HFE
Homeostatic iron regulator
Gene Number: 3077
Location: 6p22.2
Key Functions: Regulation of systemic iron absorption, modulation of hepcidin signaling, maintenance of iron homeostasis, prevention of iron overload and oxidative damage
HFE (homeostatic iron regulator) encodes a transmembrane glycoprotein structurally similar to major histocompatibility complex (MHC) class I molecules. It associates with β2-microglobulin (β2M) to form a functional complex on the cell surface, primarily in hepatocytes, macrophages, and enterocytes. The HFE protein modulates the interaction between transferrin receptor 1 (TfR1) and transferrin (Tf)—the principal iron-transport protein in plasma—thereby serving as a critical sensor of circulating iron levels.
Excessive iron deposition, particularly in the liver, pancreas, heart, and joints, leads to oxidative stress via Fenton chemistry, generating reactive oxygen species (ROS) that damage lipids, proteins, and DNA. This contributes to hepatic cirrhosis, cardiomyopathy, diabetes mellitus, arthropathy, and increased hepatocellular carcinoma (HCC) risk. Notably, the clinical penetrance of HFE mutations varies considerably: although up to 1 in 200 individuals of Northern European descent are C282Y homozygotes, only a subset develop severe iron overload, suggesting a role for modifying loci (e.g., HAMP, BMP2, TMPRSS6) and environmental cofactors such as alcohol intake, infections, or metabolic syndrome.
SNP ID | Your Genotype | Alternative Alleles | Interpretation |
|---|---|---|---|
rs1800562 | Analyze your DNA to see your genotype | A | Analyze your DNA to see a personalized result. |
rs1799945 | Analyze your DNA to see your genotype | G | Analyze your DNA to see a personalized result. |
rs1800562
GG – Typical HFE function; normal iron absorption (R).
AG – Moderate to high risk; increased hemochromatosis risk especially when homozygous or in presence of other risk variants (R).
AA – High risk; significantly elevated risk for hereditary hemochromatosis with potential organ damage, particularly in men (R).
Functional effect: The A allele (C282Y) causes loss of interaction with transferrin receptors, disrupting hepcidin regulation and permitting unchecked iron absorption. This leads to iron overload, particularly in homozygotes or compound heterozygotes with H63D (R).
rs1799945
CC – Reference genotype; baseline iron regulation (R).
CG –Mild risk; associated with modest iron accumulation, especially in combination with C282Y, and may support endurance performance (R).
GG – Elevated risk; homozygous carriers have higher susceptibility to iron overload when combined with dietary or comorbid stressors, though overall penetrance is low (R).
Functional effect: The G allele (H63D) subtly disrupts iron homeostasis. Alone, it doesn't typically cause clinical hemochromatosis, but in compound heterozygotes (e.g., C282Y + H63D) or under environmental stress, iron accumulation risk increases (R).
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