Collaborative research initiatives in cardiovascular disease J Danesh October 2005.

Collaborative research initiatives in

cardiovascular disease

J DaneshOctober 2005

Literature-based meta-analyses of some novel blood-based risk factors

Cytomegalovirus 700 0.9 (0.7-1.2) Lancet 1997Mixed strains of H pylori 3500 1.2 (0.9-1.5) BMJ 1999Cytotoxic strains of H pylori 600 1.3 (0.9-1.9) Circulation 2000C pneumoniae IgG titres 3000 1.2 (1.0-1.4) BMJ 2000C pneumoniae IgA titres 2300 1.2 (1.0-1.5) Eur Heart J 2000

Lancet 2001ICAM-1 1400 1.2 (1.0-1.6) Lancet VCAM-1 1300 1.0 (0.8-1.3) Lancet 2001P-selectin 800 1.1 (0.7-1.4) Lancet 2001

RheologyViscosity 1300 1.6 (1.3-1.9) Eur Heart J 2000Haematocrit 8000 1.2 (1.1-1.3) Eur Heart J 2000ESR 1700 1.3 (1.2-1.5) Eur Heart J 2000

Risk ratio Reference (Danesh et al)

Acute-phase reactantsFibrinogen 3000 1.8 (1.6-2.0) JAMA 1998Albumin 3700 1.5 (1.3-1.7) BMJ 2000Leucocyte count 6000 1.4 (1.3-1.5) BMJ 2000Serum amyloid A protein 600 1.6 (1.1-2.2) BMJ 2000C-reative protein 7000 1.5 (1.4-1.6) NEJM 2004

Haemostaticvon Willebrand factor 1500 1.5 (1.1-2.0) Eur Heart J 2002Fibrin D-dimer 1300 1.7 (1.3-2.2) Circulation 2001tPA antigen 1500 1.5 (1.1-2.0) Eur Heart J 2004

Lipids

Lipoprotein(a)Triglycerides

38008000

1.7 (1.4-1.9)1.5 (1.4-1.6)

Circulation 2000In preparation

Chronic infections

Cell adhesion moleculesE-selectin 800 1.2 (0.9-1.6) 2001

MetalloproteinsFerritin

600 1.0 (0.8-1.3) Circulation 1999

Transferrin6000 0.9 (0.7-1.1) Circulation 1999

Vitamin-relatedHomocysteine 1000 1.3 (1.1-1.5) J Card Risk 1998

Type of factor/examples No. of CHD cases

Interleukin-6 1500 1.8 (1.3-2.4) In preparation

LP-PLA2 1700 1.4 (1.2-1.7) in preparation

Fibrinogen

• Large glycoprotein

• Usual values, 3.5 vs 2.5 g/L Top and Bottom 1/3

• ~4-fold rise

Prospective studies of fibrinogen and coronary heart disease reported by 1998

Danesh et al, JAMA 1998

1

Usual Fibrinogen (g/L)

2·5 3·0 3·5 4·0

1

2

4

8

16

32

64

Haz

ard

ratio

(flo

atin

g ab

soul

e ris

k (9

5% C

I)

(7118 cases)a) CHD


2·5 3·0 3·5 4·0

1

2

4

8

16

32

64

b) Stroke(2775 cases)


2·5 3·0 3·5 4·0

1

2

4

8

16

32

64

c) Other vascular deaths(988 cases)


2·5 3·0 3·5 4·0

1

2

4

8

16

32

64

d) Non vascular deaths(7473 cases)

-

70-89

Age at risk:

60-69

40-59

70-89

Age at risk:

60-69

40-59

70-89

Age at risk:

60-69

40-59

70-89

Age at risk:

60-69

40-59H

azar

d ra

tio(f

loat

ing

abso

ule

risk

(95%

CI)

Haz

ard

ratio

(flo

atin

g ab

soul

e ris

k (9

5% C

I)

Haz

ard

ratio

(flo

atin

g ab

soul

e ris

k (9

5% C

I)

Fibrinogen Studies Collaboration: individual data on 154 000participants with 20 000 fatal and non-fatal endpoints

Fibrinogen Studies Collaboration, JAMA 2005

• protocol published in 2004

• 38 studies

• 121 co-authors

Impact of fibrinogen on CHD in different subgroups: individual data on 154 000 participants

