AS343 - Cardiovascular Disease Biomarkers and Mediation of Hormone Therapy Effects
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Investigator Names and Contact Information
Ross Prentice [rprentic@whi.org]
Introduction/Intent
This research has two aims, each of which includes coronary heart disease and stroke sub-aims. Prior studies based on in-depth quantitative proteomic mass spectrometry profiling of plasma samples collected before a diagnosis of CHD or stroke among subjects in the Women's Health Initiative study cohort, compared with matched controls from the same cohort, have identified a subset of proteins in plasma as novel candidate risk markers. Additionally proteomic profiling of blood specimens collected before and after hormone replacement therapy led to findings of a substantial effect of HRT on the plasma proteome, including some of the protein candidates we have identified as associated with risk for CHD and stroke. These provocative findings require further validation in an independent set of cases and controls, which we propose to undertake using ELISA based assays.
- Novel Plasma Protein Risk Factor Identification for CHD and Stroke
Building on our recent proteomic discovery research, we propose to measure concentrations of alpha-1-acid glycoprotein 1 (ORM1), thrombospondin 1 (THBS1), complement factor D preprotein (CFD), glutathione peroxidase 3 (GPX3), and insulin-like growth factor binding protein 1 (IGFBP1) in baseline plasma samples from women who developed coronary heart disease (CHD) during the intervention phase of the Women's Health Initiative (WHI) postmenopausal hormone therapy (HT) trials and matched controls, and to associate these concentrations with subsequent CHD incidence.
Similarly, we propose to measure concentrations of IGFBP2, IGFBP6, insulin-like growth factor 2 (IGF2), hemopexin (HPX), and beta 2 microglobulin (B2M) in baseline plasma samples from women who experienced a stroke during the intervention phase of the HT trials and matched controls, and to associate these with subsequent stroke incidence.
- Proteomic Mediators of Postmenopausal Hormone Therapy Effects on CHD and Stroke
We propose also to measure plasma concentrations at one year following randomization for the subset of proteins listed above for which the concentration changed during the first year of hormone therapy use, in CHD and stroke cases occurring after one year and their matched controls, and to examine the extent to which these changes in concentration mediate the HT effects on CHD and stroke, as observed in the WHI trials. The proteins to be measured in plasma samples taken at one year following randomization are CFD and IGFBP1 for CHD, and IGFBP2, IGFBP6, IGF2, HPX, and B2M for stroke. Statistical methods that accommodate measurement 'error', deriving from temporal variation in biomarkers that is unlikely to be associated with disease risk, will be developed further, and used to strengthen these mediation analyses.