Collaborative research initiatives in cardiovascular disease J Danesh October 2005.

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Slide 1 Collaborative research initiatives in cardiovascular disease J Danesh October 2005 Slide 2 Literature-based meta-analyses of some novel blood-based risk factors Cytomegalovirus7000.9 (0.7-1.2) Lancet 1997 Mixed strains of H pylori 35001.2 (0.9-1.5) BMJ 1999 Cytotoxic strains of H pylori 6001.3 (0.9-1.9) Circulation 2000 C pneumoniae IgG titres30001.2 (1.0-1.4) BMJ 2000 C pneumoniae IgA titres 23001.2 (1.0-1.5) Eur Heart J 2000 Lancet 2001 ICAM-114001.2 (1.0-1.6) Lancet VCAM-113001.0 (0.8-1.3) Lancet 2001 P-selectin 8001.1 (0.7-1.4) Lancet 2001 Rheology Viscosity13001.6 (1.3-1.9) Eur Heart J 2000 Haematocrit80001.2 (1.1-1.3) Eur Heart J 2000 ESR17001.3 (1.2-1.5) Eur Heart J 2000 Risk ratioReference (Danesh et al) Acute-phase reactants Fibrinogen30001.8 (1.6-2.0) JAMA 1998 Albumin37001.5 (1.3-1.7) BMJ 2000 Leucocyte count60001.4 (1.3-1.5)BMJ 2000 Serum amyloid A protein 6001.6 (1.1-2.2)BMJ 2000 C-reative protein70001.5 (1.4-1.6)NEJM 2004 Haemostatic von Willebrand factor15001.5 (1.1-2.0) Eur Heart J 2002 Fibrin D-dimer13001.7 (1.3-2.2) Circulation 2001 tPA antigen15001.5 (1.1-2.0) Eur Heart J 2004 Lipids Lipoprotein(a) Triglycerides 3800 8000 1.7 (1.4-1.9) 1.5 (1.4-1.6) Circulation 2000 In preparation Chronic infections Cell adhesion molecules E-selectin800 1.2 (0.9-1.6) 2001 Metalloproteins Ferritin 6001.0 (0.8-1.3)Circulation1999 Transferrin 60000.9 (0.7-1.1)Circulation 1999 Vitamin-related Homocysteine10001.3 (1.1-1.5)J Card Risk1998 Type of factor/examplesNo. of CHD cases Interleukin-6 1500 1.8 (1.3-2.4) In preparation LP-PLA2 17001.4 (1.2-1.7) in preparation Slide 3 Fibrinogen Large glycoprotein Usual values, 3.5 vs 2.5 g/L Top and Bottom 1/3 ~4-fold rise Slide 4 Prospective studies of fibrinogen and coronary heart disease reported by 1998 Danesh et al, JAMA 1998 Slide 5 1 UsualFibrinogen (g/L) 25303540 1 2 4 8 16 32 64 Hazard ratio (floating absoule risk (95% CI) (7118 cases) a) CHD UsualFibrinogen (g/L) 25303540 1 2 4 8 16 32 64 b) Stroke (2775 cases) UsualFibrinogen(g/L) 25303540 1 2 4 8 16 32 64 c) Other vascular deaths (988 cases) UsualFibrinogen(g/L) 25303540 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 40-59 Hazard ratio (floating absoule risk (95% CI) Hazard ratio (floating absoule risk (95% CI) Hazard ratio (floating absoule risk (95% CI) Fibrinogen Studies Collaboration: individual data on 154 000 participants with 20 000 fatal and non-fatal endpoints Fibrinogen Studies Collaboration, JAMA 2005 protocol published in 2004 38 studies 121 co-authors Slide 6 Impact of fibrinogen on CHD in different subgroups: individual data on 154 000 participants 2 Fibrinogen Studies Collaboration, JAMA 2005 Slide 7 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) Slide 8 Literature-based meta-analyses of some genetic factors in CHD Phenotypic pathwayGenePolymorphism No. cases/controls Per allele risk ratio (95%CI) LIPIDS Paraoxonase/HDLPON1gln192arg 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) PON2ser311cys 1500/2100 1.04 (0.93-1.17) Apolipoprotein