Hemochromatosis – Genes involved

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

This is a personal cause for me, and getting the word out to as many people as possible is important because this is one bit of genetic information that can make a huge impact on the quality of life.

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

What is hemochromatosis?

“Hereditary (genetic) hemochromatosis (HHC) an inherited disorder of abnormal iron metabolism. Individuals with hereditary hemochromatosis absorb too much dietary iron. Once absorbed, the body does not have an efficient way of excreting iron excesses.  Over time, these excesses build a condition of iron overload, which is a toxic [sic] to cells. Glands and organs, including the liver, heart, pituitary, thyroid, pancreas, synovium (joints) and bone marrow burdened with excess iron cannot function properly.  Symptoms develop and the disease progresses.”  Iron Disorders Institute

Symptoms of building up iron can include

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

The Science behind Iron Overload:

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 to prevent iron-loving bacteria from reproducing rapidly.  [ref]

“Hereditary hemochromatosis is caused by a deficiency of the iron-regulatory hormone hepcidin (Ganz and Nemeth, 2011). Hepcidin is a 25 amino acid peptide secreted by hepatocytes. It controls iron concentrations in extracellular fluid and blood plasma by regulating the amount of ferroportin, the sole known cellular iron exporter. Ferroportin transports absorbed, recycled or stored iron from tissues into plasma (Donovan et al., 2005). Hepcidin binding to ferroportin triggers its degradation, resulting in the decreased transfer of iron to plasma and consequently hypoferremia (Nemeth et al., 2004b). During infections or in response to injection of microbial molecules, hepcidin production is greatly enhanced (Armitage et al., 2011; Rodriguez et al., 2014), stimulated by inflammatory cytokines including IL-6 (Nemeth et al., 2004a; Rodriguez et al., 2014) and possibly activin B (Besson-Fournier et al., 2012). It has been proposed that hepcidin-mediated hypoferremia functions as a host defense mechanism that evolved to restrict iron availability for pathogen growth (Drakesmith and Prentice, 2012; Ganz, 2009) but this has never been demonstrated. Hepcidin was also reported to have direct bactericidal activity in vitro (Krause et al., 2000; Park et al., 2001), but the effect is seen only at unphysiologically high concentrations.” – https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4296238/


Genetic Mutations:

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 (23andMe v4, v5; AncestryDNA):

  • A/A: most common cause of hereditary hemochromatosis, highest ferritin levels – two copies of C282Y
  • A/G: increased ferritin levels, check to see if compound heterozygous with rs1799945
  • G/G: normal

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

  • G/G: can cause (usually milder) hemochromatosis, increased ferritin levels, two copies of H63D
  • C/G: somewhat higher ferritin levels, check to see if compound heterozygous with rs1800562
  • C/C: normal

Check your genetic data for rs180073 (23andMe  v4 only):

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

Iron buildup — carrying just one copy of the mutation:

So you’ve checked your genetic data and found that you are heterozygous (one variant) for one of the HFE variants… While most of the official hemochromatosis sites will say that you are ‘just a carrier’, in actuality, it could be causing problems, just not to the extreme extent that being homozygous for the variant could cause.

Doctors and researchers seem to be focused (rightly so) on the long-term consequences such as liver failure and heart failure of extreme iron overload. But if you know that you are genetically susceptible to building up iron, you can take action to avoid the irritations that come with too much iron, such as random joint pain, fatigue, and/or abdominal pain.

Recent studies showing higher disease risk due to HFE variants:

  • increased risk of non-alcoholic fatty liver disease [ref][ref]
  • metabolic syndrome  [ref]
  • cardiovascular disease [ref] including women with heterozygous variants [ref]
  • slightly higher risk of cancer [ref] meta-study [ref] breast cancer[ref] liver[ref]
  • increased risk of Alzheimer’s disease, including heterozygous carriers [ref]
  • musculoskeletal problems (osteoarthritis like symptoms) [ref]
  • high blood pressure [ref]
  • hyperuricemia (gout) [ref]
  • lung fibrosis  [ref]
  • diabetes[ref]
  • cardiovascular disease in kidney disease patients [ref]
  • increased lead levels [ref] [ref]

Other Genes Involved:

Not everyone who is homozygous 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: rs235756 (v.4)-A allele is associated with higher ferritin levels with HFE variants (several studies) [ref] [ref]
  • BTBD9 gene: rs3923809 (v.4 and v.5)-G allele is associated with higher ferritin levels [ref]
  • HBS1L-MYB gene: rs4895441 (v.4 and v.5)- G allele protects against anemia [ref]
  • SLC40A1 gene: rs1439816 (not in 23andME v.4/v.5 data) – C allele may lead to more liver damage [ref] [ref]
  • TMPRSS6 gene: rs855791 (v.4 and v.5)- G allele associated with higher iron stores in men [ref
  • SLC40A1 gene: rs11568350 (not in 23andMe data) (Q248H) – leads to higher ferritin levels

Rare genetic forms of hemochromatosis (mostly non-HFE):

  • Hemochromatosis type 2A: listed in 23andMe as i5001498 (T is the risk allele)(v.4 and v.5)[ref]
  • Hemochromatosis type 2A: listed in 23andMe as i5001502 (A is the risk allele)(v.4 and v.5) [ref]
  • Hemochromatosis type 2A: listed in 23andMe as i5001501 (C is the risk allele)(v.4) [ref]
  • Hemochromatosis type 2A: listed in 23andMe as i5000096 (T 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: rs28939076 (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 “increase 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, has also been studied for its iron chelation properties.[ref]  A 2014 study in rats found: “Rutin administration to iron-overloaded rats resulted in 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 and in bulk powder.

