Hemochromatosis – Genes involved

Hemochromatosis is a fairly common genetic disease that causes iron to build up in the body. Knowledge is power here.

Knowing that you carry the genetic variants for hemochromatosis can literally add years to your life since you can prevent the buildup of iron through giving blood.

23andMe and AncestryDNA genetic data can tell you if you likely carry the more common genetic mutations for hemochromatosis. Read on to find out how to check your data…

What is hemochromatosis?

Hemochromatosis is the disease state of building up too much iron in the body. It can be caused by genetic mutations in iron-related genes, or it can be due to excessive blood transfusions for anemia or liver disease. [Mayo clinic article]

Iron is essential – but needs to be in just the right amount. People with hereditary hemochromatosis absorb more iron from food than they should due to genetic variants.

Once iron is absorbed in the intestines, the body doesn’t have a good way to get rid of it. Normally, the body tightly regulates the amount of iron absorbed. When a little bit too much iron is absorbed, such as for people carrying genetic variants that cause hemochromatosis, the excess builds up over time. The body stores the excess iron in the organs, including the liver, heart, pancreas, skin, pituitary, and thyroid. You also can store iron in your joints and bone marrow. [refTrusted Source: Peer Reviewed Paper]

Symptoms of building up too much iron can include:

  • joint pain
  • tiredness
  • abdominal pain
  • liver disease
  • diabetes
  • irregular heartbeat
  • bronzed skin color
  • hypothyroidism
  • elevated blood sugar and more.

Why do we need iron?

Iron is used by the body in numerous ways. In fact, every cell in the body uses iron in one form or another. Iron is involved in redox reactions, moving electrons in the mitochondria to produce energy. It is also needed in red blood cells as a critical component for moving oxygen throughout the body.

When you think about iron out in nature, rusty old iron parts may come to mind. Rust forms because iron can be easily oxidized, forming compounds with oxygen.  This ability to move electrons around makes iron incredibly important – and also incredibly reactive – in the body.

Regulating Iron in the Body:

The body regulates the absorption of iron tightly. Not only do we need to control oxidation (no ‘rusting’ in the body ;-), but our body also regulates iron to keep it away from iron-loving bacteria.  Certain pathogenic species of bacteria thrive and multiply rapidly when the iron is available. Thus, we don’t want too much iron in the body, and we have ways of quickly sequestering, or storing, the iron when the body is fighting off a pathogen.[refTrusted Source: Peer Reviewed Paper]

Hepcidin is the iron regulatory hormone produced by the liver. Hepcidin was discovered and named in 2000, and scientists have since figured out that it controls the regulation of iron in the body and responds to lipopolysaccharides, a component of bacteria, to prevent iron-loving bacteria from reproducing rapidly.[refTrusted Source: Peer Reviewed Paper]

The HFE gene was discovered in 1996 and linked to hereditary hemochromatosis. This gene codes for a protein that controls how iron is taken into the intestinal cells. Free iron is bound to transferrin, which then binds to a transferrin receptor in order to be taken into the cell.  HFE can also bind to the transferrin receptor, blocking the receptor from taking iron into the cells. In this way, HFE is a negative regulator of iron absorption. [refTrusted Source: Peer Reviewed Paper]

When there is too much absorbed, whether because of a mutation in the HFE gene or other genes regulating iron, the body stores it in different organs. Excess iron causes oxidative stress and DNA damage to the tissue. This can cause fibrosis and cell death, leading to cirrhosis of the liver or other organ damage.[refTrusted Source: Peer Reviewed Paper]

Hereditary Hemochromatosis:

There are multiple causes of hereditary hemochromatosis. The most common cause is a genetic variant that impacts the HFE gene. This allows too much iron to be absorbed into the body and is called type 1, or classic, hemochromatosis.

Other rare causes of hemochromatosis include mutations in other genes involved in hepcidin regulation and in the transport of iron. These are known as hemochromatosis type 2, 3, and 4.

Interestingly, hemochromatosis was first described in the 1700s as ‘bronze diabetes’ or ‘pigmented cirrhosis. This refers to the way iron accumulating in the skin can make it look bronzed, along with the damage to the pancreas causing diabetes or the liver causing cirrhosis. [ref]

How rare is hemochromatosis?

