Genetic and Biochemical Etiology of Cardiovascular Disease
As an investigator at the Cardiovascular Health Research Unit, I conduct several studies that focus on genetic and biochemical risk factors for the development of cardiovascular disease.
Our initial studies on these topics were conducted as part of the Women's Cardiovascular Health Study (WCHS), a population-based case-control study of risk factors for myocardial infarction and stroke in young women. The study was originally funded by the National Institute of Child Health and Human Development (NICHD) to examine the role of low-dose oral contraceptives on the risk of these conditions. Briefly, 18-44 year-old women diagnosed with incident MI or stroke (either ischemic or hemorrhagic, arterial or venous) were identified through a surveillance system of more than 30 hospitals serving the population of King, Pierce, or Snohomish counties, Washington. A sample of women of similar age from the same counties was recruited to serve as controls using random digit telephone dialing (RDD). All women participated in an in-person interview that elicited histories of known and suspected behavioral and medical risk factors for cardiovascular disease. A sample of women in the study provided venous blood specimen. We have used the blood specimens to examine the relationship between MI and plasma homocysteine levels, and the role of prothrombotic mutations in the risk of MI and stroke.
Our work on the WCHS paved the way for a new population-based study of the genetic epidemiology of early-onset myocardial infarction. The Heart Attack Risk in Puget Sound (HARPS) study is funded by the National Heart Lung and Blood Institute (NHLBI), and is similar in design to the WCHS. Patients with incident MI (women 18-59 years of age and men 18-49 years of age) are identified from over 25 acute care hospitals serving King, Pierce, and Snohomish counties in Washington State. Age and sex-matched controls are identified by RDD. Cases and controls are recruited into a protocol consisting of an in-person interview and a blood draw. As data and samples accumulate, we will be conducting analyses to follow-up on our findings in the WCHS regarding the prothrombotic factors Factor V R506Q and Prothrombin G20210A. We also will be examining the contribution of genetic factors in genes related to the metabolism and levels of lipids and lipoproteins, and genes involved in the growth and development of atherosclerotic plaques (e.g., stromelysin, E-selectin). My collaborators at the CHRU are David Siscovick (co-Investigator), Bruce Psaty (co-Investigator), and Thomas Lumley (Biostatistician). Molecular genetic analyses and statistical genetic expertise are provided by collaborators at Leiden University, Netherlands (Frits Rosendaal and Hans Vos) and Hebrew University, Jerusalem (Yechiel Friedlander and Eran Leitersdorf).
Related Publications
Hindorff LA, Schwartz SM, Siscovick DS, Psaty BM, Longstreth WT Jr, Reiner AP. The association of PAI-1 promoter 4G/5G insertion/deletion polymorphism with myocardial infarction and stroke in young women. J Cardiovascular Risk 2002; 9:131-7.
Reiner AP, Frank MB, Schwartz SM, Linenberger ML, Longstreth WT Jr, Teramura G, Rosendaal FR, Psaty BM, Siscovick DS. Coagulation factor XIII polymorphisms, and the risk of myocardial infarction and ischemic stroke in young women. Br J Haematol 2002;116:376-82.
Friedlander Y, Arbogast P, Schwartz SM, Marcovina SM, Austin MA, Rosendaal FR, Reiner AP, Psaty BM, Siscovick DS. Family history as a risk factor for early onset myocardial infarction in young women. Atherosclerosis 2001;156:201-207.
Kamigaki AS, Siscovick DS, Schwartz SM, Psaty BM, Edwards KL, Raghunathan TE, Austin MA. Low-density lipoprotein particle size and risk of early-onset myocardial infarction in women. Am J Epidemiol 2001;153:939-945.
Reiner AP, Schwartz SM, Frank MB, Longstreth Jr WT, Hindorff LA, Teramura G, Rosendaal FR, Gaur LK, Psaty BM, Siscovick DS. Polymorphisms of coagulation factor XIII subunit A and risk of non-fatal hemorrhagic stroke in young white women. Stroke 2001;32:2580-7.
Reiner AP, Schwartz SM, Kumar PN, Rosendaal FR, Pearce RM, Aramaki KM, Psaty BM, Siscovick DS. Association of platelet glycoprotein IIb polymorphism with myocardial infarction in young women. Br J Haematol 2001;112:632-636.
Frank MB, Reiner AP, Schwartz SM, Kumar PN, Pearce RM, Arbogast PG, Longstreth WT Jr, Rosendaal FR, Psaty BM, Siscovick DS. The Kozak sequence polymorphism of platelet glycoprotein Iba and risk of non-fatal myocardial infarction and non-fatal stroke in young women. Blood 2001;97:875-879.
Reiner AP, Kumar PN, Schwartz SM, Longstreth WT Jr, Pearce RM, Rosendaal FR, Psaty BM, Siscovick DS. Genetic variants of platelet glycoprotein receptors and risk of stroke in young women. Stroke 2000; 31:1628-1633.
Longstreth WT Jr, Rosendaal FR, Siscovick DS, Vos HL, Schwartz SM. Psaty BM, Raghunathan TE, Koepsell TD, Reitsma PH. Risk of stroke in young women and two prothrombotic mutations: Factor V Leiden and prothrombin gene variant (G20210A). Stroke 1998; 29:577-580.
Rosendaal FR, Siscovick DS, Schwartz SM, Beverly RK, Psaty BM, Longstreth WT Jr, Raghunathan TE, Koepsell TD, Reitsma PH. Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women. Blood 1997; 89:2817-2821.
Schwartz SM, Siscovick DS, Malinow MR, Rosendaal FR, Beverly RK, Hess DL, Psaty BM, Longstreth WT Jr, Koepsell TD, Raghunathan TE, Reitsma PH. Myocardial infarction in young women in relation to plasma total homocysteine, folate, and a common variant in the methylenetetrahydrofolate reductase gene. Circulation 1997; 96:412-417.
Rosendaal FR, Siscovick DS, Schwartz SM, Psaty BM, Raghunathan TE, Vos H. A common prothrombin variant (20210 G to A) increases the risk of myocardial infarction in young women. Blood 1997; 90:1747-1750.
Siscovick DS, Schwartz SM, Rosendaal FR, Psaty BM. Thrombosis in the young: effect of atherosclerotic risk factors on the risk of myocardial infarction associated with prothrombotic factors. Thromb Haem 1997; 78:7-12.