According to a research study by the University of Exeter Medical School in the United Kingdom, men with hemochromatosis, a common genetic disorder due to iron build-up, are ten times more likely to develop liver cancer. 

What is Hemochromatosis?

Hemochromatosis, also called the iron-overload disease, is a condition where too much iron builds up in the body. Usually, the intestines absorb adequate amounts of iron and excrete the rest.

With hemochromatosis, excess iron is absorbed by the intestines, and the body has no way of getting rid of it. As a result, iron gets built up in joints, the pituitary gland, and organs like the liver, heart, and pancreas.

This gradually results in the shutting down of these organs if hemochromatosis is not treated.

Hemochromatosis is more serious in men. Women may be partially protected as they lose some iron during menstruation and childbirth.

Some common symptoms associated with hemochromatosis include:

  1. Joint pain
  2. Weight loss
  3. Fatigue
  4. Low sex drive
  5. Abdominal pain

The HFE Gene

HFE gene is associated with iron homeostasis. A variant (type) of the HFE gene, called the C282Y (the faulty type), is significantly associated with hereditary hemochromatosis.

According to a study published in the American Journal of Human Genetics, the C282Y variant contributes to 26% variation in ferritin levels among monozygotic twins.

Hemochromatosis and Liver Cancer

With hemochromatosis, the iron build-up is commonly seen in the liver. This enlarges the liver and messes up the liver enzymes. It can result in an increased risk of liver conditions like cirrhosis, fibrosis, and cancer. 

Hepatocellular carcinoma (HCC), a primary form of liver cancer, was the first condition in which hepatic iron overload was shown to predispose to the development of HCC.

According to a study, 8-10% of people with hemochromatosis develop HCC.

The Study

The study was led by the University of Exeter Medical School along with the University of Connecticut, Western University in Ontario, and South Warwickshire NHS Foundation Trust.  

This study focused on men and women with two copies of the faulty HFE gene - C282Y. The data of 2890 people aged 40-70 years were analyzed over a nine-year period.

The following were observed:

  1. 21 out of the 1,294 men with faulty genes developed liver cancer
  2. 14 out of these 21 men died of liver cancer
  3. 10 out of these 21 men were not diagnosed with hemochromatosis by the time they developed liver cancer
  4. **More than 7% of the men** with two faulty genes develop liver cancer by 75 years of age
  5. No increase in liver cancer risk was found in women with the faulty genes

The study insists on the importance of early diagnosis of hemochromatosis in order to avoid health complications and even death.

The NHS advises that “it is important to talk to your GP if you have a parent or sibling with hemochromatosis, even if you don’t have symptoms yourself” to identify your risk. 

The lack of impact on women from the faulty HFE gene variant may suggest that periodic blood donations might play a protective role.

Summary

  1. Hemochromatosis is a condition where your body absorbs too much iron resulting in its build-up in joints and organs. It leads to complications like low sex drive, fatigue, and abdominal pain.
  2. When iron builds up in the liver, it can alter the size of the liver and disturb the liver enzymes. Both these factors contribute to the increased susceptibility to liver diseases like fibrosis, cirrhosis, and cancer.
  3. The HFE gene is associated with the regulation of iron levels in the body. The faulty type of the HFE gene called C282Y increases your risk for hemochromatosis. 
  4. A study by the University of Exeter Medical School revealed that men with two copies of the faulty gene are at an increased risk of developing liver cancer. According to the study, by the age of 75, more than 7% of these men had developed liver cancer. No association was found in women with the faulty genes and liver cancer risk.
  5. Genetic testing, which analyzes your HFE gene type, is a key way to prevent and manage hemochromatosis. The NHS advises people who have a sibling or a close family member with hemochromatosis to talk to their healthcare provider for suitable tests.

Reference:

  1. https://www.sciencecodex.com/liver-cancer-ten-times-more-likely-men-common-genetic-disorder-haemochromatosis-661896
  2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668053/
  3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3995380/

Transmembrane Protease, Serine 6 (TMPRSS6) gene is associated with the synthesis of transmembrane protease, serine 6 (also known as matriptase-2), a liver serine protease. TMPRSS6 cleaves the bone morphogenetic protein (BMP) and down-regulates the iron hormone hepcidin, facilitating iron absorption. Inactivation of TMPRSS6 is associated with iron deficiency anemia.