The variants in the HFE gene are more common in people of Northern European heritage. But not everyone who carries the variants will end up with a diagnosis of hemochromatosis. Estimates show that 1in 8 to 1 in 16 Caucasian people carry one copy of an HFE variant (more on this below).

Studies on hemochromatosis vary quite a bit in their estimates of how common hemochromatosis is amongst people with the variants, and this is mainly due to differences in the clinical definition. Some define hemochromatosis as having a ferritin (measure of storage iron) level of over1,000 mcg/l  — along with liver disease, heart failure, and bronzed skin. Others define hemochromatosis as having elevated ferritin (>300 mcg/l) along with liver failure. [refTrusted Source: Peer Reviewed Paper]

The question, then, is whereupon the spectrum of organ damage do physicians define hemochromatosis – is just having the pancreas damaged and causing diabetes enough, or do you also need liver damage? The clinical diagnosis and research study definitions vary quite a bit.

Problems with iron long before hemochromatosis diagnosis:

As you can imagine, the symptoms of iron building up can occur over the decades leading up to the point of organ failure. Joint pain, fatigue, and irritability are common complaints in people with HFE genetic variants.  Common diagnoses prior to learning about hemochromatosis include fibromyalgia and arthritis. [refTrusted Source: Peer Reviewed Paper][refTrusted Source: Peer Reviewed Paper]  Reduced libido and erectile dysfunction in men is common with iron build up.  Diabetes and heart disease diagnosis also can often precede the clinical diagnosis of hemochromatosis.[refTrusted Source: Peer Reviewed Paper]

The key here is that all of these problems due to excess iron can be prevented. You aren’t destined to have aches and pains leading up to liver failure or diabetes — knowledge is power here and iron levels can be reduced. (More on this in the Lifehacks section below).


Genetic Mutations:

Members perk: Genetic Lifehacks members can easily see their genetic data for all of the genetic variants listed below on the Disease Prevention Topic Summary.  Not a member? Join now.

HFE Gene:
The most common type of hemochromatosis is Type 1, or Classic, and is usually caused by variants in the HFE gene.

Check your genetic data for rs1800562 C282Y (23andMe v4, v5; AncestryDNA):

  • A/A: two copies of C282Y variant, most common cause of hereditary hemochromatosis, highest ferritin levels
  • A/G: one copy of C282Y, increased ferritin levels, hemochromatosis possible but less likely, check to see if combined with H63D (below) – combo increases risk of hemochromatosis
  • G/G: typical

Check your genetic data for rs1799945  H63D (23andMe v4, v5; AncestryDNA):

  • G/G: two copies of H63D variant, can cause (usually mild) hemochromatosis, increased ferritin levels
  • C/G:  one copy of H63D, somewhat higher ferritin levels, can cause hemochromatosis in conjunction with one copy of C282Y (above)
  • C/C: typical

Check your genetic data for rs1800730  S65C (23andMe v4; AncestryDNA):

  • T/T: two copies of S65C variant, can cause (usually milder) hemochromatosis, increased ferritin levels
  • A/T: possibly increased ferritin levels
  • A/A: normal

Carrying just one copy of the HFE mutation:

While most of the official hemochromatosis sites will say that you are ‘just a carrier’ for hemochromatosis with one copy of the HFE variant, in actuality, excess iron could be causing problems (just not usually to the extent of liver failure). The initial problems that come with too much iron include random joint pain, fatigue, irritability, and/or abdominal pain.

Research studies also show that carriers of HFE variants (mainly C282Y) are at a higher risk of :

