W57 – Extend CVD Biomarker Study Using HT Proteomics Study Findings

This page provides study documentation for the W57 Core Study. For description of the specimen results, see Specimen Results Description (open to public). Data sets of the specimen results are included in the existing WHI datasets located on the WHI Data on this site (sign in and a completed Data Distribution Agreement are required; see details on the Data site).

Investigator Names and Contact Information

Core study approved by WHI Steering Committee


The ‘core’ CVD Biomarker Study (W6) examined  baseline biomarkers that may relate to E+P or E-alone effects on cardiovascular disease, and biomarker changes that may help to explain early hormone therapy effects on CHD, stroke and venous disease. Some interacting factors were identified (e.g. baseline LDL cholesterol related to hazard ratio for CHD; Rossouw et al, 2008), but much remains to be learned concerning the key mediators of  HT effects on these diseases. The ‘core’ HT proteomic project identified a large number of proteins that changed serum concentration as a result of E-alone or E+P, with independent ELISA validation of several that were top-ranked (Katayama et al,2009; Pitteri et al, 2009). In fact there was evidence of change with E+P or with E-alone for a remarkable 44.7% of the 378 proteins quantified in this ‘discovery’ project. A BAA project (BAA04) has helped to sort through the leads from the HT Proteomics project, by comparing plasma protein concentrations between CHD cases and matched controls, and stroke cases and matched controls. A manuscript from that project is under P&P review (Prentice et al, attached). After restricting to proteins that are affected by HT, and that relate to the risk of CHD or stroke, quite a few candidates remain for HT effect mediation. However, there is one candidate for each of CHD (beta 2 microglobulin) and stroke (IGFBP4) that has low estimated false discovery rate (0.03 for B2M;0.04 for IGFBP4), and for which a reliable ELISA kits are commercially  available. Funds are requested to extend the CVD Biomarker Study by assessing B2M  in CHD cases and matched controls, and IGFBP4 in stroke cases and matched controls.  The changes in B2M and IGFBP4 observed in the HT Proteomics project, and the association of these proteins with disease risk, combine to suggests that these changes could be major contributors to  hormone therapy effects on these diseases, as observed in the HT trials.  Complementary ancillary study proposal(s) will be submitted to request external funds for assessment of a broader set of candidates derived from these preliminary studies. Results from this proposed extension of the CVD Biomarker Study could both provide timely input to the elucidation of HT effects on CHD and stroke, and provide valuable data to support a more comprehensive study of plasma proteins in relation to CHD and stroke risk, and as mediators of HT effects on these diseases.


Carry out ELISA assessments of B2M on baseline and 1-year specimens for CHD cases occurring after the first year in the E+P and E-Alone trials , including all cases though Feb 2001 and their 1-1 matched controls (as chosen in the CVD Biomarker Study). This will involve about 356 cases and 356 controls and a total of 1424 determinations.
Similarly, carry out ELISA assessments of IGFBP4 at baseline and 1-year for 248 stroke cases occurring after year 1 in the E+P and E-Alone trials, though Feb 2001, and their 1-1 matched controls in the CVD Biomarker Study, for a total of 992 determinations.
Data analyses will examine the extent to which the change in concentration of these proteins can provide an explanation for observed clinical effects, and will provide a confirmation of these proteins as disease risk factors. A ‘mediation model’ will be developed to estimate the odds ratio associated with these biomarker changes in conjunction with changes in other biomarkers evaluated in the CVD Biomarker Study. The variation between baseline and 1-year concentrations among control women will allow correction for biomarker measurement error to be included in these analyses.

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See Publication:  1065.  WHI publications by study lists published WHI papers that have been generated by ancillary studies. A complete list of WHI papers is available in the Bibliography section of this website.


Rossouw JE, Cushman M, Greenland P et al. Inflammatory, lipid, thrombotic, and genetic markers of coronary heart disease risk in the Women’s health Initiative trials of hormone therapy. Arch Intern med 2008,168:2245-2253.
Katayama H, Paczesny S, Prentice RL, et al. Application of serum proteomics to the Women’s health Initiative conjugated equine estrogens trial reveals a multitude of effects relevant to clinical findings. Genome Med 2009;1:47.
Pitteri SJ, Hanash SM, Aragaki A et al. Postmenopausal estrogen and progestin effects on the serum proteome. Accepted Genome Med, 2009.