MTHFR, Gout, Hearing loss, Cardiovascular disease, Depression - MTHFR Support Australia

https://www.mthfrsupport.com.au/mthfr-polymorphisms-and-cardiovascular-disease/

The link between MTHFR polymorphisms and cardiovascular disease has been known for some time, however recent research confirms increased risk of depression, bi-polar and schizophrenia.

This paper summarises the latest research.

The MTHFR C677T polymorphism causes thermolability and reduced MTHFR activity, leading to lower levels of 5-methyltetrahydrofolate, an accumulation of 5,10-methylene THG, increased plasma homocysteine levels and change in the cellular composition of one-carbon folate derivatives (Frisco et al 2002). Studies have also indicated that another polymorphism in the MTHFR gene (A1298C) may modulate the genomic methylation in human lymphocytes, although the degree and direction of change have not been clearly established (Frisco et al 2005)

Approximately 50-75% of folate is lost through food harvesting, storage, processing and preparation (Ly et al 2012), however folinic acid and active 5-MTHF (the predominant folate found in the blood) are highly stable for months or even years.

Methylation plays a pivotal role in the maintenance of DNA integrity and stability and in chromatin modifications and repair. (Ly et al 2012)
Folate deficiency has been linked to the development of anaemia, cardiovascular disease, neural tube defects and congenital disorders, adverse pregnancy outcomes, neuropsychiatric disorders and cognitive impairements (Food and nutrition board, Institutes of medicine 1998). The research on Folic acid shows that there may be some risks, however the active 5MTHF shows more promise (Ly et al 2012).

Synthesis of the active forms of folic acid is a complex process requiring several enzymes, as well as adequate supplies of niacin [B3], riboflavin [B2] 5’phosphate, P5P [methyl-B6] and serine as cofactors.

1. Cancer â€" Folate, a water-soluble B vitamin, have been of intense interest because of an inverse association between folate status and the risk of several malignancies (particularly colorectal cancer) and its potential to modulate DNA methylation. Aberrant patterns and dysregulation of DNA methylation are mechanistically related to carcinogenesis. (ly et al 2012). The role of folate in colorectal carcinogenesis has been further strengthened by the observations that genetic polymorphism in the folate metabolic pathway (MTHFR C677T) modify CRC risk. (Kim YI 2009).
A substantial amount of epidemiologic evidence suggests an inverse relationship between folate levels and the risk of several malignancies including cancer of the lungs, oropharynx, oesophagus, stomach, colorectum, pancreas, cervix, ovary, prostate and breast and the risk of neuroblastoma and leukaemia. (Kim YI. 2008). FA supplementation is able to reverse pre-existing global DNA hypomethylation and increase the extent of global DNA methylation above the pre-existing level thereby reducing the risk of neoplastic transformation. (Ly et al 2012).

Slattery et al found that subjects heterozygous or homozygous for the MTHFR A1298C genotype with low folate/low methionine/high alcohol intake had more than twofold greater odds of developing tumours presenting CpG island hypermethylation compared with subjects with the wild type genotype and high folate/high methionine/low alcohol intake (Curtin et al, 2007). These studies suggest that common MTHFR polymorphisms associated with impaired enzyme activity interact with folate in a manner that modulates both genomic and gene-specific DNA methylation.
In a study Methyltetrahydrofolate for 8 weeks restored genomic DNA methylation in lymphocytes to normal levels in 32 men with uremia, hyperhomocysteinemia and pre-existing genomic DNA hypomethylation in colorectal adenoma or cancer. (Ly et al 2012)

2. Pregnancy â€" women carrying the 677 T allele had a greater risk of global DNA hypomethylation if they were vitamin B6 deficient. (La Merrill M et al 2012.
Bisphenol A is an estrogenic xenobiotic chemical used in the manufacturing of polycarbonate plastics and is associated with higher body weight, increased risk of cancer and other chronic health conditions. FA supplementation successfully reversed the epigenetic and phenotypic effects of bisphenol A. (Dolinoy DC et al 2007). Hyperhomocysteinemia is implicated in neural tube defects, spontaneous abortion, placental abruption, low birth weight (Miller & Kelly 1997)
The MTHFR C677T variant is associated with greater depressed mood during pregnancy (Devlin A, 2010)

3. Cardiovascular disease
Mildly elevated homocysteine (Hcy) increases the risk for atherothrombotic vascular disease in the coronary, cerebrovascular and peripheral arterial circulations. The molecular mechanisms responsible for decreased bioavailability of endothelium-derived nitric oxide (NO) by Hcy involve an increase of vascular oxidant stress and inhibition of important antioxidant capacity. Glutathione peroxidase â€" 1 (GPx-1) is decreased by Hcy. (Lubos et al 2007). Alterations in cellular redox status may contribute to alterations in gene expression, endoplasmic reticulum (ER) stress and activation of cholesterol biosynthesis. Hcy may also cause oxidative stress, in part by inhibiting the expression of antioxidant enzymes, such as cellular glutathione peroxidase-1. Plasma Hcy levels above the median are associated with a 3-fold increase in cardiovascular risk, whereas Hcy loses its independent risk in individuals with increased antioxidant capacity (Lubos et al).

THE MTHFR studies collaboration group found that individuals with folate levels below the median and the TT genotype have a greater risk for coronary heart disease than individuals with the cc genotype and folate levels above the median (Lobos et al 2007).