  • non-alcoholic fatty liver disease [refTrusted Source: Peer Reviewed Paper][refTrusted Source: Peer Reviewed Paper]
  • metabolic syndrome  [refTrusted Source: Peer Reviewed Paper]
  • cardiovascular disease [refTrusted Source: Peer Reviewed Paper] including women with heterozygous variants [refTrusted Source: Peer Reviewed Paper]
  • slightly higher risk of cancer [refTrusted Source: Peer Reviewed Paper] [refTrusted Source: Peer Reviewed Paper] including breast cancer[refTrusted Source: Peer Reviewed Paper] and liver cancer [refTrusted Source: Peer Reviewed Paper]
  • Alzheimer’s disease, including heterozygous carriers [refTrusted Source: Peer Reviewed Paper]
  • musculoskeletal problems (arthritis symptoms) [refTrusted Source: Peer Reviewed Paper]
  • high blood pressure [refTrusted Source: Peer Reviewed Paper]
  • high uric acid (gout) [refTrusted Source: Peer Reviewed Paper]
  • lung fibrosis  [refTrusted Source: Peer Reviewed Paper]
  • diabetes[refTrusted Source: Peer Reviewed Paper]
  • cardiovascular disease in kidney disease patients [refTrusted Source: Peer Reviewed Paper]
  • increased lead levels [refTrusted Source: Peer Reviewed Paper] [refTrusted Source: Peer Reviewed Paper]

Other Genes Involved in Iron Buildup:

Not everyone who is homozygous or compound heterozygous for the hemochromatosis variants will develop iron overload.  Diet and lifestyle play a role in the rate at which iron accumulates. Additionally, there are other genes that play a role in ferritin levels and iron levels in the body. Some of these are listed below:

BMP2 gene: bone morphogenetic protein influences hepcidin levels, which regulates iron accumulation

Check your genetic data for rs235756 (23andMe v4; AncestryDNA):

  • G/G: lower transferrin
  • A/G: increased transferrin
  • A/A: most common genotype; increase ferritin levels in people with HFE variants [refTrusted Source: Peer Reviewed Paper] [refTrusted Source: Peer Reviewed Paper]

BTBD9 gene:

Check your genetic data for rs3921809 (23andMe v4, v5; AncestryDNA):

  • G/G: higher ferritin levels  [refTrusted Source: Peer Reviewed Paper]
  • A/G: higher ferritin levels
  • A/A: lower ferritin levels

TMPRSS6 gene: Transmembrane Protease gene, Serine 6 which regulates hepcidin levels

Check your genetic data for rs855791 (23andMe v4, v5; AncestryDNA):

  • G/G: higher iron stores in men with HFE variants[ref
  • A/G: higher iron stores in men with HFE variants
  • A/A: lower iron stores in men

If you have whole-genome sequencing data, check for  rs1439816 (SLC40A1 gene) – C allele may lead to more liver damage [refTrusted Source: Peer Reviewed Paper] [refTrusted Source: Peer Reviewed Paper]

Rare genetic mutations causing other forms of hemochromatosis:

Hemochromatosis can also be caused by mutations in other iron regulatory genes. These are really rare, but the mutations can cause hemochromatosis starting at a young age.

Check your genetic data for rs121434375 (23andMe i5001498 v4; AncestryDNA):

  • A/A: typical*
  • A/T: HFE2 mutation, pathogenic for hemochromatosis type 2A [ref]

*Note: given in forward orientation to match 23andMe or AncestryDNA data

Check your genetic data for rs28939076 (23andMe v4; AncestryDNA):

  • G/G: typical
  • G/T: Hemochromatosis type 4 mutation[ref]

Check your genetic data for rs74315325 (23andMe i5001502 v4; AncestryDNA):

  • T/T: typical*
  • T/A: Hemochromatosis type 2A [ref]

Check your genetic data for rs74315326 (23andMe i5001503 v4; AncestryDNA):

  • T/T: typical
  • C/T: hemochromatosis type 2A[ref]

Other mutations:

Hemochromatosis type 2A: listed in 23andMe as i5001501 (C is the risk allele)(v.4) [ref]

  • Hemochromatosis type 2A: listed in 23andMe as i5001503 (T is the risk allele)(v.4) [ref]
  • Hemochromatosis type 4: i5006507 (T is the risk allele)(v.4)[ref]
  • Hemochromatosis type 4: i5006505 (A is the risk allele)(v.4)[ref]
  • Hemochromatosis type 2B: listed in 23andMe as i5003867 (T is the risk allele)(v.4) [ref]
  • Hemochromatosis type 1: i5012781 (C is the risk allele)(v.4) [ref]
  • Hemochromatosis type 1: i5012784 (C is the risk allele)(v.4) [ref]
  • Hemochromatosis type 1: rs1800562 (A is the risk allele) (v.4 and v.5) [ref]

Lifehacks:

Get a blood test done!

