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Functional Variants in Platelet Receptor Genes are Associated with Carotid Intima-Media Thickness in Healthy Adults Jennifer N. Cooper 1, Maria Mori Brooks.

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Presentation on theme: "Functional Variants in Platelet Receptor Genes are Associated with Carotid Intima-Media Thickness in Healthy Adults Jennifer N. Cooper 1, Maria Mori Brooks."— Presentation transcript:

1 Functional Variants in Platelet Receptor Genes are Associated with Carotid Intima-Media Thickness in Healthy Adults Jennifer N. Cooper 1, Maria Mori Brooks 1,2, Joseph M. Zmuda 1,3, Rhobert W. Evans 1, Chris Holmes 4, Kim Sutton-Tyrrell 1 1 Departments of Epidemiology, 2 Biostatistics, and 3 Human Genetics, Graduate School of Public Health, University of Pittsburgh 4 Colchester Research Facility, University of Vermont College of Medicine 1

2 Background Platelets play key role in atherosclerosis ↑ platelet activation associated with ↑ carotid intima- media thickness (IMT) Platelet activation ↑ in obesity and ↓ with weight loss Gawaz et al. J Clin Invest ;115:

3 Platelet Receptors Jennings. Thromb Haemost. 2009; 102: 248–57. 3

4 SAVE Trial RCT assessing impacts of weight loss and reduced sodium intervention on vascular health Goals – 10% weight loss – ↑ in weekly activity of 150 minutes Randomized to low sodium or control sodium lifestyle intervention Evaluated CVD risk factors and non-invasive vascular measures at baseline and 6, 12, and 24 months 4

5 Study population Overweight or obese adults aged (n=349) Exclusion criteria – Physically active – Diabetic – Hypertensive – Cholesterol lowering, anti-psychotic, vasoactive meds; vasoactive devices – Pregnant or breast feeding Genetic study (N=266 white, N=50 black) Sub-study of platelet activity (N=88) 5

6 Hypotheses SNPs are associated with segment-specific IMT Lifestyle modification eliminates these associations ↓ circulating platelet activity associated with – ↓ IMT – Weight loss 6

7 Methods Baseline – Common carotid, carotid bulb, and internal carotid IMT Follow-up – Common carotid IMT – β-thromboglobulin ( β-TG) 7

8 Statistical Analyses Dominant genetic model, stratified by race ANCOVA Linear Mixed Effects Models Spearman correlations and multiple linear regression False discovery rate (FDR) 8

9 Baseline Characteristics CharacteristicTotal (N=316) White Non- Hispanic (N=266) Black Non- Hispanic (N=50) Age (years)37.9 (6.1)37.9 (6.3)38.2 (5.3) Women (n, %)246 (77.9)199 (74.8)47 (94.0) BMI (kg/m 2 )32.9 (3.9)32.9 (4.0)33.0 (3.5) SBP (mmHg)113.5 (10.5)113.1 (10.1)115.4 (12.3) HDL-C (mg/dL)52.8 (13.6)51.6 (12.6)59.1 (17.0) Triglycerides (mg/dL)114.5 (78, 169)121 (82, 175)80 (64, 119) Mean Internal Carotid IMT (mm)0.57 (0.15) 0.56 (0.17) Mean Carotid Bulb IMT (mm)0.69 (0.16)0.68 (0.16)0.71 (0.17) Mean CCA IMT (mm)0.60 (0.08)0.59 (0.07)0.64 (0.11) 9

10 Baseline IMT by rs (PAR-1) Genotype 10

11 Longitudinal Changes in CCA IMT by rs (PAR-1) Genotype Whites Blacks 11

12 Platelet activity and CVD risk factors Variabler (p) Waist circumference0.25 (0.02) LDL-C0.29 (0.006) HDL-C-0.17 (0.11) Triglycerides0.23 (0.03) CRP0.09 (0.39) SBP0.05 (0.66) Insulin0.08 (0.48) CCA IMT0.07 (0.54) 12

