High Levels of Growth Differentiation Factor 15 in Patients with Congenital Dyserythtopoietic Anemia Type I

Growth differentiation factor 15 (GDF15) is a member of the TGF-beta superfamily of cytokines previously found to suppress hepcidin in primary human hepatocytes. GDF15 is secreted from human erythroblasts, and extremely high serum levels are present in β-thalassemia patients (Tanno et al., Nat. Med. 2007, 13, 1096-1101). To determine if elevated GDF15 levels are unique for thalassemia or more generally associated with iron-loading related to ineffective erythropoiesis, we determined the GDF15 levels, as well as, serum hepcidin (Swinkels DW et al, PLoS ONE. 2008; 3:e2706), ferritin, erythropoietin (EPO) and soluble transferrin receptor (sTfR) in patients with the congenital dyserythropoietic anemia type I (CDA I). Seventeen Israeli Bedouins with CDA I were studied, all homozygous for the founder R1040W mutation in the CDAN1 gene. All of the patients studied were young adults with a mean age of 29 years. Two patients previously underwent splenectomy, and one patient is currently transfusion-dependent. For comparison, ten healthy volunteers (HV) were studied. The mean level of GDF15 in CDA I patients was significantly elevated [10,239 ± 3,049 pg/ml (range 5,530-17,008) compared to 269 ± 238 pg/ml in healthy controls; p = 1.5x10^-10]. Consistent with a previous study of dyserythropoietic anemia patients, significantly higher levels of soluble transferrin receptor were detected among the CDA I population (sTfR; CDA I, 86.4 ± 14.0 nmol/L; HV, 21.4 ± 6.2 nmol/L, p = 7.4x10^-15). Serum EPO levels were also elevated (EPO; CDA I, 118 ± 59 IU/dL; HV, 2.0 ± 1.5 IU/dL, p = 2.3x10^-7). For iron analyses, three patients with extensive transfusion histories were excluded. Among the remaining 14 patients, iron overload was demonstrated by elevated serum ferritin (CDA I, 916 ± 507 ng/ml; HV, 72 ± 60 ng/ml, p = 1.4x10^-5). Despite the significant elevation in iron stores, significantly elevated levels of hepcidin 25 (Hep25) were not detected in the CDA I patients. Instead, a minor decrease in serum Hep25 levels were detected (Hep25; CDA I, 3.3 ± 2.8 nM; HV, 4.1 ± 3.0 nM, p = 0.27). Correlation analyses were performed between the iron parameters (Ferritin and Hep25) and GDF15, sTfR, or EPO levels. Only GDF15 demonstrated a significant positive correlation with ferritin and significant inverse correlations with Hep25 and the Hep25/Ferritin ratio. Weaker correlations with EPO were identified. Unexpectedly, the correlation trends for sTfR were opposite those of GDF15 in this group. These results demonstrate that GDF15 is immensely over-expressed in CDA I, and further suggest this cytokine contributes to hepcidin dysregulation and secondary hemochromatosis in humans with ineffective erythropoiesis.