Middle-aged men and menopausal women who are heterozygous or homozygous for any of the HFE variants, should, in my non-medical doctor opinion, go get their serum iron, TIBC, and ferritin levels checked or ask their doctor to test them. Ordering serum iron w/ TBIC and ferritin should give you enough information to know if you are storing too much iron. An inexpensive option if you want to order your own test is UltaLabs.

Give Blood Regularly

If you have slightly elevated iron levels, the simplest way to manage iron levels is to give blood! You will probably feel good, and you will definitely help out someone else with your blood donation. It is a win-win!

Natural Iron Chelators and Inhibitors:

In addition to giving blood, natural and pharmaceutical iron chelators have been used to reduce iron levels in the body.[ref]

Quercetin, a flavonoid found in fruits and vegetables, has been studied for its iron-chelating properties.[ref]  A 2017 study on dendritic (immune system) cells found that quercetin “increases extracellular iron export, resulting in an overall decrease in the intracellular iron content and consequent diminished inflammatory abilities.” And a 2014 study on quercetin concluded: “Potentially, diets rich in polyphenols might be beneficial for patients groups at risk of iron loading by limiting the rate of intestinal iron absorption.” Foods high in quercetin include apples, dark cherries, tomatoes, capers, onions, and cranberries. Quercetin supplements including pure quercetin powder are also readily available.

Another flavonoid, rutin, which is a metabolite of quercetin, has also been studied for its iron chelation properties.[ref]  A 2014 study in rats found: “Rutin administration to iron-overloaded rats resulted in a significant decrease in serum total iron, TIBC, Tf, TS%, ferritin levels…”  Foods high in rutin include capers, black olives, buckwheat, asparagus, and berries.  Rutin is also available as a supplement.

Okra: A 2015 study found that okra “dramatically decreases intracellular iron levels in H63D cells compared to untreated cells”.[ref]  Time to make some gumbo!

Dietary phenols such as EGCG from green tea and grape seed extract also have been shown to inhibit iron uptake in the intestinal cells.  [ref]

The jury is still out on curcumin.  In a double-blind, placebo-controlled, randomized, cross-over study, curcumin was found to decrease hepcidin and increase ferritin.[ref]  Other studies, though, refer to curcumin as a possible iron chelator.[ref]

Taurine, in a mouse model of hemochromatosis, was found to protect against liver damage from excess iron.  The study is worth reading and looking into if you are worried about iron-induced liver damage.

Iron Fortified Foods…

Iron-fortified foods may be a problem for those carrying the hemochromatosis genetic variants.  In the US, white rice and refined wheat products are fortified with iron.

  • A Swedish study looked at the effect of iron-fortified foods on iron absorption in men with hemochromatosis.  The study found that eliminating iron fortification from foods significantly reduced the iron absorbed by the men in the study.  The study also found that the time needed between phlebotomy (to maintain proper iron levels in hemochromatosis patients) was increased significantly.
  • A US study in 2012, though, declared that there is no evidence that dietary iron content made a difference in ferritin concentration. In the study,  they gave 200 people (homozygous for the HFE C282Y variant and high serum ferritin levels) surveys asking for information on the type of diet they had eaten for the last few years as well as alcohol intake. Then they compared the survey data to their serum ferritin levels to look for a correlation and drew the conclusion that iron intake doesn’t impact hemochromatosis. [ref]

Leaches and Bloodletting…

Bloodletting in 1860. Public domain photo.

It hit me while researching all of this, that the bloodletters of yesteryear probably did some good for the minority of people who were overloaded with iron. Leeches to reduce blood and iron stores were probably effective against bacterial infections from iron-loving bacteria.

Fortification of iron into all wheat products in the US, which began in the 1940s, is good for children and most women of childbearing age, but it adds to the iron overload burden for some men and older women.  When looking at the forced fortification of foods with iron and folic acid, it really does seem that the policymakers are focused on the majority, at the expense of a minority who genetically are harmed by it.  Since iron can takes decades to build up in the body, it may be that we are now seeing the consequences in the baby boomer generation.

Additional research studies:

Alzheimer’s:

Hemochromatosis:

Interesting:

 



Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between scientific research and the lay person's ability to utilize that information. To contact Debbie, visit the contact page.