Know Your Genes: HFE “The Iron Overload Gene”

The human Hemochromatosis Protein (HFE) gene is associated with the synthesis of HFE protein. This protein has been shown to be associated with the regulation of the circulating iron by regulating the interaction of the transferrin receptor with transferrin.

The concentration of iron in the blood is detected by a complex of HFE, transferrin receptor 1 and transferrin receptor 2. When diferric (two iron atoms) transferrin binds to transferrin receptor 1, the HFE protein is removed, which then binds to transferrin receptor 2 and triggers the release of hepcidin (a hormone that regulates iron uptake)

Healthy individuals usually take up 8 to 10% of iron from the diet (about 1mg), however, some individuals tend to absorb nearly 4 times more. The additional iron accumulates slowly and leads to a condition known as hemochromatosis

There are many single nucleotide polymorphisms associated with this gene, but we look at two significant polymorphisms which are shown to be associated with the development of hemochromatosis, rs1800562 and rs1799945. Variations of the HFE gene are shown to be associated with a reduction in hepcidin release, which increases the absorption of iron from the intestine and increases the storage of iron in the liver and other tissues.

Ancestry

The variations in the HFE gene that have been shown to increase the absorption, and thereby, storage of iron, were probably adaptations to safeguard against maternal iron deficiency for the fetus.

One of the variations (rs1800562) dates back to a mutation about 6000 years ago, among ancestors of the Celtic population. In this variant (C282Y), tyrosine replaces cytosine, preventing the protein from folding properly. This results in an inability of the HFE protein to bind to transferrin receptor, with reduced production of hepcidin. Only individuals who carry the AA variant of the gene are shown to be associated with iron overload.

Another iron retaining variant of the HFE gene is rs1799945, which developed several thousand years ago in the Basque region in North Spain. This variance is associated with lower iron retention than rs1800562.

Individuals with the AA variant of rs1800562 are at a higher risk for hemochromatosis but the diet consumed and gender play an important role in the extent of iron present in the blood. Men and post-menopausal women are at a higher risk for hemochromatosis, as women in the reproductive age tend to lose iron during their menstrual cycle. Not everyone with the variant allele of this gene develops hemochromatosis, but an understanding of the genotype carried will help in monitoring blood iron levels and watching out for symptoms of iron overload.

Symptoms of Iron Overload

The symptoms of iron overload include abdominal pain, memory problems, fatigue, abnormal skin color (ashen-grey) and an irregular heartbeat. Iron overload can also lead to other associated disease conditions like an enlarged heart, liver failure, osteoarthritis and hypogonadism.

Screening Threshold For Hereditary Hemochromatosis

The screening threshold for individuals with hereditary hemochromatosis is

Fasting transferrin saturation of 45-50%
Serum iron concentration is greater than 150 mcg/dL

Association with Iron Levels:

In a study conducted on 1657 male and 2077 female patients, people with the AA variant of the gene (rs1800562) were shown to be associated with hereditary hemochromatosis, with higher levels of serum iron and hemoglobin. In another study conducted on menstruating women, the presence of the minor alleles (AA of rs1800562, GG of rs1799945) had a compensatory effect on iron levels)

In a review study conducted on 101,168 participants, individuals with the AA variant of the gene (rs1800562) were shown to be associated with hemochromatosis, with expression of the disease ranging from no evidence of iron overload to organ dysfunction and massive iron overload. 10% of individuals with compound heterozygote (one copy of A variant (rs1800562) and one copy of G variant (rs1799945)) were shown to be associated with mild to moderate iron overload, with severe iron overload associated with viral hepatitis or alcoholism.

Does your 23andme, Ancestry DNA, FTDNA raw data have HFE gene variant information?

CHIP Version	HFE SNPs
23andMe (Use your 23andme raw data to know your HFE Variant)
v1 23andme	Present
v2 23andme	Present
v3 23andme	Present
v4 23andme	Present
V5 23andme (current chip)	Present
AncestryDNA (Use your ancestry DNA raw data to know your HFE Variant)
v1 ancestry DNA	Present
V2 ancestry DNA (current chip)	Present
Family Tree DNA (Use your FTDNA raw data to know your HFE Variant)
OmniExpress microarray chip	Present

Association With Endurance:

Hemoglobin, which are iron containing metalloproteins, are shown to be associated with oxygen transport from the lungs to the rest of the body, which is required to carry out any physical activity. Therefore, Iron deficiency is associated with reduced ability to carry out physical work. Endurance capacity is also lowered among individuals with iron deficiency as there is lowered cellular oxidative capacity due to lowered oxygen transport.

Alternatively, individuals carrying the GG variant of rs1799945, with an increased tendency for iron overload, have an increased potential to boost aerobic capacity among athletes. Many endurance athletes take iron supplements during their active sporting life and a study was conducted to identify if individuals with the HFE variants A(rs1800562) or G (rs1799945) were significantly represented among endurance athletes. The study found that there was a high prevalence of individuals with HFE mutations among endurance athletes than among sedentary controls.

Genotype rs1800562	Phenotype
AA	[Limitation] More likely to have higher risk for iron overload with high serum iron
AG	[Advantage] Less likely to have higher risk for iron overload
GG	[Advantage] Less likely to have higher risk for iron overload

Genotype rs1799945	Phenotype
GG	[Limitation] More likely at risk of moderate iron overload
CG	[Advantage] Less likely at risk of moderate iron overload
CC	[Advantage] Less likely at risk of moderate iron overload

For people with AA variant (rs1800562) and G variant of (rs1799945)- Elevated serum iron levels People with high iron overload should consider blood donation several times a year, which will help other people and lower the blood levels of the individual There is a high risk of infection from gram negative bacteria, so people with high iron overload should avoid eating raw seafood Drinking black coffee with meals will limit the absorption of non-heme iron from the diet Iron fortified cereals and iron rich supplements should be avoided, along with consumption of red meat Alcohol consumptions should be restricted, unless there is no sign of liver damage. Young women with the AA variant are at a lower risk for iron overload