Differences in Non-heme Iron Absorption Between Healthy Adults of East Asian and Northern European Ancestry: A Stable Iron Isotope Study

Objectives: Since humans have no regulated mechanisms for excreting excess iron (Fe), dietary Fe absorption must be tightly controlled to ensure optimal body Fe levels. We have previously shown that healthy East Asian (EA) adults have higher body Fe stores compared to Northern European (NE) individuals, but the physiological basis for this difference is unknown. We aimed to evaluate differences in non-heme Fe absorption and its regulation in EA and NE participants using a stable Fe isotope approach. Methods: We studied males (M) and pre-menopausal, non-pregnant females (F) of genetically confirmed EA (F: n=112, M: n=98) and NE (F: n=111, M: n=102) ancestry who were 18-50 y of age, non-smokers, and did not have obesity or other underlying diseases. Participants ingested a stable 57Fe isotope as FeSO4 and returned 2 weeks later for a blood draw. Fe absorption was calculated based on erythrocyte 57Fe incorporation 2 weeks post-dosing, which was measured using a thermal ionization mass spectrometer, and normalized to a fixed serum ferritin (SF) to control for interindividual variability in Fe status. Fe status biomarkers (SF, soluble transferrin receptor (sTfR), total body iron (TBI)) and serum hepcidin levels were measured and evaluated in relation to Fe absorption using linear regression with an interaction term for ancestry and controlling for age and sex. Results: Median normalized Fe absorption was 3.4 % [IQR: 1.1] in EA and 2.9 % [IQR: 1.04] in NE (p=2.0x10-9). When categorized by sex, both EA males and females had higher normalized Fe absorption compared to their NE counterparts (F: p=3.0x10-8, M: p=0.005). SF, TBI, and hepcidin were higher among EA compared to NE (all p< 0.001), but sTfR did not differ (p=0.09). Fe absorption was negatively associated with SF (β=-0.5, p< 2.0x10-16), TBI (β=-0.1, p=2.5x10-12), and hepcidin (β=-0.6, p=1.7x10-9), and positively associated with sTfR (β=0.6, p=0.02). The slope of the relationship with either marker did not differ between ancestry groups (all p-interaction >0.05). Conclusions: Participants of EA ancestry absorbed more Fe for a fixed amount of storage Fe compared to NE participants. These findings suggest that EA individuals have a higher Fe storage threshold at which they downregulate Fe absorption. Future investigations are needed to uncover the genetic and environmental factors underlying these differences.