Growth differentiation factor 15 in a community-based sample: age-dependent reference limits and prognostic impact

Ups J Med Sci. 2018 Jun;123(2):86-93. doi: 10.1080/03009734.2018.1460427. Epub 2018 May 1.


Background: Despite the growing body of evidence on growth differentiation factor 15 (GDF-15) reference values for patients with existing cardiovascular disease, limited investigation has been dedicated to characterizing the distribution and prognostic impact of GDF-15 in predominantly healthy populations. Furthermore, current cutoff values for GDF-15 fail to account for the well-documented age-dependence of circulating GDF-15.

Methods: From 810 community-dwelling older adults, we selected a group of apparently healthy participants (n = 268). From this sample, circulating GDF-15 was modeled using the generalized additive models for location scale and shape (GAMLSS) to develop age-dependent centile values. Unadjusted and adjusted Cox proportional hazards models were used to assess the association between the derived GDF-15 reference values (expressed as centiles) and all-cause mortality.

Results: Smoothed centile curves showed increasing GDF-15 with age in the apparently healthy participants. An approximately three-fold difference was observed between the 95th and 5th GDF-15 centiles across ages. In a median 8.0 years of follow-up, 97 all-cause deaths were observed in 806 participants with eligible values. In unadjusted Cox regression analyses, the hazard ratio (95% CI) for all-cause mortality per 25-unit increase in GDF-15 centile was 1.80 (1.48-2.20) and dichotomized at the 95th centile, ≥95th versus <95th, was 3.04 (1.99-4.65). Age-dependent GDF-15 centiles remained a significant predictor of all-cause mortality in all subsequent adjusted models.

Conclusions: Age-dependent GDF-15 centile values developed from a population of apparently healthy older adults are independently predictive of all-cause mortality. Therefore, GDF-15 reference values could be a useful tool for risk-stratification in a clinical setting. Identifier: NCT01452178.

Keywords: All-cause mortality; GDF-15; protein biomarkers; reference values; survival analysis.

MeSH terms

  • Age Factors
  • Aged
  • Aged, 80 and over
  • Aging
  • Biomarkers / blood
  • Cardiovascular Diseases / blood
  • Cardiovascular Diseases / diagnosis*
  • Cardiovascular Diseases / mortality*
  • Female
  • Follow-Up Studies
  • Growth Differentiation Factor 15 / blood*
  • Humans
  • Male
  • Middle Aged
  • Prognosis*
  • Proportional Hazards Models
  • Reference Values
  • Regression Analysis
  • Risk Assessment


  • Biomarkers
  • GDF15 protein, human
  • Growth Differentiation Factor 15

Associated data