Anemia is a condition in which there is a deficiency of red blood cells in the blood, which leads to a reduced ability of the blood to carry oxygen to the body’s tissues. Certain genetic variants can predispose one to inadequate amounts of vitamin B12, Iron and Folate, thereby resulting in anemia. This article will discuss what anemia is, how it happens and also two genetic variants that can be involved.
Types of Anemia
Anemia can occur for various reasons based on the type and size of the red blood cells. There are quite a range of different types, but these are the most common:
1. Iron-Deficiency Anemia (Microcytic Anemia): Iron-deficiency anemia is caused by a lack of sufficient iron to produce hemoglobin, the protein in red blood cells that carries oxygen. Iron is a key component of hemoglobin. Ferritin is a protein that stores iron in the body, so low ferritin levels indicate depleted iron stores. Together, low iron and low ferritin suggest iron-deficiency anemia. This type of anemia is typically microcytic (small red blood cells) and hypochromic (pale red blood cells due to low hemoglobin content). (Note that you can have iron deficiency without anemia. This is when your body’s iron stores are low, but your hemoglobin level is still in the normal range, so you don’t meet the definition of anemia yet. It can still cause symptoms and affect health.)
2. Vitamin Deficiency Anemia: (Megoloblastic Anemia) This occurs due to impaired DNA synthesis in red blood cell precursors, caused by deficiencies in folate (vitamin B9) and vitamin B12. Both nutrients are essential for DNA synthesis and cell division. Deficiency in either can cause the production of abnormally large and immature red blood cells known as megaloblasts, leading to megaloblastic anemia.
3. Folate Deficiency Anemia:Folate (Vitamin B9) is another B vitamin that is essential for DNA synthesis and cell division. Like vitamin B12, folate is crucial for the production of healthy red blood cells.
4.Combination Anemia: A Mixed Picture: Having low folate, low ferritin, low iron, and low B12 means you could have a mixed or combined anemia, where two or more types of anemia are present simultaneously. The types involved would be megaloblastic anemia (due to low folate and B12) and iron-deficiency anemia (due to low ferritin and iron). Note that in the case of a combined iron and B12 deficiency, a complete blood count can be normal. This is because Iron deficiency produces small red blood cells and B12 deficiency produces large red blood cells and this cancels out readings like hemoglobin (the small and large cells are calculated together to give an average reading which appears normal). Someone may have normal hemoglobin and normal MCV yet still have serious B12-related nerve issues. That’s why symptoms matter.
5. B12 Deficiency Anemia (Macrocytic anemia): B12 deficiency has progressed enough to impair red blood cell production. It often leads to macrocytic anemia (red blood cells larger than normal), Low hemoglobin and hemotocrit, High MCV, Low reticulocyte count and Low B12. (Note that you can also get A functional B12 deficiency without anemia)
General symptoms of Anemia
– Fatigue and weakness
– Shortness of breath
– Dizziness
– Pale or yellowish skin
– Cold hands and feet
– Chest pain or palpitations
– Headaches
Potential Causes of Multiple Nutrient Deficiencies
- Poor Diet: Insufficient intake of iron-rich foods (like meat, beans, spinach), folate-rich foods (like leafy greens, fruits, and legumes), and foods rich in vitamin B12 (like meat, dairy).
- Vegans and vegetarians are most often at risk.
- Malabsorption Disorders: Conditions like celiac disease, Crohn’s disease
- Surgical removal of parts of the stomach or small intestine can impair absorption of multiple nutrients.(gastric bypass)
- Increased Requirements: Pregnancy, breast-feeding, or growth spurts in children can increase the body’s need for these nutrients.
- Age: older people tend to experience nutrient deficiencies due to consuming less food as well as the body loosing it’s ability to absorb nutrients and slowing down.
- Chronic Blood Loss: Conditions such as heavy menstrual periods, gastrointestinal bleeding, or frequent blood donations can lead to iron and folate depletion.
- Alcohol: Can lead to poor dietary intake, malabsorption of nutrients, and direct toxic effects on the bone marrow.
- Excessive caffeine intake: can hinder vital nutrients from being absorbed.
