Iron regulatory hormones and their associations with iron status biomarkers among healthy adults of East Asian or Northern European ancestry: A cross-sectional comparison from the Iron Genes in East Asian and Northern European Adults Study (FeGenes).

Background: Individuals of East Asian (EA) ancestry have greater risk of elevated iron (Fe) stores compared with individuals of Northern European (NE) ancestry, but no studies have assessed differences in Fe regulatory hormones between these populations.

Objectives: This study aimed to evaluate hepcidin, erythropoietin, and erythroferrone as a function of ancestry and examine their associations with Fe status markers in United States adults of genetically confirmed EA or NE ancestry.

Methods: Participants in this cross-sectional study were healthy EA (n = 251) or NE (n = 253) males and premenopausal, nonpregnant females, aged 18-50 y, and without obesity. Serum hepcidin, erythropoietin, and erythroferrone concentrations were measured using ELISAs. Fe status [serum ferritin (SF), soluble transferrin receptor, total body iron, and transferrin], hematologic (complete blood count), and inflammatory (C-reactive protein and IL-6) markers were measured. Results are shown as the geometric mean (95% CI).

Results: Hepcidin (ng/mL) was significantly higher in EA (43.9; 95% CI: 39.6, 48.7) compared with NE (31.3; 95% CI: 28.4, 34.5) males (P < 0.001) but did not differ between EA (21.8; 95% CI: 19.4, 24.6) and NE (21.3; 95% CI: 19.0, 23.8) females (P = 0.66). Interestingly, the hepcidin:SF ratio was lower in EA males (0.26; 95% CI: 0.23, 0.28) and females (0.51; 95% CI: 0.46, 0.57) compared with NE males (0.37; 95% CI: 0.33, 0.40; P < 0.001) and females (0.65; 95% CI: 0.57, 0.73; P = 0.01), respectively. These differences remained significant after adjustment for C-reactive protein (males: P-adjusted < 0.001; females: P-adjusted = 0.008) or IL-6 (males: P-adjusted < 0.001; females: P-adjusted = 0.006). Erythropoietin did not differ between ancestry groups in males (P = 0.11) or females (P = 0.96). Lastly, erythroferrone (ng/mL) was higher in EA (1.3; 95% CI: 0.8, 1.9) compared with NE (0.6; 95% CI: 0.4, 0.9; P = 0.009) males but did not differ between females (EA: 0.7; 95% CI: 0.5, 1.1; NE: 0.5; 95% CI: 0.3, 0.7; P = 0.11).

Conclusions: A lower hepcidin:SF ratio in EA compared with NE participants suggests that among EAs, hepcidin concentrations are lower relative to the load of Fe present. Further studies are needed to elucidate the mechanisms underlying the observed differences. This study was registered at clinicaltrials.gov as NCT04198545.