2 1.0 1.5 2.0 4.0

Characteristic

Western EuropeNorth America

Population registerWorkforcePrevention trial

Clotting timeClot weightNon-clotting

Within a few daysWithin a few weeksMore than a few weeksNot stated

MaleFemale

<5.735.73-6.73>6.73

<1.291.29-2.00>2.00

<131131-150>150

Non currentCurrent

No historyPositive history of diabetesNot recorded

<2525-28>28

No. of CHD cases

53691718

4345 9741799

4382 6102126

3611125212241031

6171 947

237623782364

117511651145

245023752293

37843334

4703 6451770

280923002009

Geographical Location ‡

Study Population

Assay Method

Assay timing*

Sex

Total Cholesterol (mmol/L)

Triglycerides (mmol/L)†

SBP (mmHg)

Smoking Status

History of Diabetes

BMI (kg/m2)

Fibrinogen Studies Collaboration, JAMA 2005

Emerging Risk Factors Collaboration(extension of the Fibrinogen Studies Collaboration)

• Factors to be studied: triglycerides, HDL,

C-reactive protein, leucocytes,

lipoprotein(a), apo-A1 –B,

albumin etc

• Potential scope: 70+ cohorts with primary data

on >700 000 individuals

(primary data already supplied for 500 000 participants)

Literature-based meta-analyses of some genetic factors in CHD

Phenotypic pathway Gene Polymorphism No. cases/controls Per allele risk ratio (95%CI)LIPIDS

Paraoxonase/HDL PON1 gln192arg 9800/11000 1.12 (1.07-1.17)leu55met 5700/5700 1.01 (0.95-1.07) T(-107)C 1400/1300 1.02 (0.92-1.14)

PON2 ser311cys 1500/2100 1.04 (0.93-1.17)Apolipoprotein A1APO-A1 G(-75)A

C*3TApolipoprotein B APO-B I/D signal peptideApolipoprotein C-lll APO-Clll C(-482)T

C1100TApolipoprotein E APO E E2/E3 3000/4000 1.18 (1.12-1.24)

E2/E4 1600/2000 1.37 (1.26-1.48)Lipoprotein(a) LP-a C93T

G121AA11764C

Lipoprotein lipaseLPL gln188glu 950/9300 4.9 (1.2-19.6)LPL asp9asn 1000/1000 1.4 (0.8-2.4)LPL asn291ser 2300/10200 1.2 (0.9-1.5)LPL ser447ter 1600/1900 0.8 (0.7-1.0)

ATP binding cassette ABCA-1 R219KLDL receptor C766TLeptin-like LDL receptor LOX-1 G501CHepatic lipase C(-514)T

C(-480)TG(-250)A

Cholesterol transport CETP C(-629)ATaq1B

VASCULAR FUNCTIONEndothelial nitric oxide NOS3 E298D 8650/5690 1.11 (1.05-1.18)

NOS3 4a/b 6950/4950 1.02 (0.94-1.10)NOS3 T(-786)C 1300/1300 1.25 (1.10-1.41)

Beta-2 adrenergic receptor gln27gluarg16gly

Superoxide production p22 Phox C242TGap junctions Connexin-37 C1019T

continued…..

Literature-based meta-analyses of somegenetic factors in CHD contd….

Phenotypic pathway Gene Polymorphism No. cases/controls Per allele risk ratio (95%CI)

INFLAMMATIONCytokines CD14 C(-159)T 6400/6400 1.08 (1.01-1.15)

IL6 G(-174)C 3800/5100 1.04 (0.96-1.12)IL6 G(-572)C 1200/4200 1.00 (0.80-1.24)TNF alpha G(-308)A 3400/2100 0.98 (0.88-1.09)TNF alpha G(-238)A 1100/1200 1.05 (0.81-1.37)IL10

C-reactive proteinCRP G1059Cvon Willebrand factor VWF A(-1185)G

G(-1051)A

HAEMOSTASISFibrinogen Beta-fib G(-455)A 9500/18500 1.00 (0.95-1.05)Coagulation factor V Leiden G1691A 7800/23000 1.16 (1.04-1.29)Coagulation factor VIICoagulation factor XIIIProthrombin FII G2021A 7000/8200 1.13 (0.85-1.52)Plasmingen inhibitor SERPIN1 4G/5G 6100/7300Platelet receptor GP la/lla C807T 2600/2500 1.03 (0.91-1.15)Platelet receptor GPIIIa A1/A2 12800/12000Platelet receptor GP Ib C1018THemoglobin binding Haptoglobin HP1/2 700/700

