HFE c.845 G>A (C282Y / H282Y)
HFE c.845 G>A is the most common genetic variant associated with hereditary hemochromatosis (HH), an inherited disease that leads to increased absorption and storage of iron in the body. The mutation causes a change in the HFE protein where the amino acid cysteine is replaced by tyrosine at position 282, which is called Cys282Tyr or C282Y/H282Y.
The HFE gene is important for the body's regulation of iron metabolism and affects the production of the hormone hepcidin, which controls how much iron is absorbed from the intestine. In the case of the H282Y mutation, the HFE protein functions less well, which can lead to reduced hepcidin production and increased absorption of iron from the diet.
Over time, iron can accumulate in several organs, especially in the liver, but also in the heart, pancreas, joints and hormone-producing organs. Pronounced iron accumulation can eventually cause tissue damage and increase the risk of conditions such as liver fibrosis, cirrhosis, diabetes, heart damage and hormonal disorders.
Why is HFE c.845 G>A analyzed?
Analysis of HFE c.845 G>A is used in the investigation of suspected hereditary hemochromatosis and to identify genetic variants that may be linked to increased iron absorption and iron overload in the body. The mutation, also called C282Y or H282Y, is the most common genetic change associated with classic HFE-related hemochromatosis.
The analysis may be relevant in cases of elevated iron parameters such as ferritin or transferrin saturation, in cases of suspicion of iron storage disease or in family studies where hereditary hemochromatosis occurs in close relatives.
The result can occur in three different genetic combinations:
- G/G – no detected H282Y mutation
- G/A – heterozygous carrier of H282Y
- A/A – homozygous carrier of H282Y
People who are homozygous carriers (A/A) have a clearly increased risk of developing hereditary hemochromatosis and clinically significant iron overload. However, not all individuals with this genetic variant develop disease or organ symptoms, since both genetic and environmental factors influence the development of the disease.
Heterozygous carriers (G/A) usually do not develop pronounced hemochromatosis but may sometimes show slightly elevated iron parameters or mild effects on iron metabolism.
H282Y and hereditary hemochromatosis
The H282Y mutation is the mutation most strongly associated with classic hereditary hemochromatosis of the HFE type. Approximately 80–90% of people with clinically manifest HFE-related hemochromatosis are homozygous for H282Y. In the disease, the body absorbs more iron than it needs, which gradually leads to iron storage in various tissues. Because the body lacks an effective mechanism to actively excrete excess iron, iron levels can gradually increase over many years.
Symptoms often develop slowly and may initially be nonspecific. Common symptoms and findings of iron overload include:
- fatigue and lack of energy
- joint pain
- elevated ferritin
- elevated transferrin saturation
- liver effects
- diabetes
- heart effects
- decreased libido and hormonal effects
Application in healthcare
Genetic analysis of HFE c.845 G>A is used in the investigation of suspected hereditary hemochromatosis or in the case of unexplained elevated iron parameters.
The analysis may be relevant in the case of:
- elevated ferritin
- elevated transferrin saturation
- suspected iron overload
- unexplained liver involvement
- investigation of hereditary hemochromatosis
- family investigation in case of known HFE mutation
- symptoms consistent with iron storage disease.
Because hereditary hemochromatosis is an inherited disease, genetic screening of close relatives is often recommended when a disease-associated mutation has been identified.
Interpretation of HFE c.845 G>A
HFE 845 A/A (homozygous H282Y)
Compatible with homozygous H282Y mutation, which means that the individual carries the mutation on both alleles of the HFE gene. This is the genetic variant most strongly associated with classical hereditary hemochromatosis and clearly carries an increased risk of increased iron absorption and development of iron overload. However, the risk of clinical disease varies between individuals and is also influenced by factors such as gender, age, alcohol intake, diet and concomitant liver disease.
HFE 845 G/A (heterozygous H282Y)
Compatible with heterozygous carriership of the H282Y mutation. This means that the individual carries the mutation on one allele of the HFE gene. Heterozygous carriers usually do not develop clinically significant hereditary hemochromatosis but may in some cases show slightly elevated iron parameters or mild effects on iron metabolism.
HFE 845 G/G
No H282Y mutation in the HFE gene has been detected.
HFE c.845 G>A and H63D
In genetic investigation of hereditary hemochromatosis, H282Y is often analyzed together with the H63D mutation (HFE c.187 C>G). People who are so-called double heterozygotes, that is, those who carry both H282Y and H63D, may have an increased risk of milder forms of iron overload and effects on iron parameters.
Double heterozygosity generally entails a lower risk of pronounced iron storage disease compared to homozygous H282Y (A/A), but some individuals may develop elevated ferritin or elevated transferrin saturation over time.
The genetic risk must always be interpreted together with clinical findings and laboratory analyses such as ferritin, transferrin saturation, iron status and liver tests.