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 EGC/G 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, or may not, 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.  (I actually don’t agree with their ability to draw that conclusion based on the method of doing the study.)  Basically, 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]
  • A few studies have looked at the impact of the overabundance of iron on obesity.   But while the risk for each of these diseases increases with higher ferritin levels, no one seems to be publishing studies showing that iron fortification is causing them.

Final thoughts…

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 product in the US, which began in the 1940’s, 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.

More to read:

Alzheimer’s:

Hemochromatosis:

Interesting:

11 Comments on “Hemochromatosis – Genes involved

  1. Pingback: Empowering YOU to Understand Your Genes | Genetic Lifehacks

    • I had no variants for celiac or the other one you mentioned. I cannot help but wonder if this gene caused the inflammation years ago in my gut to cause the colitis. I have read many reports that suggest it causes inflammation etc. Thank you.

      • Too much iron can cause a variety of different issues in the body (as I’m sure you’re aware of). Abdominal pain is often listed as a symptom for hemochromatosis.

  2. Pingback: The little bit of Irish DNA that could kill you: saving lives this St. Patrick’s Day — Celtic Curse

  3. RR: C282Y heterozygous

    Per Dr Eric Lewis,

    “Another important point is that we should not dismiss the impact that one single hemochromatosis gene mutation can have upon our health. Even one missense copy of C282Y can lead to a degree of iron overload in some individuals. This scenario can absolutely be an underlying cause of health challenges, symptoms, illness, or disease for a number of people.

    Many doctors, lab testing companies, books, and other websites tend to “down-play” the potential health consequences of having only one hemochromatosis gene. You may read or hear that one missense copy is not “clinically relevant”.

    To me, this seems to ignore the stories and symptoms of people whose health have been compromised by a moderate level of iron overload. Many individuals from around the world have written me and told me about their health challenges due to high iron… even though they “only” have one gene mutation.

    Likewise, I have heard numerous stories from people who did not understand their potential health risk or the implications of storing too much iron. I have seen countless cases in which individuals were told their health was fine, or that it was “all in their head”.

    Perhaps worst is when a person is told by a doctor that they have a hemochromatosis gene, but that they do not need to do anything about it, because they only have one mutation. I have even heard of stories where people were discouraged to donate blood, even a single time, even with elevated ferritin!

    My guess is that many healthcare practitioners just do not think about hemochromatosis or they may not even know about hemochromatosis.”

    http://hemochromatosishelp.com/type-1-hereditary-hemochromatosis/

    • Thanks so much for the link to http://hemochromatosishelp.com/ — looks like a lot of good information on that site. It is so important to get the word out to everyone who has had genetic testing done to go ahead and check to see if they carry either of the hemochromatosis polymorphisms.

  4. My 23andme data has nothing for the above two SNPs. Are they blocking us now from seeing this data?

  5. I have done a lot of research on hemochromatosis. My mom died from it. I have the h63d. Went through 23 and me. My dr just kind of dismissed any risk for me. Even though he did iron panel. My ferritin was 232 but other ranges were just barely normal range. I do have colitis issues so I know inflammation could play part in the ferritin. But, I have many ailments that are symptoms. He says I’m not at risk and not even to worry about donating blood and, no need for another iron test. He said my hemoglobin needed to be checked yearly. So, I know one gene carriers can load iron. I am waiting to donate blood when a blood bank comes through. Thank you.

    • Hi Elizabeth –
      Thanks for posting this — it is a great reminder to everyone that even a carrier of just one of the risk alleles can start building up iron.
      Giving blood is a great way to prevent more damage from iron in your joints and organs. I hope that you feel better after donating. I know several people (heterozygous) who feel great after donating blood — plus you’re doing a good deed for someone else.
      Debbie

    • The lab ranges are ridiculous .. too high! Optional values below:
      Iron Opt=100
      TIBC Opt=285
      Transferrin Opt=300)
      Sat % Opt=25-30
      Ferritin Opt=~20

      Your ferritin at 232 is way too high. What do the rest of the iron panel labs look like? Begin donating blood now. I’ve been donating since Aug 2016 about every 56 days and iron still too high! I’m getting there, though. I do have several Gene’s that can contribute to this, including C282Y.

      Iron 138 ug/dl (Opt=100)
      TIBC 385 (Opt=285)
      Transferrin 300 (Opt=300) !!!
      Sat % 36 (Opt=25-30)
      Ferritin 31 (Opt=~20)

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