13 Platelet Activity and Weight Loss β = , p=

14 Conclusions T allele carriers of rs – ↑ baseline carotid bulb IMT in whites – Greater ↑ in CCA IMT over one year in blacks Possible association between this SNP and platelet function PAR-1 is important in intimal proliferation, inflammation Lower circulating platelet activity – ↓ concurrent body size, ↓ concurrent LDL-C and triglycerides – Greater ↓ in body size during intervention Platelet activation may be associated with IMT only in more advanced atherosclerosis Platelet activation remains lowered after successful lifestyle modification 14

15 Limitations Small sample size Not all measures performed longitudinally 15

16 Strengths Longitudinal study Normotensive participants; no use of medications affecting the vasculature 16

17 Thank you! Grant Support: R01 HL A2, T32 HL (NHLBI) 17

18 EXTRA SLIDES 18

19 Intervention Results Variable 6 Months (N=261) 12 Months (N=233) Weight (kg)-6.8 (6.1)-6.2 (7.3) SBP (mmHg)-2.7 (8.1)-2.9 (8.2) Triglycerides (mg/dL)-19 (-43, 8)-18 (-51, 7) Insulin (µU/mL)-0.8 (-3.6, 1.6)-0.8 (-3.8, 2.3) Mean CCA IMT (mm)0.003 (0.04)0.01 (0.05) 19

20 Intervention Results by Race WhitesBlacks Variable Six Months (N=224) Twelve Months (N=199) Six Months (N=40) Twelve Months (N=34) Weight (kg)-7.1 (6.2)-6.3 (7.5)-5.2 (5.3)-5.6 (6.2) SBP (mmHg)-3.0 (8.1)-3.2 (8.1)-1.2 (8.4)-1.3 (8.6) Triglycerides (mg/dL)-20 (-47, 7)-19.(-54., 7)-2.5 ( )-17 (-27, 6.5) Insulin (µU/mL)-0.7 (-3.5, 1.8)-0.5 (-3.0, 2.4)-2.0 (-4.9, 1.2)-2.8 (-5.0, 0.7) Mean CCA IMT (mm)0.004 (0.04)0.009 (0.05) (0.05)0.017 (0.07) 20