PLAQUE FORMATIONMetalloproteinase-1 MMP1 G(-1607)GGMetalloproteinase-9 MMP9 C(-1562)T

R279QMetalloproteinase-12 MMP12 A(-82)GStromelysin MMP3 5a(-1171)6A

OXIDATIVE STRESSHeme oxygenase HO-1 GTn repeat

Paraoxonase-1Serum protein foundon HDL

Breaks downinsecticides

Variations in PON1Gene (7q21.3) correlate stronglywith PON1 enzymeactivity

27Kb 30Kb 110Kb

43 studies of paraoxonase Gln192Arg polymorphisms: 11 000 coronary cases and 13 000 controls

0.5 1.0 2.0 4.0

Subtotal

Subtotal

Study

Yamada, 2002Cascorbi, 1999Herrmann, 1996Gardemann, 2000Wang, 2003Senti, 2001Sen-Banerjee, 2000Rice, 1997Ferre, 2002Aubo, 2000Serrato, 1995Ko, 1998Suehiro, 1996Pfohl, 1999Heijmans, 2000Ombres, 1998Salonen, 1999Ayub, 1999Turban, 2001

Gardemann, 2000Cascorbi, 1999Mackness, 2001Imai, 2000Sanghera, 1997Rice, 1997Chen, 2003Wang, 2003Antikainen, 1996Ruiz, 1995Osei-Hyiaman, 2001Hong, 2001Serrato, 1995Hasselwander, 1999Sanghera, 1997Ko, 1998Ombres, 1998Pati, 1998Pfohl, 1999Aynacioglu, 2000Zama, 1997Suehiro, 1996Odawara, 1997Watzinger, 2002Turban, 2001Letellier, 2002

Cases/controls

1035/1168 649/983 642/701 1059/535 330/475 280/396 492/518 173/607 215/215 156/310 134/247 114/218 91/252 95/170 62/604 80/204 55/109 48/50 13/301

768/535 324/983 417/282 210/431 246/244 153/607 178/411 144/475 380/169 171/263 201/231 113/191 89/247 103/388 122/165 104/218 95/204 120/80 75/170 96/105 75/115 43/252 42/122 43/260 35/301 36/96

Genotype frequencies1

RR

13% vs 11% 7% vs 7%10% vs 11% 8% vs 7%18% vs 11%11% vs 10% 1% vs 3% 10% vs 9% 11% vs 7% 8% vs 11%15% vs 11%46% vs 42%35% vs 37%13% vs 12% 6% vs 8% 6% vs 7% 7% vs 6% 6% vs 6% 0% vs 7%

7% vs 7% 6% vs 7% 8% vs 10%53% vs 44%35% vs 33% 9% vs 9% 8% vs 9%15% vs 11% 8% vs 4% 10% vs 5% 11% vs 3%17% vs 17%22% vs 11% 9% vs 8%14% vs 13%38% vs 42% 7% vs 7%17% vs 10%11% vs 12%36% vs 49%52% vs 32%35% vs 37%40% vs 36% 2% vs 7% 11% vs 7% 8% vs 3%

QR

42% vs 44%40% vs 40%42% vs 38%42% vs 40%47% vs 48%39% vs 42%52% vs 44%39% vs 40%40% vs 43%38% vs 40%57% vs 40%42% vs 44%49% vs 49%42% vs 45%58% vs 44%46% vs 41%35% vs 39%50% vs 30%38% vs 48%

44% vs 40%41% vs 40%41% vs 35%42% vs 42%48% vs 50%40% vs 40%44% vs 40%44% vs 48%37% vs 44%50% vs 42%21% vs 19%44% vs 44%44% vs 40%43% vs 46%59% vs 40%52% vs 44%46% vs 41%58% vs 15%49% vs 45%52% vs 41%44% vs 53%51% vs 49%57% vs 43%51% vs 37%14% vs 48%31% vs 40%

QQ

45% vs 45%53% vs 53%48% vs 52%50% vs 52%36% vs 41%50% vs 49%47% vs 54%50% vs 51%49% vs 49%54% vs 50%28% vs 49%12% vs 14%15% vs 13%45% vs 43%35% vs 48%48% vs 52%58% vs 54%44% vs 64%62% vs 45%

