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Identifying new markers for risk of coronary heart disease through blood protein analysis

The original article is very dense: I was asked to prepare a single page summary for doctors that focuses on why this study is a breakthrough.

Background: The Women’s Health Initiative (WHI) has been tracking the health of 93,676 women since 1993. The focus of the on-going study has been to establish the effects of hormone replacement therapy (HRT) on future risk for coronary heart disease (CHD), stroke and breast cancer.

Summary: In this study, 3200 blood samples were selected from samples submitted upon enrollment in the WHI ; 800 from woman who later developed CHD, 800 from women who later had strokes, plus 1600 from case-matched controls who did not develop either.

Proteomics allows researchers to analyze all proteins present in large sets of plasma rather than select proteins. Plasma levels of three proteins were strongly correlated with CHD and six proteins were moderately correlated. Strong correlations to stroke were found in three different proteins and a moderate link to stroke was established for fourteen additional proteins. Most of these proteins were already known to be involved in inflammatory cascades or known to be affected by hormone replacement therapy. Five of the six proteins strongly correlated with disease were also correlated with HRT. The various proteins that changed during HRT tracked to pathways for coagulation, inflammation, immune response, metabolism, cell adhesion, growth factors and osteogenesis.

An analysis of plasma samples from 106 from women who developed CHD in the first year of HRT showed that their blood concentrations of beta-2-microglobulin (B2M) were 17.9% higher than controls prior to treatment. B2M is known to be elevated in patients with bone disease or undergoing dialysis, inversely associated with HDL cholesterol and correlated with mortality for elderly Japanese. The association with CHD is novel.

Analysis of samples from 68 women who had significant strokes in the first year on HRT showed that their insulin-like growth factor-binding protein 4 (IGFBP4) was 16.9% higher than controls prior to HRT. There have been some previous reports suggesting that other proteins in the same family are associated with protecting neurons during a stroke. Correlating IGFBP4 to strokes is a new finding.

The current study is a follow-up to a proteomic study demonstrating blood protein changes in women after one year of randomized HRT and controls. The goal of the new study is to learn how to predict disease risk.

Implications: Before the use of proteomics, plasma markers for disease were identified by looking at chemical cascades involved in a disease, theorizing which specific blood proteins might change and testing for that change in the presence of disease. Proteomics reverses the process of discovering disease markers. Very large numbers of blood samples are analyzed to identify all proteins present and determine which are associated with the disease in question.

Proteins that are discovered to correlate to the disease may not be previously known to be involved in the disease. These novel markers are then studied to learn how the protein is involved in the disease process and thereby advance the understanding of the disease process itself. At some point in the future, the new knowledge about the disease may lead to novel treatment modalities and the markers will allow clinicians to customize medical treatments for individuals.

Prentice, RL, Paczesny SJ, Aragaki A, Amon L, Chen L, Pitteri S, McIntosh M, Wang P, Busald TB, Hsia J, Jackson RD, Rossouw JE, Manson JE, Johnson K, Eaton C, Hanash SM: Novel proteins associated with risk for coronary heart disease or stroke among postmenopausal women identified by in-depth plasma proteome profiling. Genome Medicine 2:48, 2010.