MTHFR gene mutation symptoms in Men: Understanding the Impact of Gene Variations

Nutrigenomics, Epigenetics, MTHFR and How They Affect Methylation

What do nutrigenomics and epigenetics have to do with MTHFR?

Nutrigenomics is the study of how nutrition and genes interact, and how your diet and your genes may influence your risk of developing certain health conditions. Scientists have learned that certain nutrients are required to carry out specific chemical reactions in your body, including the turning on and off of genes.

Epigenetics, on the other hand, explores how your behaviors and the environment you live in can cause changes that affect the way your genes work. Epigenetic research has shown that our lifestyle choices, our environment, and our exposure to toxins can actually impact how genes are expressed. Genes that are expressed explain some of our differences, including our individual vulnerabilities to certain health conditions.

One major type of epigenetic mechanism is DNA methylation. This occurs when molecules called methyl groups attach to certain pieces of DNA, which can affect a gene’s activity, turning its expression ‘on’ or ‘off.’

The methylenetetrahydrofolate reductase gene (MTHFR) is crucial in this context as it plays a significant role in processing amino acids, which are the building blocks of proteins.

The MTHFR protein, produced by this gene, is essential for processing folate and regulating homocysteine levels, which can influence various health conditions.

There are a few different ways that epigenetic changes can affect gene expression, including DNA methylation, histone modification, and non-coding RNA (ncRNA).

DNA Methylation: Methylation is a chemical reaction in which a small molecule called a methyl group is added to DNA, proteins, or other molecules. Adding methyl groups can then affect how these molecules act in the body.

In DNA methylation, methyl groups (one carbon and three hydrogens) are added to the gene. The methyl group then instructs that gene how to function. Changes in the methylation patterns of genes or proteins can affect a person’s risk of developing certain diseases, such as cancer. MTHFR polymorphisms can influence these methylation patterns, impacting gene expression and disease risk.

MTHFR variants can also influence epigenetic mechanisms, affecting DNA synthesis and DNA methylation, which are crucial for cellular processes.

Histones modification: Histones are proteins within the nucleus of the cell which package the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, the active component of chromosomes. DNA winds around histones, which then influences gene regulation.

Histones undergo changes which alter how they interact with DNA and nuclear proteins. Long-term changes in these histone/DNA interactions cause epigenetic effects.

Non-coding RNA: A non-coding RNA (ncRNA) is a functional RNA molecule that is not translated into a protein. NcRNAs can be modulators of epigenetics through chromatin remodeling or by regulating gene expression at transcriptional or post-transcriptional level.

DNA methylation, histone modification, and ncRNA function are the main epigenetic mechanisms involved in the regulation of gene expression. Single nucleotide polymorphisms (SNPs) can affect all of these. In fact, every part of the body’s methylation pathway can be influenced by SNPs.

SNPs are the one-letter place where your genome varies from another genome sequence. Specifically, SNPs are locations within the human genome where the type of nucleotide present (A,T, G, or C) can differ between individuals. While over 99% of the human genome is identical between individuals, SNPs are what make you different from someone else.

One of the more popular and well-studied genetic SNPs is methylenetetrahydrofolate reductase (or MTHFR). Some genetic SNPs - like MTHFR - can also predispose us to symptoms like anxiety and depression among others. MTHFR deficiency, a severe form of deficiency, can have significant health impacts, including cardiovascular disease, neural tube defects, and developmental disorders.

Many SNPs have no effect on the body’s function and health. However, some can have a significant impact on how your body works. When SNPs are present throughout the methylation cycle, they can cause too much or too little of an important biological enzyme(s) to be produced.

Finding out which SNPs you have can help you to understand more about how your body works.

Genetic analysis usually tests for two common SNPs: MTHFR 677 and MTHFR 1298. When a mutation is present on just one of the genes, it is called a heterozygous polymorphism (i.e. MTHFR C677T or MTHFR A1298C). This can cause enzyme function to be around 65% of normal.

A double mutation on one of the genes is considered a homozygous polymorphism. This can include MTHFR 677TT or MTHFR 1298CC. In people who are homozygous for MTHFR C677T, there is only 30% of normal enzyme function.