21 References 1. Jennings, L.K., Mechanisms of platelet activation: need for new strategies to protect against platelet-mediated atherothrombosis. Thromb Haemost, (2): p Meisel, C., Lopez, J.A., and Stangl, K., Role of platelet glycoprotein polymorphisms in cardiovascular diseases. Naunyn Schmiedebergs Arch Pharmacol, (1): p Koyama, H., Maeno, T., Fukumoto, S., Shoji, T., Yamane, T., Yokoyama, H., Emoto, M., Tahara, H., Inaba, M., Hino, M., Shioi, A., Miki, T., and Nishizawa, Y., Platelet P-selectin expression is associated with atherosclerotic wall thickness in carotid artery in humans. Circulation, (5): p Nomura, E., Kohriyama, T., Yamaguchi, S., Kajikawa, H., and Nakamura, S., [Significance of the coagulation and fibrinolytic parameters as predictors for carotid atherosclerosis]. Rinsho Shinkeigaku, (6): p Kawamori, R., Imano, E., Watarai, T., Nishizawa, H., Matsushima, H., Kodama, M., Yamasaki, Y., and Kamada, T., Platelet activation in diabetic patients with asymptomatic atherosclerosis. Diabetes Res Clin Pract, (2): p Ghaddar, H.B., Cortes, J., Salomaa, V., Kark, J.D., Davis, C.E., Folsom, A.R., Heiss, G., Stinson, V., and Wu, K.K., Correlation of specific platelet activation markers with carotid arterial wall thickness. Thromb Haemost, (3): p Shoji, T., Koyama, H., Fukumoto, S., Maeno, T., Yokoyama, H., Shinohara, K., Emoto, M., Yamane, T., Hino, M., Shioi, A., and Nishizawa, Y., Platelet activation is associated with hypoadiponectinemia and carotid atherosclerosis. Atherosclerosis, (1): p Lorenz, M.W., Markus, H.S., Bots, M.L., Rosvall, M., and Sitzer, M., Prediction of Clinical Cardiovascular Events With Carotid Intima-Media Thickness: A Systematic Review and Meta-Analysis. Circulation, (4): p Davi, G. Patrono, C., Platelet activation and atherothrombosis. N Engl J Med, (24): p Davi, G., Gresele, P., Violi, F., Basili, S., Catalano, M., Giammarresi, C., Volpato, R., Nenci, G.G., Ciabattoni, G., and Patrono, C., Diabetes mellitus, hypercholesterolemia, and hypertension but not vascular disease per se are associated with persistent platelet activation in vivo. Evidence derived from the study of peripheral arterial disease. Circulation, (1): p Coban, E., Yilmaz, A., and Sari, R., The effect of weight loss on the mean platelet volume in obese patients. Platelets, (3): p Davi, G., Guagnano, M.T., Ciabattoni, G., Basili, S., Falco, A., Marinopiccoli, M., Nutini, M., Sensi, S., and Patrono, C., Platelet activation in obese women: role of inflammation and oxidant stress. JAMA, (16): p Smith, S.M., Judge, H.M., Peters, G., Armstrong, M., Dupont, A., Gaussem, P., and Storey, R.F., PAR-1 genotype influences platelet aggregation and procoagulant responses in patients with coronary artery disease prior to and during clopidogrel therapy. Platelets, (6): p Dupont, A., Fontana, P., Bachelot-Loza, C., Reny, J.L., Bieche, I., Desvard, F., Aiach, M., and Gaussem, P., An intronic polymorphism in the PAR-1 gene is associated with platelet receptor density and the response to SFLLRN. Blood, (5): p Fontana, P., Dupont, A., Gandrille, S., Bachelot-Loza, C., Reny, J.L., Aiach, M., and Gaussem, P., Adenosine diphosphate-induced platelet aggregation is associated with P2Y12 gene sequence variations in healthy subjects. Circulation, (8): p Fontana, P., Dupont, A., Gandrille, S., Bachelot-Loza, C., Reny, J.L., Aiach, M., and Gaussem, P., Adenosine diphosphate-induced platelet aggregation is associated with P2Y12 gene sequence variations in healthy subjects. Circulation, (8): p Loncar, R., Stoldt, V., Hellmig, S., Zotz, R., Mihalj, M., and Scharf, R., HPA-1 polymorphism of alphaIIbbeta3 modulates platelet adhesion onto immobilized fibrinogen in an in-vitro flow system. Thrombosis Journal, (1): p Michelson, A.D., Furman, M.I., Goldschmidt-Clermont, P., Mascelli, M.A., Hendrix, C., Coleman, L., Hamlington, J., Barnard, M.R., Kickler, T., Christie, D.J., Kundu, S., and Bray, P.F., Platelet GP IIIa Pl(A) polymorphisms display different sensitivities to agonists. Circulation, (9): p

