Amaral et al., (2017) did a cross-sectional study on polymorphisms of MTHFR C667T, A1298C and a cystathionine beta-synthase (CBS) gene to test serum levels of folic acid, vitamin B12 and Homocysteine (Hcy). Hcy has a toxic effect on endothelial cells making it a risk factor for venous and thrombotic diseases. CBS is the first key enzyme of the hcy trans-sulfuration pathway using B12 as a cofactor in methionine synthase. They found an increased risk of venous thrombosis was found for carriers of MTHFR 1298CC and homozygous for CBS. An increased risk of higher Hcy levels was seen in those with heterozygous CBS haplotype, also concluding birth control and environmental factors can play a role in increasing levels 1.
MTHFR and its relationship to many other polymorphisms are still unknown, they are now researching and finding many links. A study by Smith, et al., (2014) looked at the interactions between COMT, ESR1, GCH1 and MTHFR enzyme activity in relation to pain. Noting that the direction of COMT single nucleotide polymorphisms (SNPs) effects can be modified from interactions other genes in local molecular pathways. Disease risk is augmented by low activity of the MTHFR gene, which regulates bioavailability of S-adenosyl-L-homocysteine (SAH) which is an inhibitor of COMT. ESR1 is an estrogen receptor that regulates COMT gene expression and GCH1 influence COMT enzymes and pain. They concluded COMT plays a critical role in development and maintenance of pain, along with other genetic conditions 10.