Growth differentiation factor 15: a canary in a coal mine?

It has been 50 years since Dr. William B. Kannel coined the term “factors of risk” in relation to cardiovascular disease (1). Since then, clinical risk assessment, including the use of circulating biomarkers, has become an integral part of medical practice. The current era of genomics, proteomics, and metabolomics is projected to lead to the discovery of an immense number of novel candidate biomarkers. With that in mind, the American Heart Association recently issued a statement emphasizing the critical appraisal of novel risk markers to determine their clinical utility (2). Although very few candidate biomarkers will likely survive the test of time (3), the study by Rohatgi et al. published in the present issue of Clinical Chemistry demonstrates the strengths of one such biomarker, growth differentiation factor 15 (GDF-15), as a prognostic marker in the community (4). In this study from the Dallas Heart Study, the authors investigated the association of GDF-15 with subclinical coronary atherosclerosis and mortality. Increasing circulating GDF-15 concentrations were cross-sectionally associated with cardiovascular risk factors and coronary artery calcium. More importantly, GDF-15 was a significant predictor of all-cause and cardiovascular mortality independently of traditional risk factors and other novel biomarkers (high-sensitivity C-reactive protein, N-terminal pro–B-type natriuretic peptide, and high-sensitivity cardiac troponin T). This study is an important contribution to the mounting evidence that GDF-15 bears prognostic importance in the general population. GDF-15 has been shown to predict all-cause, cardiovascular, and noncardiovascular mortality in older individuals in the Rancho Bernardo Study (5 ) and to be associated with endothelial and cardiac dysfunction in elderly participants in the Prospective Investigation of the Vasculature in Uppsala Seniors study (6 ). Although relatively underpowered for the end point of cardiovascular death (n 48), the findings in the Dallas Heart Study certainly add to those of existing community-based studies and, importantly, extend the prognostic role of GDF-15 to a substantially younger population of mixed race. Also notable is that GDF-15 concentrations were measured with an assay different from what has been used in the majority of other published studies. The similarities in the distributions of GDF-15 values between different studies, as well as the robustness of findings, support the reproducibility and feasibility of GDF-15 measurement in ambulatory individuals. In light of this growing body of evidence for GDF-15 as an emerging biomarker, 2 questions are worth addressing. First, what biological insights can be gathered, and, second, what is the clinical utility of measuring GDF-15?