The evaluation of kidney filtration is the central point of diagnosing chronic kidney disease classification (CKD). The effects of methionine metabolism and total homocysteine levels have a strong association with decreased glomerular filtration rate (GFR). Furthermore, the enzymes and cofactors involved in the methionine metabolism process are crucial in maintaining homocysteine (tHcy) levels. Therefore, the methylenetetrahydrofolate reductase (MTHFR) enzymatic function is essential to modulate tHcy and increase GFR. Nowadays, detecting single nucleotide polymorphisms (SNPs) in MTFHR is a key determinant to assess CKD and prevent co-morbidities like stroke and coronary heart disease.

MTHFR

Methylenetetrahydrofolate reductase (MTHFR) is the catalytic enzyme that converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. Consequently, this causes the remethylation of homocysteine to methionine. The recycled homocysteine is reused to build other proteins, and vitamins like folate, cobalamin, and pyridoxine serve as cofactors that modulate MTHFR function. However, genetic mutations in the MTHFR can provoke a non-optimal functionality of such an enzyme and result in elevated homocysteine levels.

Genetic Mutations in the MTHFR gene

Our parents commonly inherit genetic mutations. Every patient inherits two MTHFR genes, and if only one of their MTHFR genes is mutated, this patient is considered heterozygous. However, if both of their genes present the mutation, this patient is deemed to be homozygous.

MTHFR C677T

The SNP C->T at nucleotide position 677 results in a codon substitution that leads to an Ala-> Val amino acid change. Furthermore, this amino acid change is associated with hyperhomocysteinemia, linked to neural tube defects, coronary heart disease, depression, schizophrenia, cancer, stroke, and a higher risk of developing CVD.

Molecular Genetics

C667T SNP and populations

The existing literature links the prevalence of MTHFR C677T polymorphism to Chinese males to lower eGFR and high blood pressure. In a 2012 report that associated the presence of the C677T SNP in the Chinese population with lower filtration rate and kidney function. Indeed, this study determined that effect was more common in Chinese males when compared to Chinese women.

Additionally, it is essential to note that this SNP prevalence is highly variable within the population. For example, the C677T SNP is less common in the black population (1-2%) when compared to those with European or Australian heritage (8-20%). 

In heterozygous patients, the enzymatic function of MTHFR can be reduced up to 65%. On the other hand, those patients considered homozygous have a 30% enzyme functionality.

MTHFR A1298C

European, North American, and Australian populations have a higher prevalence of having the A1298C mutation. On the other hand, the Asian, Hispanic, and Chinese populations have a lower mutation rate.

However, having two mutations of the MTHFR gene (the A1298C and C677T) results in a combined action, reflecting a decreased enzymatic function and higher tHcy levels.

Does an MTHFR mutation results in health complication?

The main answer is that it depends. A deficient enzymatic function of MTHFR associates with cardiovascular disease, pregnancy complications, neural tube defects, and elevated homocysteine. However, patients with an MTHFR mutation can have normal homocysteine levels. In fact, if the homozygous or heterozygous patient has a constant vitamin B supplementation, this could reduce their risk of developing cardiovascular disease. 

Furthermore, in multiple countries, folic acid fortified food is the primary prevention factor in reducing the prevalence of pregnancy loss, preeclampsia, clotting disorders, hypertension, and CVD.

Who should get tested for MTHFR mutations?

This question has mixed answers. Kidney failure specialists had become aware of the interaction between genetic mutations and lower eGFR. However, the MTHFR gene mutations have a stronger association with higher homocysteine levels, which can be lowered by folic acid supplementation. This supplementation recommendation is consistent with the KDOQI guidelines specification on vitamins and minerals. 

On the other hand, in the Chinese male population, the TT genotype directly links with lower eGFR (1.37 ml/min/1.73 m2) than the CC and CT genotypes. On the other hand, the AHA makes evident that there is no indication for mutation testing. However, they consider the recommendations of the American College of Medical Genetics and the American College of Obstetricians and Gynecologists, which state the following:

“Pregnant women should not be tested for MTHFR or homocysteine due to the lack of association between the MTHFR C677T polymorphism and any negative pregnancy outcomes.”

What should we do? Instead, all of the past institutions point back to the importance of supplementing 0.4mg of folic acid to those women of childbearing age. In addition, they are punctual about the fact that MTHFR mutations are not clotting disorders, and they are not predictors of an adverse medical outcome. – Ana Paola Rodríguez Arciniega, MS.

References:

Dong, Qing et al. “Methylenetetrahydrofolate reductase C677T polymorphism is associated with estimated glomerular filtration rate in hypertensive Chinese males.” BMC medical genetics vol. 13 74. 16 Aug. 2012, doi:10.1186/1471-2350-13-74

Moll, Stephan, and Elizabeth A. Varga. “Homocysteine and MTHFR mutations.” Circulation 132.1 (2015): e6-e9.

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