Understanding the clinical utility of MTHFR gene testing for chronic disease management
By Ali Baedke, MS, RD, Clinical Education Coordinator, HDL, Inc.
Elevated homocysteine (Hcy) levels have been linked with a number of health concerns, including depression, dementia, and increased risk for cardiovascular disease, stroke and deep-vein thrombosis. An NIH report analyzing data from the Framingham study found that individuals with elevated levels of blood Hcy (> 14µmol/L) doubled their risk of developing Alzheimer’s disease (AD) or dementia within eight years, while increasing their chance of AD by 40% with each additional 5µmol/L increase in Hcy1.
Treatment of elevated Hcy levels with supplemental folic acid has yielded mixed results2, possibly due to individual variability in how folic acid is metabolized. For example, those with a genetic mutation in the methyltetrahydrofolate reductase (MTHFR) gene may have less of the active MTHFR enzyme, required to convert the folic acid derivative 5,10-methylenetetrahydrofolate (CH2-THF) to its active form, 5-methyltetrahydrofolate (MTHF)3. This methylation is key in converting Hcy into methionine, an amino acid used in the formation of proteins and phospholipids. Thus, an individual who produces insufficient MTHFR has an increased risk of elevated Hcy levels owing to reduced conversion of Hcy to methionine.
Both folic acid and vitamin B12 are required in the conversion of CH2-THF to MTHF, which then converts Hcy to methionine1. Providing increased dosages of folic acid and/or vitamin B12 may provide enough substrate to drive the enzymatic reaction despite decreased MTHFR enzyme production. If this does not effectively lower Hcy levels, however, the individual may need supplemental MTHF to bypass the metabolic step requiring the MTHFR enzyme. At this point, prescription forms of MTHF, provided by Metanx (Pamlab LLC), or over-the-counter supplements, are potential avenues for reducing Hcy levels. Additional betaine supplementation may also help lower Hcy levels in MTHFR mutation carriers3.
The most common MTHFR mutation, a cytosine to thymidine substitution at nucleotide position 677 of the gene, occurs in ~ 40% individuals as the heterozygous state (C/T), with ~9-17% homozygous for the rare allele (T/T)4,5. Although known to cause moderate increases in serum Hcy levels, expression of MTHFR
677C>T varies according to environmental factors (e.g. dietary folate intake), which reduce Hcy levels.
Knowing an individual’s MTHFR 677C>T genotype can provide important clues not only in the treatment of patients presenting with hyperhomocysteinemia, but also in understanding patient response to medication dosages. There is evidence to suggest that medications affecting folate metabolism, e.g. bile acid sequestrants, antacids, oral medications for diabetes, certain types of chemotherapy and H2 blockers, may be more toxic in MTHFR mutation carriers than non-carriers4-7.
In summary, knowing whether an individual has a genetic predisposition to produce more or less of the active MTHFR enzyme can be vitally important in making medication dosage decisions, lead to more effective interventions in lowering blood levels of Hcy and thereby reduce risk for chronic diseases.
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