Interpreting Genetic Testing for Methylation Issues: A Guide for Healthcare Practitioners

Methylation is an epigenetic process that affects how different genes are expressed, without actually altering the DNA sequences of those genes. Different biological processes in the body, including DNA repair, neurotransmitter synthesis, and detoxification, are regulated in part through methylation.

In this guide, healthcare practitioners will learn the basics of methylation, clinical applications of methylation issues, and how to understand and interpret genetic testing related to methylation efficiency.

[signup]

Basics of Methylation

In methylation, a methyl group is added to DNA, RNA, or histone proteins to modify gene expression. This is a reversible modification that plays an important role in gene silencing, or inactivation of a gene. By controlling the expression of various genes, methylation contributes to chronic disease prevention, regulation of hormones and neurotransmitters, and DNA repair.

Methylation is a crucial process for normal growth and development, with a group of enzymes called methyltransferases playing a central role in the process. Excessive methylation or reduced methylation can impact different physiological processes in the body that can impact mood, inflammation, and chronic disease risk.  

Various factors can influence the rate of methylation, including genetics, diet, and lifestyle. Genetic variants such as variants of the MTHFR genes directly impact the rate of methylation, as they encode the methyltetrahydrofolate reductase enzyme that methylates folate and begins the process of methylation. This particular enzymatic reaction is essential for lowering homocysteine levels in the body and optimizing other processes such as hormone metabolism and detoxification. Certain variants of the MTHFR gene can make individuals prone to higher homocysteine levels, slower detoxification, and low levels of B vitamins. 

Because many micronutrients are essential to the methylation process, including folate and other B vitamins, an individual’s diet may also positively or negatively impact methylation efficiency.  Lifestyle also plays a role, with exercise, smoking, and alcohol use all having the potential to impact methylation efficiency. 

Understanding Genetic Testing for Methylation

Functional medicine lab testing can assess methylation function through analysis of related gene variants as well as the efficiency of methylation itself. Looking at genetic variants and the status of micronutrients important to methylation can help functional practitioners ensure a patient has a comprehensive plan in place to support methylation based on their unique methylation profile.  

Over 818 genes related to methylation have been identified, though variants in some of these genes have been better studied than others. Oftentimes, these variants are single nucleotide polymorphisms (SNPs) that can play a direct role in disease risk by affecting the function of the gene. SNPs can be analyzed using genomic testing to help practitioners understand a patient’s risk profile for certain diseases related to the genes being tested. In addition to MTHFR genes, other genes that are tested using panels such as the DNA Methylation Pathways Panel by Doctor’s Data include COMT, VDR, MAOA, MTR, MTRR, CBS, and more.

Identifying gene variants in various pathways related to methylation - including detoxification, vitamin D production, and amino acid metabolism - can help practitioners understand the efficiency of methylation in a given patient, and identify susceptibilities in these foundational health pathways that may put a patient at risk for chronic disease.

Another option for practitioners is the Methylation Panel by Genova Diagnostics, which looks at various genetic SNPs as well as methylation metabolites to gain a comprehensive understanding of an individual’s ability to methylation efficiency. It reveals a patient’s nutritional support needs relative to methylation, and can be useful for understanding a wide array of symptoms, from mood disorders like anxiety or depression to chronic fatigue.  

Interpreting Genetic Test Results

MTHFR variants are perhaps the most commonly tested SNPs as related to methylation. The MTHFR gene has two variants, called C677T and A1298C. The C677T polymorphism is the most common, estimated to affect 20-40% of white and Hispanic individuals in the US and 1-2% of African Americans. The A1298C variant may affect 7-12% of North Americans, Europeans, and Australians.

Individuals may be homozygous for these SNPs affecting methylation, meaning both copies of the gene are affected, or they may be heterozygous and have one SNP and one standard copy of the gene. Having a homozygous profile can reduce methylation of folate to 5-tetramethylhydrofolate (5-MTHF) by up to 75%, making it challenging for the affected individual to efficiently run basic metabolic processes that rely on methylation, including homocysteine regulation, neurotransmitter and mood regulation, and basic DNA repair. These patients are at a higher risk for cardiovascular disease and inflammation, migraines, and other health concerns.  

Another common methylation-related genetic polymorphism that can be analyzed using genomic tests is the V158M variant of the COMT gene, a gene that encodes for the enzyme catechol-O-methyltransferase. This polymorphism can result in a slowing down of the COMT enzyme, leading to altered dopamine and estrogen metabolism. Other methylation polymorphisms include variants of the MTR and MTRR genes, which encode two other enzymes that are important to the process of methylation and recycling homocysteine so it doesn’t build up in the blood. 

‍CBS gene polymorphisms may also contribute to elevated homocysteine levels and risk of hypertension and stroke. All of these polymorphisms and others tested on genomic panels will be shown as “heterozygous” or “homozygous,” helping the practitioner to understand the potential impact of the polymorphism on methylation efficiency.

While understanding a patient’s underlying genomic profile as related to methylation is important to assess for pathway efficiency and associated risks of poor methylation, it’s best to consider genomic testing results alongside the bigger picture of a patient’s health, including diet, lifestyle, and current symptomatology.  Lifestyle can play a large role in methylation efficiency, with habits such as smoking, alcohol use, and physical activity all impacting the methylation pathway.  

