Macrophage inhibitory cytokine‐1 (MIC‐1/GDF15): a new marker of all‐cause mortality

Abstract

Summary Macrophage inhibitory cytokine-1 (MIC-1/GDF15) is a member of the TGF-b superfamily, previously studied in cancer and inflammation. In addition to regulating body weight, MIC-1/GDF15 may be used to predict mortality and/or disease course in cancer, cardiovascular disease, chronic renal and heart failure, as well as pulmonary embolism. These data suggested that MIC-1/GDF15 may be a marker of all-cause mortality. To determine if serum MIC-1/GDF15 estimation is a predictor of all-cause mortality we examined a cohort of 876 male subjects aged 35 to 80 years, selected from the Swedish Population Registry, and followed them for overall mortality. Serum MIC-1/GDF15 levels were determined for all subjects from samples taken at study entry. A second (independent) cohort of 324 same-sex twins (69% female) from the Swedish Twin Registry was similarly examined. All the twins had telomere length measured and 183 had serum levels of interleukin 6 (IL-6) and C reactive protein (CRP) available. Patients were followed for up to 14 years and had cause specific and all-cause mortality determined. Serum MIC-1/GDF15 levels predicted mortality in the all-male cohort with an adjusted odds ratio of death of 3.38 (95%CI 1.38–8.26). This finding was validated in the twin cohort. Serum MIC-1/GDF15 remained an independent predictor of mortality when further adjusted for telomere length, IL-6 and CRP. Additionally, serum MIC-1/GDF15 levels were directly correlated with survival time independently of genetic background. Serum MIC-1/GDF15 is a novel predictor of all-cause mortality.

Evaluation of Temporal Changes in Cardiovascular Biomarker Concentrations Improves Risk Prediction in an Elderly Population from the Community

“…Whether chronic increases in GDF-15 play an adaptive or maladaptive role in CV disease remains to be elucidated. GDF-15 expression may also increase in prognostically adverse non-CV conditions, e.g., renal failure (5,18 ), rheumatoid arthritis (25 ), and malignancies (26 ), and has been related to shortened telomere length, an indicator of premature aging at the cellular level (27 ). This likely explains the association of GDF-15 with both CV and non-CV mortality, corresponding to the data reported by Wiklund et al (27 ).…”

“…The appropriate timing of repeat measurements, however, remains to be determined, also taking the biologic variability of these biomarkers into account (34,35 ). For GDF-15, these recommendations are not similarly straightforward given the association of this biomarker with both CV and non-CV conditions (5,10,14,(25)(26)(27). Nevertheless, a high or increasing GDF-15 concentration should prompt the search for the source of tissue injury with appropriate medical actions taken depending on test results and also considering the biological age of each assessed individual.…”

Growth Differentiation Factor 15, Its 12-Month Relative Change, and Risk of Cardiovascular Events and Total Mortality in Patients with Stable Coronary Heart Disease: 10-Year Follow-up of the KAROLA Study

“…In relatively healthy individuals GDF-15 concentrations have been more strongly associated with mortality than with nonfatal CVE (23 ), and among those with ACS the association with mortality was also stronger than with recurrent MI (20,26,27 ). This observed association with total mortality could be related to the process of aging, which is known to be associated with cumulative oxidative stress, protein glycosylation, and inflammation; processes which also induce GDF-15 expression (28 ). Further studies evaluating the underlying pathophysiological mechanisms and the involving signaling pathways are urgently needed to understand whether GDF-15 should be seen as a messenger of a poor outcome without specific therapeutic implications (25 ), whether GDF-15 concentrations can be modified through new intervention modalities with a subsequent reduction of the risk for a CVE and mortality, or whether GDF-15 concentrations could further help to stratify patients for specific treatment options according to their overall risk.…”

Macrophage inhibitory cytokine-1 is associated with cognitive impairment and predicts cognitive decline - the Sydney Memory and Aging Study

“…It is unclear whether elevated levels of MIC-1/GDF15 are directly damaging or whether these levels represent the body's response to mitigate the damage caused by an injurious insult (Wiklund et al, 2010) as we hypothesized. Because we controlled for other inflammatory markers, such as CRP, TNF-a, and interleukins 6 and 12, and these markers did not predict cognitive decline, the role of MIC-1/GDF15 on brain function requires further investigation.…”