There are two single nucleotide polymorphisms associated with this gene, rs855791 and rs4820268. Variations in this gene are shown to be associated with serum iron, hemoglobin transferrin saturation and erythrocyte traits.

Iron is essential for production of blood and most of the body's iron (70%) is found in the red blood cells of the blood called hemoglobin and in muscle cells called myoglobin. Hemoglobin transfers oxygen in the blood from the lungs to the tissues. Myoglobin, present in muscle cells, transports, stores and releases oxygen.

Iron is also a constituent of certain proteins (6%) and is essential for energy metabolism and for respiration. It is a component of enzymes that are involved in the synthesis of collagen as well as for certain neurotransmitters. Iron is also required for optimum immune function.

Nearly 25% of the iron is stored as ferritin in the body.

Does your 23andme, Ancestry DNA, FTDNA raw data have TMPRSS6 gene variant information?

CHIP VersionTMPRSS6 SNPs
23andMe (Use your 23andme raw data to know your TMPRSS6 Variant)
v1 23andmePresent
v2 23andmePresent
v3 23andmePresent
v4 23andmePresent
V5 23andme (current chip)Present
AncestryDNA  (Use your ancestry DNA raw data to know your TMPRSS6 Variant)
v1 ancestry DNAPresent
V2 ancestry DNA (current chip)Present
Family Tree DNA  (Use your FTDNA raw data to know your TMPRSS6 Variant)
OmniExpress microarray chipPresent

Association with Iron Levels:

In a study conducted on 2100 elderly women, people with the T variant of the gene (rs855791) were associated with lower levels of serum iron and hemoglobin. In another study conducted on 14,100 Danish men, men with the T variant were shown to be associated with lower levels of iron.

In another study conducted on about 600 people, the G variant of the gene (rs4820268) is associated with lower hepcidin levels than the A variant.

Genotype rs855791PhenotypeRecommendation
TT[Limitation] More likely to have lower serum iron and hemoglobin levelsLikely decrease in iron levels Include chicken liver, pumpkin seeds, spinach, tofu, almonds and baked beans. Since there is a genetic predisposition for lower levels of iron, it is recommended to consume more than the daily recommended amount of iron
CTModerate level of serum ironNo genetic predisposition for lower iron levels so daily recommended level of iron may be consumed. Men should consume 8mg/day, women between 19-50 years should consume 18 mg/day and women over 50 years should consume 5mg/day
CC[Advantage] More likely to have higher serum iron and hemoglobin levelsNo genetic predisposition for lower iron levels so daily recommended level of iron may be consumed. Men should consume 8mg/day, women between 19-50 years should consume 18 mg/day and women over 50 years should consume 5mg/day
Genotype   rs4820268PhenotypeRecommendation
GG[Limitation] More likely to have lower hemoglobin levelsLikely decrease in iron levels Include chicken liver, pumpkin seeds, spinach, tofu, almonds and baked beans. Since there is a genetic predisposition for lower levels of iron, it is recommended to consume more than the daily recommended amount of iron
AGModerate level of hemoglobinNo genetic predisposition for lower iron levels so daily recommended level of iron may be consumed. Men should consume 8mg/day, women between 19-50 years should consume 18 mg/day and women over 50 years should consume 5mg/day
AA[Advantage] More likely to have higher hemoglobin levelsNo genetic predisposition for lower iron levels so daily recommended level of iron may be consumed. Men should consume 8mg/day, women between 19-50 years should consume 18 mg/day and women over 50 years should consume 5mg/day


References
:

  1. https://www.ncbi.nlm.nih.gov/pubmed/26597663
  2. https://www.ucsfhealth.org/education/hemoglobin_and_functions_of_iron/
  3. https://www.ncbi.nlm.nih.gov/pubmed/22885719
  4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3135421/
  5. https://www.ncbi.nlm.nih.gov/pubmed/22301935?dopt=Abstract

Nutrigenetics, fitness genetics, health genetics are all nascent but rapidly growing areas within human genetics. The information provided herein is based on preliminary scientific studies and it is to be read and understood in that context.”

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