There is a lot of misinformation about MTHFR, even though there are a lot of studies on this gene. This post goes through the actual science of this gene and what conditions it’s associated with.
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What is MTHFR?
The MTHFR gene codes for an enzyme known as methylenetetrahydrofolate reductase or MTHFR.
MTHFR is responsible for converting 5, 10-methylene THF to 5-methyl THF, which is essential for the conversion of the amino acid homocysteine to methionine [R, R1].
This enzyme is very important for the production of DNA and methylation pathways that are essential for all bodily functions [R].
MTHFR plays a central role in transformation of folate to form S-adenosylmethionine (SAM), the universal methyl donor in cells and affects DNA methylation status.
A different post will deal with methylation in general.
The Two Main MTHFR SNPs
Genetic variations in the MTHFR gene results in reduced activity of the enzyme produced and have been associated with a series of diseases and conditions, including cardiovascular disorders, neurological defects, some forms of cancer, psychiatric disorders, diabetes, and pregnancy complications [R, R2].
The two most common MTHFR mutations (polymorphisms) found in humans are:
- MTHFR C677T (Rs1801133). This mutation (the A allele) is associated with reduced enzyme activity, elevated total homocysteine levels and altered distribution of folate [R]. People with an “A” allele for this mutation present a 35% decrease of the normal enzyme activity and “AA” individuals a 70% decrease [R].
- MTHFR A1298C (rs1801131). This mutation also impacts the MTFHR activity and the homocysteine levels but to a lesser extent than C677T [R].
The enzymatic activity of MTHFR in people with one minor allele in each MTHFR C677T and A1298C polymorphisms is lower than the activity present if each SNP separately had a minor allele [R].
Reduced MTHFR enzyme activity results in a decreased conversion of the amino acid homocysteine to methionine and accumulation of homocysteine in the blood. Abnormally elevated homocysteine levels are referred to as “homocystinuria” or “hyperhomocysteinemia” (Hhcy) [R].
The elevation of homocysteine levels in the blood may increase susceptibility to a series of diseases [R, R1].
A series of studies have linked MTHFR polymorphisms, especially the C677T, with various types of diseases but the results are sometimes conflicting and controversial. This can be attributed to a) small sample sizes and b) geographical factors that impact on the presentation of diseases in varying ethnicities or populations [R].
The various diseases that have been associated with MTHFR polymorphisms, especially C677T, are briefly presented below.
Diseases linked to MTHFR C677Tmutations (the “A” allele)
The C677T Polymorphism is associated with increased risk for the following conditions (assuming an A allele):
There is no study for my observations, but I noticed people with the A allele are more likely to have “lectin sensitivity.”
- Strokes of various kinds in different populations [R, R1, R2, R3] and stroke in children [R]
- Heart disease if lower folate levels [R]
- High blood pressure (also GG of MTHFR A1298C) [R]
- Male infertility especially in Asian populations (homozygous AA) [R, R1,R2, R3]
- Depression [R] – high Homocysteine and dysfunction of methylation metabolic pathways are critical to the synthesis of noradrenaline and serotonin [R].
- Autism spectrum disorders [R, R1, R2, R3]
- Alzheimer’s [R, R1]
- Dementia [R]
- Parkinson’s [R, R1]
- Multiple sclerosis but the evidence in controversial [R, R1, R2]
- Rheumatoid Arthritis [R]
- ADHD (A1298C) [R]
- Migraines with or without aura [R, R1, R2] – A different study found that the “AA” genotype reduced risk of migraines..However, if this genotype did have migraine with aura, then the risk for cardiovascular disease was increased by 3.66X and 4x increased risk for ischemic stroke [R]
- Diabetes and diabetic kidney problems (nephropathy) in patients with type II diabetes. The risks vary between Caucasian, Asian, Arabic and Chinese Han populations [R, R1, R2, R3].
- Schizophrenia [R, R1]
- Unipolar depressive disorder and bipolar disorder [R, R1]
- Cancer – It has been previously demonstrated that folate deficiency can increase the incidences of different forms of cancer. MTHFR is directly involved in folate metabolism and therefore MTHFR mutations may impact on the development of cancer [R, R1].
- Prostate cancer [R, R1]
- Ovarian cancer [R, R1]
- Esophageal cancer [R, R1]
- Stomach cancer [R, R1] – The “A” allele increases the likelihood that an H Pylori infection will cause stomach cancer [R].
- Bladder cancer [R, R1]
- Brain cancer [R]
- Lung cancer [R]
- Kidney cancer [R]
- Head and neck cancer [R]
- Colon cancer [R] – and more side effects from 5-fluoruracil treatment [R]
- Hearing impairment [R]
- Lower Bone Mineral Density in the spine and neck [R]
- Cluster Headache [R]
- Epilepsy [R]
- Peripheral Arterial Disease [R]
- Worse outcomes for end stage kidney disease [R]
- Adverse effects of methotrexate in rheumatoid arthritis [R] and Increased liver toxicity from methotrexate (folate blocker) [R]
- Recurrent pregnancy loss [R, R1]
- Pre-eclampsia, a serious complication of pregnancy [R].
- Having a Down syndrome kid if the mother has a mutation [R].
- Neuronal tube defects (NTD) such as anencephaly and spina bifida in newborns [R].
- Cleft lip and palate [R]
- Lower Luteinizing Hormone [R]
- Cataracts [R]
- Alopecia Areata [R]
- More severe Colitis [R]
Testing Homocysteine and Folate
It should be noted that most of the studies done on MTHFR genes only show correlations with disease when homocysteine levels are high or folate levels are low.
Therefore, you want to get your homocysteine levels measured. This is easily done with a blood test that you can ask for from your doctor. High homocysteine levels show that you may have a methylation issue or a B12/ folate deficiency caused by a possible MTHFR mutation.
Decreasing the levels of homocysteine in the blood will reduce the risk for development of any of the disorders presented above. The intake levels of folate, vitamin B12 (cobalamin) and vitamin B6 (pyridoxal phosphate) affect the levels of homocysteine in the blood [R].
A vitamin-rich diet that includes fruits, vegetables, dark leafy greens (spinach, kale, bok choy, and Swiss chard), eggs and red meat provide the B vitamins needed to maintain the homocysteine levels low and closer to normal levels. Additionally, supplementation with all three vitamins, folate, B12 and B6, can normalize homocysteine levels [R].
Healthy control have a homocysteine under 7 μmol/l, whereas those with schizophrenia have 12 μmol/l [R].
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