Prof. Dr. H. Schunkert Medizinische Klinik II UK S-H Campus Lübeck Genome-wide association for myocardial infarction.

Prof. Dr. H. SchunkertMedizinische Klinik IIUK S-H Campus Lübeck

Genome-wide association formyocardial infarction

Clinical Demands for Genetic Testing

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

Which genes are responsible?

Genome-wide Map- Microsatellites

1 3 4 5 1514131211109876

16 20 211817 2219

2

Resolution:n=400

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

linkage-Scans for atherosclerosisgenetic hot spots for CAD

Clin Res Cardiol 2007; 96:1–7

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!

Genome-wide Map- SNPs1 3 4 5 1514131211109876

16 20 211817 2219

2

resolution:N=1.000.000

12

3

rs1333049

Better Coverage

Chromosome 9p21.3

Gene

genome scan - 500,000s SNPs

identification ofpositive regions

replication

2.000 affected individuals 2.000 healthy individuals

122

GWAs – Strategy I

GWAs – Strategy II

2000 cases3200 controls

1988 cases3000 controls

NEJM 2007; 357: 443-453

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

Structure of the chromosome 9 CAD-associated locus

T2DM SignalT2DM Signal

NEJM 2007; 357: 443-453

-Lo

g p

-val

ue


McPherson R et al. Science 2007;316:1488-1491

Most replicated locus for CAD risk to date


Helgadottir A et al. Science 2007; 316:1491-1493

Most replicated locus for CAD risk to date

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)

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)




benötigt.




benötigt.


Helgadottir et al (deCode) Nat Genet 2008 (in press)


benötigt.

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Helgadottir et al (deCode) Nat Genet 2008 (in press)


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in Korea

Shen et al ATVB 2008;28; in press

n=294 n=611

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

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

Further genomewide results

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

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

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

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)

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)

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)

Myocardial infarction

Chrom 9p21

Plaque formation

Hyperlipidemia

PCSK9 Chrom 19p13

Chrom 1p13

Vascular defect

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

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

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?

Mendels threat

Prof. Dr. H. Schunkert Medizinische Klinik II UK S-H Campus Lübeck Genome-wide association for myocardial infarction.

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