Endothelium dysfunction is characterized by decreased vasodilator capacity and Nitric oxide insufficiency. Homocysteine has been shown to decrease the production of nitric oxide. Nitric oxide is a potent vasodilator. Hyperhomocysteinemia induced oxidant stress not only leads to biological inactivation of NO but also may lead to lipid peroxidation at the cell surface and direct oxidation of low â€" density lipoprotein. HCY also has an action of the endoplasmic reticulum ER stress pathway. The cellular consequences of ER stress include dysregulation of lipid metabolism, activation of inflammatory pathways, increased proteolysis of misfolded proteins and apoptotic cell death in endothelial cells. HCY may be involved in cholesterol biosynthesis as studies have shown that Hcy increases the expression of sterol response-binding protein, a nuclear factor causing up regulation of mRNA levels of genes involved in cholesterol biosynthesis such as HMGCO A reductase. (Lubos et al 2007).

Hyperhomocysteinemia has been suggested as an independent risk factor for stroke (Perry et al 1995).
Some of the mechanisms suggested to be involved in the acceleration of vascular disease include increased platelet adhesiveness, activation of the coagulation cascade, endothelial cell injury, endothelial dysfunction and increased vascular smooth muscle cell growth. (Chan & Fonseca 2003). Woo et al showed that folate supplementation caused higher serum folate levels, lower total plasma homocysteine levels and significant improvement in endothelium dependent dilation (Woo et al 2002-2006).

4. Reduced anti-oxidant status â€" especially glutathione peroxidase.
A low glutathione peroxidase activity has been shown to be independently associated with an increased risk of future fatal and nonfatal myocardial infarction. (Lubos et al 2007) Glutathione is protective against oxidative stress. Several studies have shown that elevated Hcy levels alters the expression of glutathione peroxidase. (Lubos et al, 2007) A recent study showed that patients with low glutathione peroxidase activity below the median value have a 3 x increase in cardiovascular risk if their Hcy level is above the median value. Those with higher GPx-1 are relatively protected against adverse oxidative effects induced by hyperhomocysteinemia.

5. Hearing loss â€" Some researchers have suggested that homocysteine may interfere with blood circulation to the cochlea, the principal structure of the inner ear.  A study showed that people with the polymorphisms in the MTHFR gene had greater benefits from folic acid than people who had the normal versions of the gene in reducing hearing loss. (Durga et al 2007)

6. Type 2 diabetes . Diabetic retinopathy – A significantly higher percentage of diabetics with retinopathy exhibit the MTHFR gene mutation. Elevated levels of homocysteine levels cause cell injury to the small vessels. (Vaccaro et al 1997)

7. Dialysis â€" B6 & B12 should be supplemented as dialysis decreases these B Vitamins. Because homocysteine is cleared in the kidneys, chronic renal failure as well as absolute or relative deficiencies in 5-MTHF, methylcobalamin, P5P or betaine results in increased homocysteine levels. (Dennis et al. 1996)

8. Neuropsychiatric disorders â€" Folate is intimately linked to methylation processes and the synthesis of neurotransmitters in the central nervous system such as serotonin (5-hydroxytryptamine;5-HT). Methyltetrahydrofolate is the predominant circulating form of folate, which donates a methyl group to homocysteine during the generation of S-adenosylmethionine, a major source of methyl groups in the brain. (Gilbody. Lightfoot, Sheldon 2007). Several of the key enzymes in the 1-carbon cycle are folate dependent in their activity and this forms a biologically plausible link between folate and mood. Patients with MTHFR deficiency have reduced levels of both methionine and SAM in the cerebrospinal fluid and show demyelination in the brain and degeneration of the spinal cord. (Hyland et al 1988)

Depression – Gilbody et al found an association between the MTHFR C677T variant and depression, schizophrenia and bipolar disorder. For the C677T polymorphism, homozygote variants have a 30% enzyme activity in comparison with homozygotes for the wild type C allele. People with the 1298 CC have approx. 60% of the enzyme activity. There was an increased risk of depression among persons with the homozygote variant TT genotype and a smaller risk for those heterozygotes. (Gilbody et al 2007), One study showed a positive association with MTHFR A1298C when homozygous. (Reif A et al 2005)

Schizophrenia â€" there was an increased risk of schizophrenia among homozygote variants (TT), a non-significant association for heterozygotes. A cumulative meta-analysis showed that a moderate and significant association between schizophrenia and MTHFR C677T (Gilbody et al 2007). 2 studies showed an increased risk of schizophrenia among persons with the homozygote variant CC genotype (MTHFR A1298C). But no association found for heterozygous types. (Sazci et al 2005). Schizophrenia is increasingly considered to be a neurodevelopmental disorder with in-utero exposures and epigenetic mechanisms such as DNA methylation being important in its etiology. (Gilbody et al 2007)

Bipolar disorder â€" There is an increased risk of bipolar disorder associated with the homozygote variant genotype (Kempisty et al 2006)
Peerbooms et al found that the MTHFR C677T was significantly associated with all of the combined psychiatric disorders (schizophrenia, bipolar disorder and unipolar depressive disorder) (Peerbooms et al 2011). So too the MTHFR A1298C are a statistically significant increased risk of being diagnosed with bipolar disorder but not schizophrenia (Peerbooms et al 2011)

9. Gout â€" the C677T gene mutation is associated with increased uric acid levels. Possible mechanisms underlying these associations may be adenosine originating from S-adenosyl-homocysteine, and preferentially incorporated into a precursor pool for uric acid, would link the syntheses of homocysteine and uric acid. Second, in subjects with the T/T genotype, renovascular atherosclerosis or the complications of systemic vascular disease may reduce the renal clearance of uric acid, resulting in elevated serum uric acid (Hong et al 2004)(Wei W et al 2012)