Genetic variation underlies phenotypic diversity and complex quantitative traits including heritable diseases. We hypothesized that Such variation may underlie or determine intrinsic inter-individual differences in iron metabolism and may also play a role in variable phenotypes associated with iron-related diseases. Using hepcidin as a marker of iron homeostasis, we assessed sequence variation and the transcription potencies of promoter haplotypes For both hepcidin genes mhepc1 and mhepc2 from different strains of inbred mice. We found several single nucleotide polymorphisms (SNPs) within the promoters of both genes on one hand, and between strains oil the other. With luciferase as reporter, we also found significant variation in the basal transcription of both genes. A regulatory SNP constituting an E-box in the promoter of mhepc1 caused further expression level variation and transactivation by Upstream Stimulatory Factor, USE Inter-strain variation in hepcidin expression correlated with established phenotypic differences in iron loading in these mice. As hepcidin is critically required for iron metabolism, we posit that variation in its expression may be a quantitative trait which determines differences in iron handling within and between mouse strains, and that this may also apply to humans. Thus, regulatory variation ill hepcidin expression may be just as important as Structural variation or mutations within its coding sequence. (c) 2009 Elsevier Inc. All rights reserved.