A1APO-A1G(-75)A C*3T Apolipoprotein BAPO-BI/D signal peptide Apolipoprotein C-lllAPO-ClllC(-482)T C1100T Apolipoprotein EAPO EE2/E3 3000/4000 1.18 (1.12-1.24) E2/E4 1600/2000 1.37 (1.26-1.48) Lipoprotein(a)LP-aC93T G121A A11764C Lipoprotein lipaseLPLgln188glu 950/9300 4.9 (1.2-19.6) LPLasp9asn 1000/1000 1.4 (0.8-2.4) LPLasn291ser 2300/10200 1.2 (0.9-1.5) LPLser447ter 1600/1900 0.8 (0.7-1.0) ATP binding cassetteABCA-1R219K LDL receptorC766T Leptin-like LDL receptorLOX-1G501C Hepatic lipaseC(-514)T C(-480)T G(-250)A Cholesterol transportCETPC(-629)A Taq1B VASCULAR FUNCTION Endothelial nitric oxideNOS3E298D 8650/5690 1.11 (1.05-1.18) NOS34a/b 6950/4950 1.02 (0.94-1.10) NOS3T(-786)C 1300/1300 1.25 (1.10-1.41) Beta-2 adrenergic receptorgln27glu arg16gly Superoxide productionp22 PhoxC242T Gap junctionsConnexin-37 C1019T continued.. Slide 9 Literature-based meta-analyses of some genetic factors in CHD contd. Phenotypic pathwayGenePolymorphismNo. cases/controls Per allele risk ratio (95%CI) INFLAMMATION CytokinesCD14C(-159)T6400/6400 1.08 (1.01-1.15) IL6G(-174)C3800/5100 1.04 (0.96-1.12) IL6G(-572)C1200/4200 1.00 (0.80-1.24) TNF alphaG(-308)A3400/2100 0.98 (0.88-1.09) TNF alphaG(-238)A1100/1200 1.05 (0.81-1.37) IL10 C-reactive proteinCRPG1059C von Willebrand factorVWFA(-1185)G G(-1051)A HAEMOSTASIS FibrinogenBeta-fibG(-455)A9500/18500 1.00 (0.95-1.05) Coagulation factor VLeiden G1691A7800/23000 1.16 (1.04-1.29) Coagulation factor VII Coagulation factor XIII ProthrombinFIIG2021A7000/8200 1.13 (0.85-1.52) Plasmingen inhibitorSERPIN14G/5G6100/7300 Platelet receptorGP la/llaC807T2600/2500 1.03 (0.91-1.15) Platelet receptorGPIIIaA1/A212800/12000 Platelet receptorGP IbC1018T Hemoglobin bindingHaptoglobinHP1/2700/700 PLAQUE FORMATION Metalloproteinase-1MMP1G(-1607)GG Metalloproteinase-9MMP9C(-1562)T R279Q Metalloproteinase-12MMP12A(-82)G StromelysinMMP35a(-1171)6A OXIDATIVE STRESS Heme oxygenaseHO-1GTn repeat Slide 10 Paraoxonase-1 Serum protein found on HDL Breaks down insecticides Variations in PON1 Gene (7q21.3) correlate strongly with PON1 enzyme activity 27Kb 30Kb 110Kb Slide 11 43 studies of paraoxonase Gln192Arg polymorphisms: 11 000 coronary cases and 13 000 controls Wheeler et al, Lancet 2004 Slide 12 Studies of paraoxonase Gln192Arg polymorphism grouped by study characteristics 0.51.02.0 Groups of studies >=500 cases: 5 studies 200 to 499 cases: 10 studies Slide 13 0.51.02.04.0 Subtotal Study Cascorbi, 1999 Gardemann, 2000 Sen-Banerjee, 2000 Ferre, 2002 Arca, 2002 Yamada, 2002 Heijmans, 2000 Salonen, 1999 Ayub, 1999 Gardemann, 2000 Cascorbi, 1999 Mackness, 2001 Chen, 2003 Hasselwander, 1999 Arca, 2002 Blatter Garin, 1997 Sanghera, 1998 Imai, 2000 Watzinger, 2002 Letellier, 2002 Hong, 2001 Zama, 1997 Sanghera, 1998 Cases/ controls 650/976 1059/535 492/518 215/215 163/178 445/464 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% 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 Per-allele relative risk and 99% confidence interval 3189/3650 2800/4466 Total* 5989/6427 Wheeler et al, Lancet 2004 Slide 14 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

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