A genome-wide meta-analysis connects iron homeostasis to metabolic disease through poly-unsaturated

Individuals with genetic iron overload diseases have a higher incidence of metabolic diseases. In individuals without iron overload, serum levels of the iron biomarkers ferritin and transferrin positively correlate with type 2 diabetes. The molecular mechanisms connecting iron and metabolic dysfunction remain unknown. We performed a large-scale genome-wide association study (GWAS) of iron and glucose-related biomarkers (N = 480,389). We identified a variant, rs174560, in the FADS1/FADS2 locus associated with reduced iron and glucose levels. The variant is an expressed quantitative trait loci (eQTL) associated with reduced FADS1 expression. FADS1 plays a critical role in long chain polyunsaturated fatty acid (PUFA) synthesis. Hepatic depletion of FADS1 improves glucose clearance and limits adipose tissue expansion in vivo. Variants in the FADS1 locus are associated with blood glucose levels in previous GWAS, however, the mechanism underlying this association is unclear. Using CRISPR/Cas9 and siRNA, we targeted FADS1 expression in the liver of C57Bl/6 mice. Specific reduction of FADS1 impaired PUFA synthesis, reduced serum iron, and elevated Hamp expression confirming FADS1 involvement in iron homeostasis in vivo. In HFE^-/- mice, a genetic model of iron overload, FADS1 reduction significantly normalized serum aspartate aminotransferase levels (AST). High circulating AST levels indicate liver damage and reducing FADS1 expression may be protective against liver damage during iron overload. Our work shows a strong connection between fatty-acid biology and trace metal homeostasis. The connection to glucose metabolism found in GWAS could be secondary to improved liver health, as liver function and glucose metabolism are tightly connected.