22 References 18. McCaslin, J., Ashour, H., Bhattacharya, V., Cleanthis, M., Daly, A., and Stansby, G., Increased platelet-monocyte aggregation in male claudicants with the Pl(A1/A2) polymorphism of Gp IIb/IIIa. Eur J Vasc Endovasc Surg, (2): p Maguire, J.M., Thakkinstian, A., Sturm, J., Levi, C., Lincz, L., Parsons, M., Whyte, S., and Attia, J., Polymorphisms in platelet glycoprotein 1balpha and factor VII and risk of ischemic stroke: a meta-analysis. Stroke, (6): p Kenny, D., Muckian, C., Fitzgerald, D.J., Cannon, C.P., and Shields, D.C., Platelet glycoprotein Ib alpha receptor polymorphisms and recurrent ischaemic events in acute coronary syndrome patients. J Thromb Thrombolysis, (1): p Furihata, K., Nugent, D.J., and Kunicki, T.J., Influence of platelet collagen receptor polymorphisms on risk for arterial thrombosis. Arch Pathol Lab Med, (3): p Frank, M.B., Reiner, A.P., Schwartz, S.M., Kumar, P.N., Pearce, R.M., Arbogast, P.G., Longstreth, W.T., Jr., Rosendaal, F.R., Psaty, B.M., and Siscovick, D.S., The Kozak sequence polymorphism of platelet glycoprotein Ibalpha and risk of nonfatal myocardial infarction and nonfatal stroke in young women. Blood, (4): p Mikkelsson, J., Perola, M., Penttila, A., and Karhunen, P.J., Platelet glycoprotein Ibalpha HPA-2 Met/VNTR B haplotype as a genetic predictor of myocardial infarction and sudden cardiac death. Circulation, (8): p Reiner, A.P., Kumar, P.N., Schwartz, S.M., Longstreth, W.T., Jr., Pearce, R.M., Rosendaal, F.R., Psaty, B.M., and Siscovick, D.S., Genetic variants of platelet glycoprotein receptors and risk of stroke in young women. Stroke, (7): p Kunicki, T.J., The influence of platelet collagen receptor polymorphisms in hemostasis and thrombotic disease. Arterioscler Thromb Vasc Biol, (1): p Ollikainen, E., Mikkelsson, J., Perola, M., Penttila, A., and Karhunen, P.J., Platelet membrane collagen receptor glycoprotein VI polymorphism is associated with coronary thrombosis and fatal myocardial infarction in middle-aged men. Atherosclerosis, (1): p Ziegler, S., Schillinger, M., Funk, M., Felber, K., Exner, M., Mlekusch, W., Sabeti, S., Amighi, J., Minar, E., Brunner, M., Muller, M., and Mannhalter, C., Association of a functional polymorphism in the clopidogrel target receptor gene, P2Y12, and the risk for ischemic cerebrovascular events in patients with peripheral artery disease. Stroke, (7): p Cavallari, U., Trabetti, E., Malerba, G., Biscuola, M., Girelli, D., Olivieri, O., Martinelli, N., Angiolillo, D.J., Corrocher, R., and Pignatti, P.F., Gene sequence variations of the platelet P2Y12 receptor are associated with coronary artery disease. BMC Med Genet, : p Slowik, A., Dziedzic, T., Turaj, W., Pera, J., Glodzik-Sobanska, L., Szermer, P., Malecki, M.T., Figlewicz, D.A., and Szczudlik, A., A2 alelle of GpIIIa gene is a risk factor for stroke caused by large-vessel disease in males. Stroke, (7): p Burr, D., Doss, H., Cooke, G.E., and Goldschmidt-Clermont, P.J., A meta-analysis of studies on the association of the platelet PlA polymorphism of glycoprotein IIIa and risk of coronary heart disease. Stat Med, (10): p Martinelli, N., Trabetti, E., Pinotti, M., Olivieri, O., Sandri, M., Friso, S., Pizzolo, F., Bozzini, C., Caruso, P.P., Cavallari, U., Cheng, S., Pignatti, P.F., Bernardi, F., Corrocher, R., and Girelli, D., Combined effect of hemostatic gene polymorphisms and the risk of myocardial infarction in patients with advanced coronary atherosclerosis. PLoS One, (2): p. e Bray, P.F., Platelet glycoprotein polymorphisms as risk factors for thrombosis. Curr Opin Hematol, (5): p Gachet, C., P2 receptors, platelet function and pharmacological implications. Thromb Haemost, (3): p

