A structural deletion in the 3'UTR of SLC11A2 is associated with altered iron status: Evidence from two large Danish...

The SLC11A2 gene encodes divalent metal transporter 1, a key mediator of cellular and intestinal iron transport. While ultra-rare pathogenic variants in SLC11A2 cause autosomal recessive anaemia with iron overload, the phenotypic consequences of structural variation in this gene remain unexplored. We investigated the impact of a recently identified structural deletion in the 3' untranslated region (SLC11A2-Δ3.5kb) using genetic, biomarker and registry data from two large Danish cohorts: the Danish Blood Donor Study and the Copenhagen Hospital Biobank (CHB). Among 4847 heterozygous carriers and 320 633 non-carriers, SLC11A2-Δ3.5kb was associated with lower ferritin levels in both sexes and increased risk of iron deficiency in women. In female donors, SLC11A2-Δ3.5kb was associated with lower haemoglobin levels, increased risk of donation deferral due to low haemoglobin and increased use of prescribed iron treatment. In male CHB participants carrying HFE variants, concurrent SLC11A2-Δ3.5kb carriage was associated with a 66% reduced risk of iron overload, suggesting a potential disease-modifying role in haemochromatosis. No associations were observed with cardiometabolic, inflammatory, neurological or malignant diseases. These findings suggest that SLC11A2-Δ3.5kb affects iron homeostasis through reduced systemic iron availability and may have clinical relevance for personalised iron deficiency risk assessment and haemochromatosis penetrance.