Differences in Hepcidin Concentrations by Sickle Cell and α+‐Thalassemia Genotype: A Cross‐Sectional Study Nested Within the Kenya WASH Benefits Trial

Abstract

ObjectiveHepcidin is a key iron‐regulatory hormone, and is influenced by iron status, inflammation, and erythropoiesis. Many forms of hemoglobinopathies are characterized by ineffective erythropoiesis, which may suppress hepcidin concentrations. The objective of this study was to determine if there are differences in hepcidin concentration by sickle cell or α+‐thalassemia genotype, while controlling for iron status.MethodsInfants enrolled in this sub‐study were selected from the WASH Benefits Trial, a trial carried out in western Kenya designed to measure the impact of improvements in water, sanitation, hygiene, and nutrition on child growth, child development, and anemia. Serum samples were analyzed for hepcidin and ferritin, and packed cells were genotyped for α+‐thalassemia and sickle cell. Hepcidin concentrations were compared across sickle cell and α+‐thalassemia genotypes separately, and another comparison was made between infants who were normozygous for both conditions, and who had a gene for either of the conditions. Data were analyzed using mixed effect linear models, with robust standard errors at the cluster level.ResultsSamples were available for 435 infants, aged 14–20 months. In this population, 83.4% of the infants were normozygous for sickle cell disorder (HbAA), 15.9% had sickle cell trait (HbAS), and 1.0% had sickle cell disorder (HbSS). Of the α+‐thalassemia genotype, 53% were normozygous (αα/αα), 40% were heterozygous (−α/αα), and 7% were homozygous (−α/−α). Hepcidin concentrations were significantly higher among those with either form of hemoglobinopathy compared to those who were normal for both conditions (β 1.16 ng/mL, 95% CI 1.02–1.57, p = 0.03). A significant interaction was found between the sickle cell genotype and ferritin concentrations. Among those with HbAA, there was a significant correlation between hepcidin and ferritin (r = 0.55, p<0.001). However, among those with HbAS, there was a reduced and only marginal correlation (r = 0.22, p = 0.09). Similarly, among infants who were either normal or heterozygous for α+‐thalassemia, hepcidin and ferritin were significantly correlated (r = 0.54, p<0.001, r = 0.51, p<0.001, respectively), but in infants who were homozygous for α+‐thalassemia, there was no correlation (r = 0.33, p =0.547).ConclusionIn this study, we found that hepcidin concentrations were modestly elevated in children with either sickle cell or α+‐thalassemia traits. These data also suggest that there may be a disruption in ferritin and hepcidin signaling among those who are affected by either of these conditions.Support or Funding InformationFunding source: This project was funded by a grant to UC Berkeley from the Bill and Melinda Gates Foundation with additional support from the Thrasher Research Fund and the National Institutes of Health.