23 References 34. Coughlin, S.R., Protease-activated receptors in hemostasis, thrombosis and vascular biology. J Thromb Haemost, (8): p Kunicki, T.J., Head, S., and Salomon, D.R., Platelet receptor structures and polymorphisms. Methods Mol Biol, : p Ramstrom, S., Oberg, K.V., Akerstrom, F., Enstrom, C., and Lindahl, T.L., Platelet PAR1 receptor density--correlation to platelet activation response and changes in exposure after platelet activation. Thromb Res, (5): p Ye, Z., Liu, E.H., Higgins, J.P., Keavney, B.D., Lowe, G.D., Collins, R., and Danesh, J., Seven haemostatic gene polymorphisms in coronary disease: meta- analysis of 66,155 cases and 91,307 controls. Lancet, (9511): p Polak, J.F., Person, S.D., Wei, G.S., Godreau, A., Jacobs, D.R., Jr., Harrington, A., Sidney, S., and O'Leary, D.H., Segment-specific associations of carotid intima-media thickness with cardiovascular risk factors: the Coronary Artery Risk Development in Young Adults (CARDIA) study. Stroke, (1): p Schott, L.L., Wildman, R.P., Brockwell, S., Simkin-Silverman, L.R., Kuller, L.H., and Sutton-Tyrrell, K., Segment-specific effects of cardiovascular risk factors on carotid artery intima-medial thickness in women at midlife. Arteriosclerosis, Thrombosis, and Vascular Biology, (10): p Liao, Y.C., Lin, H.F., Rundek, T., Cheng, R., Guo, Y.C., Sacco, R.L., and Juo, S.H., Segment-specific genetic effects on carotid intima-media thickness: the Northern Manhattan study. Stroke, (12): p Wendelhag, I., Gustavsson, T., Suurkula, M., Berglund, G., and Wikstrand, J., Ultrasound measurement of wall thickness in the carotid artery: fundamental principles of a computerized analysing system. Clinical Physiology, (6): p Ellis, D., Lloyd, C., Becker, D.J., Forrest, K.Y.Z., and Orchard, T.J., The changing course of diabetic nephropathy: Low-density lipoprotein cholesterol and blood pressure correlate with regression of proteinuria. American Journal of Kidney Diseases, : p Allain, C.C., Poon, L.S., Chan, C.S., Richmond, W., and Fu, P.C., Enzymatic determination of total serum cholesterol. Clinical Chemistry, (4): p Warnick, G.R. Albers, J.J., A comprehensive evaluation of the heparin - manganese precipitation procedure for estimating high density lipoprotein cholesterol. Journal of Lipid Research, (1): p Bucolo, G. David, H., Quantitative Determination of Serum Triglycerides by the Use of Enzymes. Clinical Chemistry, (5): p Bondar, R.J.L. Mead, D.C., Evaluation of Glucose-6-Phosphate Dehydrogenase from Leuconostoc mesenteroides in the Hexokinase Method for Determining Glucose in Serum. Clinical Chemistry, (5): p Major, C.D., Santulli, R.J., Derian, C.K., and Andrade-Gordon, P., Extracellular mediators in atherosclerosis and thrombosis: lessons from thrombin receptor knockout mice. Arterioscler Thromb Vasc Biol, (6): p Gigante, B., Bellis, A., Visconti, R., Marino, M., Morisco, C., Trimarco, V., Galasso, G., Piscione, F., De Luca, N., Prince, J.A., de Faire, U., and Trimarco, B., Retrospective analysis of coagulation factor II receptor (F2R) sequence variation and coronary heart disease in hypertensive patients. Arterioscler Thromb Vasc Biol, (5): p Gigante, B., Vikstrom, M., Meuzelaar, L.S., Chernogubova, E., Silveira, A., Hooft, F.V., Hamsten, A., and de Faire, U., Variants in the coagulation factor 2 receptor (F2R) gene influence the risk of myocardial infarction in men through an interaction with interleukin 6 serum levels. Thromb Haemost, (5): p Coban, E., Ozdogan, M., Yazicioglu, G., and Akcit, F., The mean platelet volume in patients with obesity. Int J Clin Pract, (8): p