Methylation Issues and Clinical Implications

Methylation issues can contribute to a variety of health conditions in affected patients, including cardiovascular disease, mental health disorders, and autoimmune disease development. Understanding individual genetic predispositions to methylation issues can help tailor a personalized therapeutic plan to support optimal health and prevent chronic disease risk.  

Studies have shown that DNA methylation plays an important role in cardiovascular disease. 

Abnormal methylation of specific genes related to heart failure, hypertension, and heart disease can be correlated to cardiovascular disease progression. Various genetic polymorphisms related to methylation, such as the MTHFR variants, can also lead to elevations of homocysteine, which is a risk factor for cardiovascular disease and inflammation as well.

Optimizing methylation efficiency may help to slow disease progression and reduce risk altogether while understanding a given patient’s genomic profile can help practitioners understand what therapeutic interventions to prioritize to reduce cardiovascular risk, whether that be methylfolate supplementation or addressing different lifestyle habits. 

Methylation issues also appear to be connected to various mental health disorders, including anxiety, depression, bipolar disorder, and schizophrenia. DNA methylation has been associated with brain volume, structure, and function, with abnormal methylation impacting how well the brain can perform and regulate various aspects of cognitive function and mood. The MTHFR C677T polymorphism has been significantly related to the development of depression and bipolar disorder, while the other main variant, A1298C, has been marginally linked to depression.  

Methylation has also been linked to the development of autoimmune diseases. In autoimmune conditions, abnormal methylation contributes to the loss of self-tolerance and the emergence of self-reactive immune cells which is characteristic of autoimmunity. For example, rheumatoid arthritis (RA) patients can have hypomethylation at certain genes related to immune cell activity, leading to upregulation of those genes and explaining some of the excessive immune response that occurs in RA. Systemic lupus erythematosus (SLE) and multiple sclerosis (MS) also have been linked to aberrant methylation. 

Understanding one’s genetic predisposition to methylation efficiency can help practitioners personalize a therapeutic approach that will best support a given patient, considering their genomic makeup, lifestyle, nutrition, and symptomatology. 

Addressing Methylation Issues: Nutritional and Lifestyle Interventions

Personalized nutrition interventions and lifestyle changes can play an important role in managing methylation issues based on genetic testing results. Micronutrients including folate, vitamin B6, vitamin B12, betaine, and choline are all important cofactors needed for methylation to occur properly, and those with genetic polymorphisms of methylation-related genes may need specific types of supplementation in addition to prioritizing nutrient intake through food. 

Folate is found in leafy greens like spinach, kale, and Brussels sprouts, and also in legumes such as lentils and chickpeas. Those with MTHFR mutations may need a higher intake of methyl folate through supplementation because the gene impacts how effectively the body can metabolize folate to its active form. Other B vitamins, including B6 and B12, are also important to emphasize in the diet to support methylation. 

‍Vitamin B6 is found in foods like poultry, fish, potatoes, and non-citrus fruits, while Vitamin B12 is typically obtained from meat, fish, or dairy products. If a patient needs B vitamin supplementation, ensuring a B complex that has both folate and B12 in their methylated forms is important for individuals with MTHFR and MTRR genetic polymorphisms.  

Additionally, lifestyle changes play an important role in managing methylation and may positively or negatively influence the efficiency of the methylation pathway. Considering sleep quality, stress management, exercise, and minimizing toxin exposure are all practical ways that practitioners can help patients with supporting methylation. Chronic stress can directly impact methylation and can raise the risk for inflammation and chronic disease, making stress reduction techniques a particularly important component of a therapeutic plan for optimal methylation.  

Ethical Considerations and Patient Communication

It’s important to note ethical considerations in genetic testing, including privacy, patient consent, and potential psychological impacts of gene testing. Practitioners must ensure that a patient’s genomic data is protected remains private, and is not shared with any third-party companies or research studies without specific patient consent. Genetic information is directly related to a person’s identity, and confidentiality is important for health care, insurance coverage, and employment, in addition to the possible implications for extended family.

Additionally, patients may experience a wide variety of psychological responses to genomic data and laboratory results in general, including anxiety, relief, or confusion. Learning of abnormal results may lead to anxiety in patients who don’t understand the implications of their test results, while “normal” results may lead to frustration or anxiety in patients who are experiencing ongoing symptoms in their day to day lives and may have been expecting more definitive answers.

Effective communication of what lab results mean is an essential part of a functional medicine approach to healthcare, particularly when it comes to genomic testing. Having strong communication skills forms the foundation of an effective patient-provider relationship, and helps build patient trust while also leading to better patient outcomes. Providing patient education on genomic testing results and managing methylation through diet, supplementation, and lifestyle changes, while also providing space for patients to ask questions and get the answers they seek can help lead to better communication between patients and practitioners.  

[signup]

Key Takeaways

Integrating genetic testing into functional medicine practice can be a key way to highly personalize a treatment approach for optimal health and disease management.

Understanding genetic testing for methylation issues can help practitioners not only identify genetic variants that put patients at a higher risk for aberrant methylation, but also see how their methylation efficiency is being affected so they can suggest nutrition, supplement, and lifestyle changes accordingly.