James P. Corsetti, M.D., Ph.D.
Brown University Bio/Med Sciences
Department of Pathology and Laboratory Medicine
The Corsetti Laboratory is involved in studies of cardiovascular disease risk in human populations using non-traditional statistical approaches, in particular, exploratory data analysis techniques for multivariable assessment of novel blood and genetic biomarkers of risk. Our approach is based upon the notion that current limitations on the implementation of personalized medicine can be broached by identification of patient subgroups with common underlying pathophysiologic features. Such subgroups, we believe, would manifest particular combinations of biomarkers of risk that, in general, will be different dependent on different underlying pathophysiologies. As such, we have developed a 3-dimensional graphical exploratory data analysis tool ("outcome event mapping") that allows identification of high-risk patient subgroups. The technique is not constrained by traditional rectilinear approaches to subgroup identification and it allows subgroup identification in unexpected regions of risk parameter spaces. Recently, we adapted the approach for the handling of differential risk associations with single-nucleotide polymorphisms (SNP).
As an example, we have demonstrated for both incident as well as recurrent coronary events a completely unexpected high-risk subgroup of individuals characterized by high levels of HDL cholesterol ("the good cholesterol") and high levels of C-reactive protein (CRP), a marker of systemic inflammation. The high CRP underscores the important role of inflammation in the transformation of HDL, normally anti-atherogenic, to a pro-atherogenic form. This is a significant finding in that intensive efforts are currently underway to decrease the residual cardiovascular disease risk characteristic of statin use by using agents to raise HDL. Future collaborative efforts will be oriented towards elucidation of mechanisms involved in elevated HDL risk including proteomic analysis of HDL particle constituents to fully characterize the physico-chemical nature of risk-associated HDL and, in addition, to elucidate the role of aberrant HDL in a potentially important aspect of the atherogenic process, namely, endothelial dysfunction induced by disturbed vascular blood flow.
In addition, we are continuing our efforts to utilize advanced exploratory data analysis approaches for biomarker assessment. Most recently, collaborative efforts are underway to develop and utilize the technique of Bayesian network analysis (BNA) to approach large databases of blood and genetic biomarkers to provide novel mechanistic insights on disease-associated pathways.
Corsetti JP, Zareba W, Moss AJ, and Sparks CE. Serum Glucose and Triglyceride Determine Hig-Risk Subgroups in Non-Diabetic Postinfarction Patients. Atherosclerosis. 2005;183:293 - 300.
Corsetti JP, Zareba W, Moss AJ, Rainwater DL, and Sparks CE. Elevated HDL Is a Risk Factor for Recurrent Coronary Events in a Subgroup of Non-Diabetic Postinfarction Patients with Hypercholesterolemia and Inflammation. Atherosclerosis. 2006;187:191 - 197.
Corsetti JP, Rainwater DL, Moss AJ, Zareba W, and Sparks CE. High Lipoprotein-Associated Phospholipase A2 Is a Risk Factor for Recurrent Coronary Events in Postinfarction Patients. Clinical Chemistry. 2006;52:1331 - 1338.
Corsetti JP, Ryan D, Moss AJ, Rainwater DL, Zareba W, and Sparks CE. Glycoprotein Iba Polymorphism (T145M), Elevated Lipoprotein-Associated Phospholipase A2, and Hypertriglyceridemia Predict risk for Recurrent Coronary Events in Diabetic Postinfarction Patients. Diabetes. 2007;56:1429 - 1435.
Corsetti JP, Ryan D, Moss AJ, Zareba W, and Sparks CE. NAD(P)H Oxidase Polymorphism (C242T) and High HDL Cholesterol Associate with Recurrent Coronary Events in Post infarction Patients. Atherosclerosis. 2008;196:461-468.
Corsetti JP, Ryan D, Moss AJ, Rainwater DL, Zareba W, and Sparks CE. Plasminogen Activator Inhibitor-1 Polymorphism (4G/5G) Predicts Recurrence in Non-Hyperlipidemic Postinfarction Patients. Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:548-554.
Corsetti JP, Ryan D, Rainwater DL, Moss AJ, Zareba W, Block RC, and Sparks CE. Lp(a) and Risk of Recurrent Cardiac Events in Obese Postinfarction Patients. Obesity. 2008;16:2717-2722.
Corsetti JP, Gansevoort RT, Sparks CE, Dullaart RPF. HDL Protection against Primary Cardiac Risk is Lost with Inflammation. European Journal of Clinical Investigation. 2010;40:483-489.
Corsetti JP, Ryan D, Rainwater DL, Moss AJ, Zareba W, and Sparks CE. Decreased CETP Activity Associates with Recurrent Risk in Postinfarction Patients with High HDL Cholesterol and High CRP. Atherosclerosis, Thrombosis, and Vascular Biology. 2010;30:1657-1664.
Corsetti JP, Gansevoort RT, Navis GJ, Sparks CE, Dullaart RPF. LPL Polymorphism (D9N) Predicts Cardiovascular Disease Risk Directly and Through Interaction with CETP Polymorphism (TaqIB) in Women with High HDL Cholesterol and CRP. Atherosclerosis. 2011;214:373-376.
Corsetti JP, Ryan D, Moss AJ, McCarthy JJ, Goldenberg I, Zareba W, Sparks CE. Thrombospondin-4 Polymorphism (A387P) Predicts Risk in Postinfarction Patients with High HDL Cholesterol and CRP Levels. Thrombosis and Haemostasis. 2011;106:1170-1178.
Corsetti JP, Gansevoort RT, Bakker SJL, Navis GJ, Sparks CE, and Dullaart RPF. Apolipoprotein E Predicts Incident Cardiovascular Disease Risk in Women but not in Men with Concurrently High Levels of High-Density Lipoprotein Cholesterol and C-Reactive Protein. Metabolism Clinical and Experimental. In Press (2012).