Relationship between Gene Expression of Duodenal Iron

46 To test the hypothesis that differences in duodenal iron absorption may explain the variable 47 phenotypic expression among HFE C282Y homozygotes, we have compared relative gene 48 expression of duodenal iron transporters among C282Y homozygotes (HH) with and without iron 49 overload. Duodenal biopsy samples were analyzed using real time PCR for expression of DMT1, 50 FPN1, DCYTB and HEPH relative to GAPDH from 23 C282Y homozygotes, including 5 “non51 expressors” (serum ferritin<ULN and absence of phenotypic features of hemochromatosis) and 18 52 “expressors”. Four subjects wild type for HFE mutations without iron overload or liver disease served 53 as controls. There was a significant difference in expression of DMT1 (p= 0.03) and DMT(IRE) 54 (p=0.0013) but not FPN1, DCYTB or HEPH between groups. Expression of DMT1(IRE) was 55 increased among HH subjects after phlebotomy compared to untreated (p=0.006) and non-expressor 56 groups (p=0.026). A positive relationship was observed among all HH subjects regardless of 57 phenotype or treatment status between relative expression of FPN and DMT1 (r=0.5854, p=0.0021), 58 FPN1 and DCYTB (r=0.5554, p=0.0040), FPN1 and HEPH (r=0.5100, p=0.0092) and DCYTB and 59 HEPH (r=0.5400, p=0.0053). In summary, phlebotomy is associated with upregulation of DMT1 60 (IRE) expression in HH subjects. HFE C282Y homozygotes without phenotypic expression do not 61 have significantly decreased duodenal gene expression of iron transport genes compared to HH 62 subjects with iron overload. There is coordinated regulation between duodenal expression of FPN 63 and DMT1, FPN and DCYTB and FPN and HEPH and also DCYTB and HEPH in HH subjects 64 regardless of phenotype. 65