- Smoking: Excessive smoking can hinder B12 absorption
- Pernicious Anemia: an autoimmune condition in which the body’s own immune system destroys stomach cells that make intrinsic factor or produces antibodies against intrinsic factor itself. As a result, vitamin B12 cannot be absorbed properly, even if you eat enough. This requires life-long B12 treatment. Contrary to popular belief this can occur at any age, not only older people.
- Low stomach acid
- medication: metformin, PPI’s, H2 blockers
GENETICS
FUT2
The FUT2 gene encodes the enzyme called fucosyltransferase 2 which encodes an enzyme responsible for adding fucose to precursor structures, forming the H antigen.
Focose is a prebiotic called 2’-fucosyllactose (2’FL) It is an oligosaccharide present in human breast milk, it also has protection factors when it comes to gut health and brain health. The gene puts fucose on the surface of the gut (the epithelial wall). Fucose is a sugar that feeds the healthy bacteria in your body. If you don’t produce fucose to feed the healthy bacteria this leads to a change in the gut microbiome and increased inflammation.
The upside of having no fucose on the lining of the gut means that the H.pylori and nova virus can’t connect but the downside is that it can cause leaky gut.
The Fut2 gene has two types: secretor or a non-secretor. What does it mean to be a secretor or a non-secretor? To put it plainly,it simply means whether you produce 2’FL or not. If you produce 2’FL it means you are a secretor and if you don’t, it means you are a non-secretor.
A secretor carries the AG or GG allele
- Makes up 80% of the population
- Produce fucose
- Risk for higher BMI
- lower vitamin B12 levels
- increased risk for anaemia
- The presence of the G allele increases one’s risk of developing psoriasis
- advantage: higher prevalence of bidobacteria in gut
- disadvantage: higher risk for rotavirus and novavirus and H.Pylori
A Non-Secretor carries the AA allele
- make up 20% of the population
- produce less fucose to line gut and impacts quality of breast milk
- lower levels of beneficial bifidobacteria in their intestine
- higher risk of developing autoimmune diseases
- Non-secretors also often have higher serum vitamin B12 levels when they get their levels tested. However, this may not truly reflect the amount of B12 being transported into the cells. It could be that you have higher serum B12 because it is not getting into the cells.
- Lower BMI
- disadvantage: linked to an altered gut microbiome
- advantage: have a protection against the adherence of certain bacteria like H.Pylori and novavirus.
To understand how FUT2 can lead to anemia, you need to understand what vitamin B12 does which I cover below. Keep in mind that secretors have an increased risk for not being able to absorb Vitamin B12. The FUT2 enzyme interferes with vitamin B12 absorption possibly due to having an infection which reduces stomach acid production and lowers the level of intrinsic factor which means less Vitamin B12 is absorbed.
The role of Vitamin B:
- Vitamin B12 is one of the most important nutrients we need for brain and neural function.
- It is a co-enzyme in many important processes including DNA synthesis, protein, lipid and carbohydrate synthesis.
- Vitamin B12 plays an important role in the formation and protection of the myelin sheath around the nerves which is needed for insulating your nerves and is also critical to your nervous system.
- A deficiency in B12 can lead to anemia, neurological conditions and poor mental health.
- Vitamin B12 is naturally present in foods of animal origin such as fish, meat, poultry, eggs, and dairy products.
Symptoms of not getting enough B12(even if you eat enough animals products) can include:
- fatigue, low energy
- anemia
- brain fog
- digestive issues
- poor memory/concentration
- skin and hair issues
- headaches
- depression/ anxiety
- nerve problems
- joint pain
- constipation
- muscle cramps
In a research study involving generally well-nourished women, it was discovered that variations in the FUT2 secretor gene were strongly linked to differences in plasma vitamin B12 levels. This finding was supported by data, suggesting a genetic influence on how vitamin B12 is processed and maintained in the body.
FUT2 variants can alter the gut microbiome and reduce vitamin B12 absorption, leading to vitamin B12 deficiency anemia, especially when there is not enough B12 in the diet.
