Which genes are at higher risk for iron overload in hereditary hemochromatosis (HH)?

From the Guidelines

The primary gene associated with a higher risk for iron overload in hereditary hemochromatosis (HH) is the HFE gene, specifically the C282Y mutation, which has a high positive predictive accuracy for phenotypic HH 1. The C282Y mutation is the most significant genetic variant, and individuals who inherit two copies of this mutation (homozygotes) have the highest risk of developing clinical iron overload, with 100% positive predictive accuracy for elevated transferrin saturation and 58% likelihood of full expression as defined by progressive tissue iron overload 1. Other important HFE mutations include H63D, which can contribute to iron overload when combined with C282Y, although the penetrance and expression of these mutations can vary 1. Key points to consider in the genetics of hereditary hemochromatosis include:

• The HFE gene mutations, particularly C282Y, are the most common cause of hereditary hemochromatosis in populations of northern European descent 1.
• Non-HFE genes such as hemojuvelin (HJV), hepcidin (HAMP), transferrin receptor 2 (TFR2), and ferroportin (SLC40A1) can also cause hereditary hemochromatosis, often leading to more severe or earlier-onset forms of the disease 1.
• The genetic mutations in hemochromatosis affect proteins involved in iron sensing and regulation of hepcidin, leading to excessive iron absorption and accumulation in organs if left untreated 1.

From the Research

Genes Associated with Iron Overload in Hereditary Hemochromatosis (HH)

The genes associated with a higher risk of iron overload in hereditary hemochromatosis (HH) include:

• HFE gene mutations, specifically C282Y, H63D, and S65C 2, 3, 4, 5, 6
• Compound heterozygous state for C282Y and H63D, which has a higher phenotypic expression 3
• Rare HFE mutations, such as IVS3 + 1G --> T, which can result in iron overload when in the compound heterozygous state with C282Y 4
• Other rare HFE mutant alleles, including c.1022_1034del13, p.Glu114Lys, p.Arg67Cys, and c.548T > C (p.Leu183Pro) 5

Risk of Iron Overload Associated with Different HFE Genotypes

The risk of iron overload associated with different HFE genotypes is as follows:

• Homozygosity for the C282Y mutation: highest risk for iron overload (OR = 4383) 6
• C282Y/H63D compound heterozygosity: increased risk for iron overload (OR = 32) 6
• H63D/H63D homozygosity: increased risk for iron overload (OR = 5.7) 6
• C282Y heterozygosity: uncertain association with iron overload (OR = 4.1) 6
• H63D heterozygosity: low risk for iron overload (OR = 1.6) 6

Factors Influencing Iron Overload in HH

Other factors that can influence iron overload in HH include:

• Dietary factors, such as iron and calcium intake 3
• Life-style factors, such as alcohol consumption 3
• Presence of other genetic mutations, such as rare HFE mutations 4, 5