What are MTHFR Genes/Polymorphisms (C677T, Rs1801133)?

Genome Analysis

What are MTHFR Genes/Polymorphisms (C677T, Rs1801133)?

The MTHFR gene codes for an enzyme known as methylenetetrahydrofolate reductase or MTHFR. This enzyme is very important for the production of DNA and  methylation  pathways that are essential for all bodily functions [R].

MTHFR is responsible for converting 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate which is essential for the conversion of the amino acid homocysteine to  methionine  [R, R1].

The two most common MTHFR mutations (polymorphisms) found in humans are:

  • MTHFR C677T mutation at nucleotide 677, which substitutes a valine for an alanine at amino acid 222. This mutation is associated with reduced enzyme activity, elevated total homocysteine levels and altered distribution of folate [R]. People heterozygous for this mutation present a 35% decrease of the normal enzyme activity and homozygous individuals a 70% decrease [R].
  • MTHFR A1298C mutation, which substitutes a  glutamate  for an alanine at amino acid 429. It also impacts on the MTFHR activity and the homocysteine levels but to a lesser extent as opposed to C677T [R].

The enzymatic activity of MTHFR in double heterozygotes for MTHFR C677T and A1298C polymorphisms is lower than the activity present in each variant separately [R]. Reduction of the 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 mutations

  •         The C677T polymorphism has been linked to an increased risk of developing haemorrhagic or ischaemic stroke in different populations [R, R1, R2, R3].
  •         The C677T polymorphism has also been associated with ischaemic stroke in children [R].
  •         Individuals homozygous for the C677T polymorphism who also have low folate levels have a higher risk for developing heart disease [R].
  •         Homozygosity of MTHFR C677T mutation has been linked to male infertility especially in Asian populations [R, R1, R2, R3].
  •         C677T polymorphism has been associated with recurrent pregnancy loss [R, R1] and the increase of the risk of pre-eclampsia, a serious complication of pregnancy [R].
  •         Maternal polymorphism of MTHFR C677T is a risk factor for Downs syndrome in offspring [R].
  •         Polymorphisms of the MTHFR gene have been associated with neuronal tube defects (NTD) such as anencephaly and spina bifida in newborns [R].
  •         The MTHFR C677T polymorphism is strongly associated with the development of unipolar depressive disorder, bipolar disorder and schizophrenia [R, R1].
  •         C677T mutation is associated with the risk of development of autism spectrum disorders [R, R1, R2, R3].
  •         It has been shown that MTHFR mutations are linked with the development of Alzheimers and Parkinsons disorders [R, R1].
  •         The MTHFR polymorphisms may be linked to multiple sclerosis but the evidence in controversial [R, R1, R2].
  •         MTHFR polymorphisms confer susceptibility to  migraines  with or without aura [R, R1, R2].
  •         The C677T polymorphism may contribute to an elevated increase of the risk for diabetes or diabetic nephropathy in patients with type II diabetes. The risks vary between Caucasian, Asian, Arabic and Chinese Han populations [R, R1, R2, R3].
  •         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. A series of studies that have been conducted within the last 20 years have demonstrated a link between MTHFR and several forms of cancer such as ovarian, oesophageal, stomach, prostate and bladder cancer. However, the ethnicity and folate consumption were found to have a big impact on the development of cancer and interfere with the outcome of the studies. For an extensive list of the studies that investigated the link between different types of cancer and MTHFR see [R, R1].

A allele or dominant model for A allele (AG + AA) had an increased risk for Alzheimer's Disease (AD) [R].

The presence of the A allele (+rs1800795 C) increased the odds of developing Alzheimer's Disease (AD) by 2.5 and Vascular Dementia (VaD) by 3.7-fold [R].

 Among male patients, TT significantly increased the risk of severe/profound Hearing Impairment (HI) (odds ratio = 4.88, p = 0.001) [R].

Individuals with TT alleles tended to have somewhat lower Bone mineral density (BMD), but the difference was not statistically significant [R].

The mutant TT genotype may increase the mortality risk in patients with End-stage renal disease (ESRD) [R].

The patients with CT or TT genotype had higher risks of adverse effects (AE's) of methotrexate (MTX) treatment for rheumatoid arthritis (RA) than those with CC genotype [R].

Patients with the CC genotype had significantly higher plasma levels of LH than patients with the CT and/or TT genotypes [R].

The minor allele T showed a significant association with an increased risk of overall Age-related cataract (ARC) (OR = 1.26, P = 0.003) [R].

There is an inverse association between the TT genotype and Ulcerative Colitis (UC) [R].

In a study of people with people who have the “AA” genotype, those who had the lowest intake of Riboflavin had a 1.8-2.6X increased risk of getting fractures (R).

The A allele of rs1801133 is reported to be associated with Homocysteine Measurement (R) . Your genotype was not identified for this SNP so we are unable to comment on your association with Homocysteine levels (WGHS).

Source: https://selfdecode.com/snp/rs1801133/

Association of the MTHFR C677T (rs1801133) polymorphism with idiopathic male infertility in a local Pakistani population

What are MTHFR Genes/Polymorphisms (C677T, Rs1801133)?

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C677T (RS1801133 ) MTHFR gene polymorphism frequency in a colombian population

What are MTHFR Genes/Polymorphisms (C677T, Rs1801133)?

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