Methylation:
Methylation uses the process of donating ‘methyl groups’ to an end product such as DNA, RNA, hormones and neurotransmitters. A methyl group consists of one carbon bound to three hydrogen atoms. Methylation controls gene regulation (switching them on and off), processing of chemicals and toxins, the production of the protective coating on nerves (myeline sheath), building of neurotransmitters and immune cells, processing of hormones, and DNA and RNA synthesis. Methylation is regulated by enzymes and substrates (end products). In order for methylation to work properly, it requires a range of nutrients and co-factors (such as B vitamins, choline, betaine, magnesium, and zinc.
I won’t discuss all the methylation Genetic variants in this post, just the ones that can impact the metabolism of vitamin B12 and folate, leading to deficiencies in these vitamins.
MTHFR (methylenetetradydrofolate reductase)
MTHFR is an enzyme involved in the folate metabolism pathway, which is critical for DNA synthesis, repair, and methylation. Inefficiency in the enzyme can lead to functional folate deficiency and potentially affect vitamin B12 status due to the interlinked nature of the methylation cycle.
When variations in the FUT2 and MTHFR genes are present together, they can cause anemia by contributing to deficiencies in vitamin B12 and folate respectively. This results in ineffective red blood cell production and a potential combined deficiency anemia, with symptoms that may range from general fatigue to neurological impairments. Effective management requires addressing both nutrient deficiencies and optimizing gut health, possibly with the guidance of a healthcare provider.
MTR (methionine synthase)
MTR is involved in the conversion of homocysteine to methionine using methylfolate as the methyl donor. This reaction needs vitamin B12 (methylcobalamin) as a cofactor and prevents homocysteine from building up. A variant in this gene can reduce the activity of methionine synthase. This means the body might not use vitamin B12 and folate as effectively as it should. As a result, people with this variant could have lower levels of B12 and folate because these vitamins are not being properly recycled and used in important metabolic processes. This can lead to deficiencies over time.
MTRR (Methionine synthase reductase)
MTRR supports the continuous function of MTR by keeping vitamin B12 in its active state, ensuring the ongoing conversion of homocysteine to methionine. A variant is linked to lower activity of the MTRR gene, which helps keep another enzyme, methionine synthase, working properly. If MTRR doesn’t work well, it can affect the function of methionine synthase, which in turn can impact how the body processes vitamin B12 and folate.
Summary of How Methylation variants and FUT2 Can Cause Anemia:
- FUT2 variants can alter the gut microbiome and reduce vitamin B12 absorption, leading to vitamin B12 deficiency anemia, another form of megaloblastic anemia.
- Variants in genes like MTHFR, MTR, MTRR,CBS, can affects the body’s process of using nutrients, which can cause a lack of vitamin B12 and folate. This happens because certain enzymes don’t work as well, or the body’s nutrient balance gets thrown off. Testing for these genetic differences can help you understand your risk for these deficiencies and get personalized nutritional support.
references:
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Hazra A, Kraft P, Selhub J, Giovannucci EL, Thomas G, Hoover RN, Chanock SJ, Hunter DJ. Common variants of FUT2 are associated with plasma vitamin B12 levels. Nat Genet. 2008 Oct;40(10):1160-2. doi: 10.1038/ng.210. Epub 2008 Sep 7. PMID: 18776911; PMCID: PMC2673801.
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Kaur P, Gupta M, Sagar V. FUT2 gene as a genetic susceptible marker of infectious diseases: A Review. Int J Mol Epidemiol Genet. 2022 Jun 15;13(1):1-14. PMID: 35892094; PMCID: PMC9301175.
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Palmer AM, Kamynina E, Field MS, Stover PJ. Folate rescues vitamin B12 depletion-induced inhibition of nuclear thymidylate biosynthesis and genome instability. Proc Natl Acad Sci U S A. 2017 May 16;114(20):E4095-E4102. doi: 10.1073/pnas.1619582114. Epub 2017 May 1. PMID: 28461497; PMCID: PMC5441772.
- Reprinted from MedlinePlus Genetics (https://medlineplus.gov/genetics/ )TCN2 gene transcobalamin 2 https://medlineplus.gov/download/genetics/gene/tcn2.pdf