The MTHFR gene is a common area of genetic variation that has drawn significant public attention. MTHFR is the abbreviation for methylenetetrahydrofolate reductase, an enzyme-producing gene important for processing B vitamins. This common genetic variation, often inaccurately called a “mutation,” is widespread across the global population. The MTHFR gene provides instructions for an enzyme that helps the body utilize folate, a process fundamental to health. This genetic difference involves a slight change in the DNA code that affects how efficiently the body performs a vital biochemical step.
The Role of the MTHFR Gene
The MTHFR gene directs the production of the methylenetetrahydrofolate reductase enzyme, a key component of the folate cycle and the methylation process. This enzyme converts 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate (L-methylfolate), the active and usable form of folate. Active folate is required to convert the amino acid homocysteine back into methionine. Methionine is then used to create S-adenosylmethionine (SAMe), which serves as the universal methyl donor for hundreds of reactions in the body, collectively known as methylation.
Methylation is a foundational biochemical process involved in DNA synthesis and repair, detoxification, gene expression regulation, and neurotransmitter production. A variation in the MTHFR gene leads to reduced enzyme activity, resulting in less efficient conversion of folate into its active form. This reduced efficiency can lead to a slight build-up of homocysteine in the blood, particularly if folate intake is low.
The two most common MTHFR variants, C677T and A1298C, affect enzyme activity differently. The C677T variant can reduce enzyme efficiency by 30% to 70%, depending on whether one or two copies are present. The A1298C variant typically causes a milder reduction of about 20% to 30%. Even with reduced activity, the body can often compensate, especially when folate levels are adequate.
Global Prevalence of MTHFR Variants
The MTHFR genetic variation is highly prevalent globally, though frequency differs significantly based on geography and ethnicity. Approximately 30% to 40% of the general population carries at least one copy of the C677T variant. Considering both common variants (C677T and A1298C), an estimated 60% to 70% of individuals have at least one variant copy.
The C677T variant shows striking ethnic differences. Approximately 47% of people of Hispanic descent are carriers, and about 36% of European populations are carriers. Conversely, the frequency is lower in African populations, with about 9% of individuals carrying the C677T variant.
The frequency of being homozygous—carrying two copies of the C677T variant (TT genotype)—also varies widely. This genotype is observed in approximately 10% to 15% of the Caucasian population. This percentage is notably higher in certain populations, such as those of Mexican Amerindian descent, where studies have reported frequencies as high as 21% to 32%.
The second common variant, A1298C, is widespread, with about 25% of the global population being carriers. This variant is found more frequently in South East Asian populations (around 42%) and in Europeans (approximately 31%). The homozygous A1298C genotype (CC genotype) is less frequent than the C677T homozygous state, occurring in roughly 8% to 11% of tested European populations.
Understanding Inheritance Patterns
The MTHFR gene is located on an autosome, a non-sex chromosome, meaning the variant is passed down from parents to children independently of gender. Humans inherit two copies of every autosomal gene, one from each parent, and MTHFR status is determined by the combination of these two copies.
A person who inherits one variant copy (such as C677T) and one normal copy is called heterozygous. Heterozygous individuals possess one working copy, resulting in a moderate reduction in enzyme activity, often 30% to 50% less than normal. This status generally does not cause health problems if adequate folate levels are maintained.
An individual who inherits a variant copy from both parents is called homozygous (e.g., TT genotype). The homozygous state for the C677T variant leads to a significant reduction in enzyme activity, sometimes up to 70%. It is also possible to inherit a “compound heterozygous” pattern, receiving one copy of C677T and one copy of A1298C. The compound heterozygous state often results in a biochemical profile that is similar to the C677T homozygous state, with a greater reduction in enzyme function compared to a single heterozygous variant.