MTHFR Polymorphisms

The Human Genome Project and the subsequent identification of single nucleotide polymorphisms (SNPs) have led to the concept of personalized medicine and personalized nutrition therapy or nutrigenomics [88]. Polymorphisms have been slow to catch on in medical practice but the MTHFR genes can be assessed by most diagnostic laboratories.

The MTHFR gene testing is a way of detecting the efficiency of the methylation cycle that occurs in each cell of the body to carry out energy production, detoxification, immune function, inflammation management, and gene replication [89]. Methylation defects contribute to addictions, chronic infections, anxiety, cardiovascular disease, diabetes, fibromyalgia, infertility, irritable bowel syndrome, migraines, neural tube defects, rheumatoid arthritis, sleep disorders, stroke, thyroid dysfunction, and many other medical conditions that a bariatric patient can present with. An estimated 30% of the population may have methylation defect genetic markers where they do not make the enzyme for methylfolate production [90]. The MTHFR gene provides instructions for making an enzyme called MTHFR along with playing a vital role in processing amino acids. A deficiency of the enzyme can be identified when homocysteine is elevated because it cannot be converted to methionine.

Both MTHFR mutations C677T and A1298C cannot convert folic acid into folate, which is needed for proper methylation. Conditions related to these MTHFR defects are: miscarriages, chronic pain, insomnia, fibromyalgia, neurological disorders, neural tube defects, elevated histamine, cardiovascular risk, hypertension, depression, cleft palate, autism, headaches/migraines, IBS, chronic fatigue, chemical sensitivity, thyroid dysfunction, anxiety, bipolar disorder, infertility, multiple sclerosis, addictive behaviors, and allergies [90].

• Conditions common with C677T: elevated homocysteine, cardiovascular disease, stroke, peripheral neuropathy, neural tube defects, cleft palate, blood clots, stillbirths, deep vein thrombosis

• Conditions common with A1298C: depression, anxiety, IBS, fibromyalgia, chronic fatigue, dementia, schizophrenia, Parkinson’s, migraines

Little is known about SNPs and overweight/obesity but Yin et al. [91,92] reported several polymorphisms that included those in MTHFR, influencing overweight/obesity. Another study on four population groups in the United Kingdom and Denmark found the MTHFR C677T genotype to be associated with an increased risk of obesity BMI>30 [93]. A Saudi study confirmed that the genetic polymorphisms MTHFR C677T and A1298C are associated with the risk of hypertension in patients with obesity and diabetes [94]. Koo et al. found the MTHFR association with homocysteine predictive of the development of premature coronary heart disease in hypertensive adolescents [95].

The MTHFR polymorphisms are associated with various diseases—vascular, cancer, neurology, diabetes, psoriasis, and so forth. Homozygous mutated patients have higher homocysteine levels, which usually need supplementation with vitamin B12 and folate [96]. Lunegova et al. reported this same MTHFR allele was associated with insulin resistance, abdominal obesity and hypertriglyceridemia [97]. Other studies confirmed the association of MTHFR C677T genotype in diabetes, insulin resistance, and obesity [97,98].

MTHFR genetic mutation testing is becoming a useful tool in nutrition assessment for personalizing dietary recommendations [99, 100]. Since bariatric surgery is rapidly becoming the treatment of choice for obesity, nutrition management needs to consider all aspects of the malabsorption caused by the surgery and genetic factors that may contribute. An example of how nutrigenomics needs to quickly evolve is provided by Yarandi et al. They present a case of an undiagnosed copper deficiency postgastric bypass where a heterozygous MTHFR A1298C gene polymorphism resulted in irreversible neurological manifestations even after copper repletion [101].

Overcoming the MTHFR defects usually requires adequate folate, a critical cofactor in metabolism. Mammals cannot synthesize folate and depend on food sources and/or supplementation to maintain normal levels [102]. Low-folate levels may be caused from poor food choices, poor absorption of the ingested folate, or drug-nutrient interactions. Supplementation of folic acid or fortified foods instead of the recommended 5-MTHFR can lead to negative effects of unconverted folic acid in peripheral circulation [102]. Preventing folate deficiency in patients with MTHFR polymorphisms is imperative to their health.

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