91 [0.51,1.65] 1.05 [0.73,1.50] 1.35 [1.03,1.76]
UK MI Study 0.72 [0.39,1.34] 1.31 [0.93,1.85] 1.37 [1.05,1.79]
Left Main Disease Study 0.79 [0.38,1.63] 0.93 [0.61,1.42] 1.31 [0.89,1.92]MONICA/KORA Study 1.58 [0.92,2.73] 1.20 [0.82,1.75] 1.27 [0.96,1.68]
PopGen 0.96 [0.55,1.69] 1.12 [0.84,1.48] 1.73 [1.39,2.16]
Test for homogeneityacross studies
0.36 0.78 0.39
0.99 [0.76,1.30] 1.12 [0.96,1.31] 1.44 [1.27,1.62]Pooled OR [95% CI]
0.94 0.14 4.08x10-9
rs1333049-C allele according to the haplotypic backgrounds
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Further genomewide results
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Other loci strongly associated with CAD identified from joint analysis of the WTCCC Study and
German MI Study
LOCUS SNP RISK ALLELE AND
FREQUENCY
ODDS RATIOPER COPY OF RISK ALLELE
P-VALUE FPRP GENES
6q25.1 rs6922269 A (0.25) 1.23 (1.15-1.33) 2.90x10-8 0.0023 MTHFD1L
2q36.3 rs2943634 C (0.65) 1.21 (1.13-1.30) 1.61x10-7 0.0190 ---
1p13.3 rs599839 A (0.77) 1.29 (1.18-1.40) 4.05x10--9 0.0006 PSRC1/ CELRS2
1q41 rs17465637 C (0.71) 1.20 (1.12-1.30) 1.27x10-6 0.1314 MIA3
10q11.21 rs501120 T (0.87) 1.33 (1.20-1.48) 9.46x10-8 0.0234 CXCL12
15q22.33 rs17228212 C (0.30) 1.21 (1.13-1.30) 1.98x10-7 0.0178 SMAD3
NEJM 2007; 357: 443-453
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100%
50%
0%
Chr 9
Chr 6
Chr 2
Population attributable risk
Genomics for risk predictionGenomics for risk prediction
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NEJM 2007; 357: 443-453
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Novel CAD loci affect risk in both men and women
LOCUS SNP ODDS RATIO MALE
P-VALUEMALE
ODDS RATIO FEMALE
P-VALUEFEMALE
1p13.3 rs599839 1.36 (1.16-1.59) 1.33x10-4 1.27 (1.14-1.41) 7.61x10-6
1q41 rs17465637 1.24 (1.12-1.36) 1.15x10-5 1.19 (1.04-1.37) 1.24x10-2
2q36.3 rs2943634 1.20 (1.10-1.32) 4.48x10-5 1.22 (1.07-1.39) 2.30x10-3
6q25.1 rs6922269 1.24 (1.13-1.37) 4.56x10-6 1.23 (1.07-1.41) 3.13x10-3
9p21.3 rs1333049 1.35 (1.24-1.47) 7.03x10-12 1.35 (1.19-1.52) 1.90x10-6
10q11.21 rs501120 1.30 (1.14-1.48) 8.20x10-5 1.56 (1.27-1.91) 1.30x10-5
15q22.33 rs17228212 1.24 (1.13,1.36) 7.68x10-6 1.16 (1.02-1.33) 2.56x10-2
2117 male cases and 2259 male controls and 684 female cases and 2323 female controls
NEJM 2007; 357: 443-453
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Graphicn=2022
0.2
0.4
0.6
0Ger MI Famn=847
P=3.8x10-6
P=1x10-4
Chol (mmol/L) per rs599839-allele
WTCCCn=2022
1.2
1.4
1.6
1Ger MI Famn=847
P=2.1x10-5
P=3.1x10-5
MI risk per rs599839-allele
NEJM 2007;357: 443-453
CELSR2 PSRC1
25.7kb 4kb 3.6kb
1 0.8
r2 0.6
0.4
0.2
0
-35000 -30000 -25000 -20000 -15000 -10000 -5000 0 5000 10000 bp from SNP rs599839
Chromosome 1p13.3
109500k 109510k 109520k 109530k 109540k
0 0.5 1
r2
rs49
7083
4
rs61
1917
rs75
2841
9
rs12
7403
74
rs66
0240
rs65
8435
rs62
9301
rs64
6776
rs17
0359
49
rs60
2633
rs59
9839
PSRC1 and CELSR2 genes associate with serum cholesterol and MI risk
(in revision)
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4 SNPs associate with MIGWA German MI Family Study
4 SNPs associate with LDLGWA MONICA/KORA Study
LDL-R locus associates with serum cholesterol and MI risk
P. Linsel-Nitschke (unpublished)
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LDL-R locus associates with serum cholesterol and MI risk
imputation of the locus
10-2
top SNPs for MI
top SNPs for LDL
P. Linsel-Nitschke (unpublished)
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Myocardial infarction
Chrom 9p21
Plaque formation
Hyperlipidemia
PCSK9 Chrom 19p13
Chrom 1p13
Vascular defect
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Genetic score for MI risk20 risk alleles
400 risk alleles
80 risk alleles
40 risk alleles
Ortlepp et al Euro J Intern Med 2002; 13:485
MI patientscontrols
10 genes = 20 alleles
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Genetic score for MI risk20 risk alleles
400 risk alleles
80 risk alleles
40 risk alleles
Ortlepp et al Euro J Intern Med 2002; 13:485
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molecular genetics of myocardial infarction
• yesterday pos. family hx : important risk factor (predictor) for CAD
• today (missed) opportunities for prevention
• tomorrow individual genetic risk prediction?
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Mendels threat