It is also possible to be homozygous for MTHFR A1298C, which leads to 60% of normal enzyme function. A double heterozygous mutation - which is one abnormal MTHFR C677T gene plus one abnormal MTHFR A1298C gene - also results in decreased enzyme function.

Because the above mutations result in different functioning capacities of the MTHFR enzyme, your treatment will depend on the type of mutation you have.

It’s worth noting that there are more than 60 different MTHFR SNPs, but the 677 and 1298 are the two most common and also the most researched.

The MTHFR gene provides instructions to your body for making methylenetetrahydrofolate reductase, an enzyme required for converting folic acid (vitamin B9) into folate. Folate is required for a multistep process that converts homocysteine to methionine, which is then required to make many other proteins, neurotransmitters, and other important compounds.

To become active folate, folic acid must go through a four-step conversion process. But in the case of a MTHFR mutation, this process cannot happen properly. The MTHFR gene defect prevents folic acid from being converted to L-5-Methylfolate(the active form) which means that the body doesn’t get the methylfolate it needs. This can lead to a wide range of health issues, including neural tube defects.

It is important to know that increasing folic acid is not a solution for those with MTHFR mutations. Instead, those with the MTHFR mutation might benefit greatly by taking a daily dose of the L-MTHF (or 5-MTHF) form of folate as a supplement.

It’s also important to note that some medications may also interfere with methylation. These include:

• It’s also important to note that some medications may also interfere with methylation. These include:
• Dilantin, Phenytoin, and Primidone (anticonvulsant medications)
• Glucofage or Metformin (to control blood sugar in type 2 diabetes)
• Sulfasalazine (to control Crohn’s disease and ulcerative colitis)
• Triamterene (a diuretic)
• Barbiturates (used as sedatives)
• Methotrexate (used for cancer and other diseases like rheumatoid arthritis)

Although you don’t have control over the genes you inherit, science is slowly revealing that you may have control over your gene expression. Gene expression is the process by which a gene is “turned on” in a cell, which then results in the phenotype, or observable trait. MTHFR mutations have been linked to various health risks, including cardiovascular diseases like premature coronary artery disease.

Methylenetetrahydrofolate reductase deficiency, caused by mutations in the MTHFR gene, can lead to a range of health issues, including occlusive vascular disease, neural tube defects, Alzheimer's disease, colon cancer, acute leukemia, male infertility, and recurrent spontaneous abortion.

If you get tested and discover that you have an MTHFR variance, understanding nutrigenomics could help you.

Diet: People with two or more variants of the MTHFR gene (i.e., homozygous for the gene or double heterozygous) are advised to avoid processed foods and foods fortified with folic acid.

Those with a MTHFR genetic mutation are unable to properly process and utilize folic acid. This can lead to a buildup of unusable folic acid in the bloodstream and on the folate receptors, which in turn can inhibit a number of downstream conversions and many of the body’s fundamental health processes.

Eating foods that are rich in folate (i.e. leafy greens like spinach, kale, chard and cruciferous vegetables like broccoli, cauliflower, and cabbage) is helpful, but only if you are careful to avoid folic acid. High levels of unmetabolized folic acid have been associated with possible adverse outcomes, such as increased risk of various diseases.

Lifestyle: Lifestyle modifications are also beneficial to assist in turning on or off of genes. Spending time outdoors, reducing stress, moderate exercise and restorative sleep also support the expression of preferred genes.

Supplements:Supplements that provide nutrients in their active form are highly beneficial when dealing with MTHFR mutations. Your body requires a range of specific nutrients to carry out many biological processes, but the most important of all is methylfolate.

L-5-Methyltetrahydrofolate is the active form of folate and is shown to bypass the MTHFR genetic mutation. A supplement that contains methylfolate is ideal for avoiding the negative health impacts of MTHFR.

Lim U, Song MA. Dietary and lifestyle factors of DNA methylation. Methods Mol Biol. 2012;863:359-76. PMID: 22359306

References

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3481686/

2. https://www.sciencedirect.com/science/article/pii/S2214540020301602

3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3096308

4. https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.114.013311

5. https://www.ncbi.nlm.nih.gov/books/NBK66131/

6. https://www.sciencedirect.com/science/article/pii/S0002916522009091 

7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3174260/