49% vs 52%54% vs 53%50% vs 55% 4% vs 14%17% vs 17%51% vs 51%48% vs 51%40% vs 41%56% vs 51%40% vs 53%68% vs 78%39% vs 39%34% vs 49%49% vs 46%27% vs 47%11% vs 14%46% vs 52%25% vs 75%40% vs 43%11% vs 10% 4% vs 15%14% vs 13% 2% vs 20%47% vs 57%74% vs 45%61% vs 57%

Myocardial infarction

Coronary stenosis 5723/8063

4383/7545

Total 10106/11786*

Per-allele relative risk and 99% confidence interval

Wheeler et al, Lancet 2004

Studies of paraoxonase Gln192Arg polymorphism grouped by study characteristics

0.5 1.0 2.0

Groups of studies

>=500 cases: 5 studies 200 to 499 cases: 10 studies <200 cases: 30 studies

Caucasian: 28 studies East Asian: 12 studies Other: 5 studies

Blinded: 19 studies Not blinded: 12 studies Unknown: 14 studies

General population: 20 studies Health check/outpatient: 12 studies Other patient/negative cardiac: 13 studies

General population: 38 studies Diabetic population: 6 studies

Cases/controls

4153/3387 3095/3944 2858/4455

6528/7471 2635/3256 943/1059

5651/5648 2527/3081 1928/3057

6286/6716 1771/2055 2048/3015

9383/10904 620/882

Study size

Ethnicity

Blinding of genotyping staff

Source of controls

Study population*



0.5 1.0 2.0 4.0

Subtotal

Subtotal

Study

Cascorbi, 1999Gardemann, 2000Sen-Banerjee, 2000Ferre, 2002Arca, 2002Yamada, 2002Heijmans, 2000Salonen, 1999Ayub, 1999

Gardemann, 2000Cascorbi, 1999Mackness, 2001Chen, 2003Hasselwander, 1999Arca, 2002Blatter Garin, 1997Sanghera, 1998Imai, 2000Watzinger, 2002Letellier, 2002Hong, 2001Zama, 1997Sanghera, 1998

Cases/controls

650/9761059/535 492/518 215/215 163/178 445/464 62/604 55/110 48/50

768/535 321/976 417/282 178/411 103/388 137/178 168/240 114/183 208/431 43/260 36/95 113/191 75/115 119/181

Genotype MM

11% vs 10%13% vs 13% 6% vs 8%14% vs 18%12% vs 12% 0% vs 0%11% vs 11%24% vs 10%13% vs 12%

15% vs 13%14% vs 10%12% vs 10%15% vs 13%10% vs 14%18% vs 12% 0% vs 0% 3% vs 5% 0% vs 1% 9% vs 15%19% vs 11% 0% vs 2% 0% vs 0% 0% vs 0%

frequencies LM

43% vs 45%43% vs 46%40% vs 36%50% vs 42%52% vs 46%12% vs 13%48% vs 48%40% vs 49%33% vs 54%

48% vs 46%44% vs 45%48% vs 53%47% vs 48%51% vs 43%40% vs 46%54% vs 64%35% vs 30%13% vs 13%28% vs 45%39% vs 57% 6% vs 8%13% vs 18% 7% vs 7%

e LL

46% vs 45%45% vs 41%54% vs 56%36% vs 40%36% vs 43%88% vs 87%40% vs 41%36% vs 41%54% vs 34%

37% vs 41%42% vs 45%40% vs 37%38% vs 39%39% vs 43%42% vs 43%46% vs 36%62% vs 65%86% vs 86%63% vs 40%42% vs 33%94% vs 91%87% vs 82%93% vs 93%

Myocardial infarction

Coronary stenosis

Studies of paraoxonase Leu55Met polymorphism and coronary heart disease


3189/3650

2800/4466

Total* 5989/6427


Summary

1) Collaborative efforts among prospective studies of plasma-based cardiovascular risk factors have demonstrated the value of this approach and have been extended to several hypotheses

2) Similar collaborative efforts are in progress for genetic factors in cardiovascular disease (eg, literature-based analyses so far include 500+ studies, >100 000 coronary cases and > 100 000 controls) and for integration of plasma and genetic factors

3) Such initiatives help to: make best use of existing data; clarify evidence; prioritize hypotheses for further investigation; create

research frameworks for novel hypotheses

Collaborative research initiatives in cardiovascular disease J Danesh October 2005.

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