Patients with diabetes mellitus have an increased risk from cardiovascular morbidity and mortality that is similar to patients, without diabetes, who have had a previous myocardial infarction. Although many explanations for this increased risk have been proposed from studies, the risk for a specific individual is difficult to determine from these studies. Plasminogen activator inhibitor-1 (PAI-1) is an important peptide in the fibrinolytic-thrombotic pathway and elevated levels of PAI-1 have been shown to correlate with cardiovascular events, such as myocardial infarction. Thus, PAI-1 may be a marker for cardiovascular risk. The renin-angiotensin system (RAS) also has profound effects on the cardiovascular system and pharmacologic blockade of the RAS can affect cardiovascular disease. The RAS can also affect levels of greater insulin resistance and a more adverse lipid profile than other sub-groups. However, not every diabetic patient is at equal risk for cardiovascular events or for elevations in PAI-1 levels. Thus, there are environmental and genetic factors that predispose certain individuals to greater cardiovascular risk. A genetic predisposition compounded by adverse environmental factors may highlight those at greatest risk. Genetic polymorphisms in the RAS may increase the adverse cardiovascular risk in diabetic subjects by increasing PAI-1 plasma levels or by creating an adverse metabolic milieu. The studies highlighted in this proposal will categorize diabetic subjects by an intermediate phenotype of the RAS, first demonstrated in hypertensive subjects. The relationship of gene polymorphisms in the RAS and PAI-1 genes and intermediate phenotypes of PAI-1 levels, lipids, obesity, and insulin resistance will be determined. The knowledge of which genotypes and intermediate phenotypes predict a greater risk for cardiovascular risk in patients with diabetes may help identify those individuals at greatest risk, may be able to predict the risk for a specific individuals, and may also help define specific therapy to reduce that risk.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23RR017394-03
Application #
6754426
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Program Officer
Wilde, David B
Project Start
2002-07-15
Project End
2007-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
3
Fiscal Year
2004
Total Cost
$145,728
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Zee, Robert Y L; Germer, Soren; Thomas, Abraham et al. (2008) C-reactive protein gene variation and type 2 diabetes mellitus: a case-control study. Atherosclerosis 197:931-6
Perlstein, Todd S; Gerhard-Herman, Marie; Hollenberg, Norman K et al. (2007) Insulin induces renal vasodilation, increases plasma renin activity, and sensitizes the renal vasculature to angiotensin receptor blockade in healthy subjects. J Am Soc Nephrol 18:944-51