AS83 - Thrombotic, inflammatory and genetic markers for coronary heart disease in postmenopausal women: a WHI umbrella study

Investigator Names and Contact Information

Paul Ridker (PRIDKER@PARTNERS.ORG)

Introduction/Intent

While lipid parameters such as total, LDL, and HDL cholesterol are important modifiable risk factors for myocardial infarction, screening for lipid abnormalities often fails to identify those at high risk for future coronary thrombosis. In an effort to address this issue, a series of molecular epidemiologic studies have been completed over the past decade which indicate that several novel plasma and genetic markers of thrombosis, exist and that these parameters can identify individuals at high risk for future cardiovascular disease who otherwise might go undetected. For example, elevations of endogenous tissue-type plasminogen activator (tPA), plasminogen activator inhibitor (PAl-1), homocysteine, D-dimer, C-reactive protein, serum amyloid A (SAA), fibrinogen, and lipoprotein (a) have all been associated with the increased risk of vascular disease, often independent of the lipid profile and other traditional vascular risk factors. In addition, recent studies of mutations in the genes coding for several of these parameters indicate significant associations between genetic determinants of thrombosis and subsequent coronary risk. To date, however, almost all of the prospective data relating these plasma and genetic determinants to risk of coronary thrombosis have derived from studies exclusively or predominantly among men. Indeed, data relating to these hypotheses are exceedingly scarce in women, particularly post-menopausal women, a group in whom coronary heart disease is the leading cause of death. Thus, the primary objective of this proposal is to comprehensively evaluate a series of putative hemostatic, thrombotic, and genetic based markers for acute coronary occlusion among apparently healthy post-menopausal women.

Specific Aims

1a. To determine whether the elevated risk associated with tPA and PAl-1 concentrations in post-menopausal women is in part a result of a 4G/5G polymorphism in the promotor of the PAl-1 gene and by Alu repeat insertion/deletion polymorphism in the tPA gene.

1b. To determine whether the risk of coronary thrombosis in post-menopausal women associated with elevated levels of tPA and PAl-1 are modified by lipid based risk factors for myocardial infarction including total, LDL, and HDL cholesterol, by behavioral factors such as cigarette and alcohol consumption, by ethnicity, and by post-menopausal estrogen replacement therapy.

2a. To determine whether the elevated risk associated with total plasma homocysteine in post-menopausal women is in part a result of a common polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene.

2b. To determine whether the risk of coronary thrombosis in post-menopausal women associated with elevated levels of homocysteine are modified by lipid based risk factors for myocardial infarction including total, LDL, and HDL cholesterol, by behavioral factors such as cigarette and alcohol consumption, by ethnicity, by post-menopausal estrogen replacement therapy, and by folate or vitamin B6 intake.

3a. To determine whether the elevated risk associated with markers of thrombin generation, fibrin turnover, and APC-R in post-menopausal women is in part a result of polymorphisms in the genes coding for thrombomodulin, prothrombin, and coagulation factor V (factor V Leiden).

3b. To determine whether the risk of coronary thrombosis in post-menopausal women associated with elevated levels of markers of thrombin generation, fibrin turnover, and factor V Leiden are modified by lipid based risk factors for myocardial infarction including total, LDL, and HDL cholesterol, by behavioral factors such as cigarette and alcohol consumption by ethnicity, and by post-menopausal estrogen replacement therapy.

4a. To determine whether the risk of coronary thrombosis in post-menopausal women associated with elevated levels of C-RP, lL-6, and slCAM-1 are modified by lipid based risk factors for myocardial infarction including total, LDL, and HDL cholesterol, by behavioral factors such as cigarette and alcohol consumption, by ethnicity, and by post-menopausal estrogen replacement therapy.

5a. To assess the impact of lifestyle and behavioral correlates such as smoking, alcohol, body mass index, physical activity, hormone replacement therapy, and dietary factors on each of the above hemostatic and thrombotic markers.

Results/Findings

Some of the publications related to this ancillary study are: 128, 129.

Ms128 - Pradhan AD, Manson JE, Rossouw JE, Siscovick DS, Mouton CP, Rifai N, Wallace RB, Jackson RD, Pettinger MB, Ridker PM. Inflammatory biomarkers, hormone replacement therapy, and incident coronary heart disease: Prospective analysis from the Women's Health Initiative Observational Study. JAMA. 2002 Aug 28;288(8):980-7

Ms129 - Pradhan AD, LaCroix AZ, Langer RD, Trevisan M, Lewis CE, Hsia JA, Oberman A, Kotchen JM, Ridker PM. Tissue plasminogen activator antigen and D-dimer as markers for atherothrombotic risk among healthy postmenopausal women. Circulation. 2004 Jul 20;110(3):292-300. Epub 2004 Jul 6.

For a complete, up-to-date list of WHI papers related to this ancillary study, please use the searchable Bibliography section of this website. To search for papers by study number, access the Simple Search, and enter the study number in the “Related Studies” field.