Recently, there have been revolutions in the cost of genetic testing and methylation cycle SNP analysis. 23andme will run ~1,000,000 SNPs for $199, and GeneticGenie will isolate 30 methylation SNPs from the 23andme raw data for free. While the cycle’s various parts and levels of function are inherently interrelated, the focus has been largely been on two SNPs on a single enzyme: MTHFR C667T and A1298C. That’s what I would like to talk about here.
Background: The C667T SNP causes an Ala–>Val substitution at AA#222. The result is a thermolabile enzyme with enhanced propensity to dissociate into monomers and to lose its FAD cofactor on dilution and a resulting loss of activity. The A1298C SNP causes a Glu–>Ala substitution at AA #429. There is debate about the relevance of the 1298 SNP. Some sources have suggested biochemical properties of the 1298 SNPs are “indistinguishable from the wild-type enzyme” (PMC64948). Others have suggested that homozygous 1298 variants alone or heterozygotes in combination with the 667 SNP causes degrees of lost activity. “Although neither the homozygous nor the heterozygous state for the 1298A>C is associated with raised plasma homocysteine or decreased plasma folate levels, the combined heterozygosity for 677C>T and 1298A>C is associated with higher homocysteine and lower plasma folate concentrations.” (PMC9545395, PMC1735448)
Be that all as it may, 667 and 1298 testing is becoming quite common–as is the intervention of giving an extremely wide range of 5MTHF doses (e.g. 400mcg to 25mg). What concerns me is that with three options for the 667 position (CC, CT, TT) and three more options for the 1298 position (AA, AC, CC) there are *NINE* possible genotype combinations for MTHFR: one normal or wild type and 8 variant combinations. Much of the discussion I have seen shows practitioners failing to distinguish which of the 8 variants a particular patient has–as if they were all the same. It makes me want to break plates when I hear that patients were told they are “positive for MTHFR.” I think we can do a lot better than this. Although it is admittedly over simplistic, I would like to find or develop a suggested methylfolate dosing schedule based on the percent of normal activity for the nine MTHFR genotypes.
I have searched for estimates of function with the nine 667/1298 genotypes. I found some older sources citing that the 677C>T polymorphism has reduced activity of 65% in heterozygotes and 30% in homozygotes (PMC1735448, PMID7647779). Others indicated that the 1298A>C change reduces the enzyme activity to 83% in heterozygotes and 61% in homozygotes (PMC1735448, PMID9545395). Back in 1998, van der Put’s group made some additional measures of 667 and 1298 enzyme function, that I could not penetrate well enough to convert into my simplistic percent of normal function goal. Assistance and other relevant references would be appreciated here.
So while I do recognize the limitations in this simplistic model, I would still like to see the following table filled in. I believe that this could lead to a more reasonable starting place for 5MTHF dosing personalized to the nine MTHFR genotypes.
Genotype—————>MTHFR Activity—–> MTHFR dose
667-CC; 1298-AA—–>100%————————> none
667-CC; 1298-AC—–> 83%————————-> 400mcg
667-CC; 1298-CC—–> 65%————————-> 800mcg
667-CT; 1298-AA—–> 55%————————> 1200mcg
667-CT; 1298-AC—–> 50%————————> 2mg
667-CT; 1298-CC—–> 30%————————> 3mg
667-TT; 1298-AA—–> 30%————————> 3mg
667-TT; 1298-AC—–> 20%————————> 4mg
667-TT; 1298-CC—–> 10%————————> 5mg
Dr. T.R. Morris is a licensed naturopathic medical doctor (ND). He is currently serving as faculty and consultant to the Institute for Functional Medicine (IFM). The IFM mission is to revolutionize medicine by teaching the latest genetic, nutritional, hormonal and other biochemically-based integrative medicine techniques to MDs and other practitioners looking for new tools to prevent and treat chronic disease. In the past, T.R. served as the medical director of a large integrative clinic and taught (genetics, physiology, biochemistry, microbiology, cellular & molecular biology) for 10 years for various medical programs in the Puget Sound. He sees patients in person (or long-distance via Skype consultations) from his home office in Seattle.
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