24 References 51. Desideri, G. Ferri, C., Effects of obesity and weight loss on soluble CD40L levels. JAMA, (14): p Russo, I., Traversa, M., Bonomo, K., De Salve, A., Mattiello, L., Del Mese, P., Doronzo, G., Cavalot, F., Trovati, M., and Anfossi, G., In central obesity, weight loss restores platelet sensitivity to nitric oxide and prostacyclin. Obesity (Silver Spring), (4): p Jakubowski, J.A., Adler, B., Thompson, C.B., Valeri, C.R., and Deykin, D., Influence of platelet volume on the ability of prostacyclin to inhibit platelet aggregation and the release reaction. Journal of Laboratory and Clinical Medicine, (2): p Rao, A.K., Goldberg, R.E., and Walsh, P.N., Platelet coagulant activities in diabetes mellitus. Evidence for relationship between platelet coagulant hyperactivity and platelet volume. Journal of Laboratory and Clinical Medicine, (1): p Unek, I.T., Bayraktar, F., Solmaz, D., Ellidokuz, H., Sisman, A.R., Yuksel, F., and Yesil, S., The levels of soluble CD40 ligand and C-reactive protein in normal weight, overweight and obese people. Clin Med Res, (2): p Samocha-Bonet, D., Justo, D., Rogowski, O., Saar, N., Abu-Abeid, S., Shenkerman, G., Shapira, I., Berliner, S., and Tomer, A., Platelet counts and platelet activation markers in obese subjects. Mediators Inflamm, : p Fabris, F., Randi, M.L., Casonato, A., Dal Bo Zanon, R., Bonvicini, P., and Girolami, A., Clinical significance of beta-thromboglobulin in patients with high platelet count. Acta Haematologica, (1): p Dellas, C., Schafer, K., Rohm, I., Lankeit, M., Ellrott, T., Faustin, V., Riggert, J., Hasenfuss, G., and Konstantinides, S., Absence of leptin resistance in platelets from morbidly obese individuals may contribute to the increased thrombosis risk in obesity. Thromb Haemost, (6): p Trovati, M. Anfossi, G., Influence of insulin and of insulin resistance on platelet and vascular smooth muscle cell function. Journal of Diabetes and Its Complications, (1): p Puccetti, L., Santilli, F., Pasqui, A.L., Lattanzio, S., Liani, R., Ciani, F., Ferrante, E., Ciabattoni, G., Scarpini, F., Ghezzi, A., Auteri, A., and Davi, G., Effects of atorvastatin and rosuvastatin on thromboxane-dependent platelet activation and oxidative stress in hypercholesterolemia. Atherosclerosis, Oka, H., Ikeda, S., Koga, S., Miyahara, Y., and Kohno, S., Atorvastatin induces associated reductions in platelet P-selectin, oxidized low-density lipoprotein, and interleukin-6 in patients with coronary artery diseases. Heart and Vessels, (4): p Akkerman, J.W., From low-density lipoprotein to platelet activation. International Journal of Biochemistry and Cell Biology, (11): p Karason, K., Wikstrand, J., Sjostrom, L., and Wendelhag, I., Weight loss and progression of early atherosclerosis in the carotid artery: a four-year controlled study of obese subjects. International Journal of Obesity and Related Metabolic Disorders, (9): p Mavri, A., Stegnar, M., Sentocnik, J.T., and Videcnik, V., Impact of weight reduction on early carotid atherosclerosis in obese premenopausal women. Obesity Research, (9): p Mackinnon, A.D., Jerrard-Dunne, P., Sitzer, M., Buehler, A., von Kegler, S., and Markus, H.S., Rates and determinants of site-specific progression of carotid artery intima-media thickness: the carotid atherosclerosis progression study. Stroke, (9): p


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