The C677 Mutation in MTHFR Gene: Correlation with Uric Acid and Cardiovascular Risk Factors

takeaway snippet

• high homocysteine associated with neurological abnormalities and vascular complications
  
• C677 MTHFR may be genetic contributor to hyper-homocysteinemia
  
• direct relation between plasma homocysteine levels and serum uric acid
  
• Serum uric acid is considered a marker of renal dysfunction, and elevated serum uric acid can predict cardiovascular disease
  
• the MTHFR mutation may be a risk factor that is involved in multiple metabolic pathways related to vascular diseases.
  
• to prevent cardiovascular disorders in those who carry the C677T MTHFR mutation, supplementation with folate, vitamin B6 and vitamin B12
• regulation of homocyteine is an example of a nutritional/genetic interaction
  

The C677 Mutation in MTHFR Gene: Correlation with Uric Acid and Cardiovascular Risk Factors

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2822300/
2004 Apr 

Abstract

The C677T mutation in the methylene tetrahydrofolate reductase (MTHFR) gene results in elevated homocysteine levels and, presumably, in increased cardiovascular risk. Moreover, elevated homocysteine levels are reportedly associated with high serum uric acid levels. We evaluated the MTHFR genotype and a panel of biochemical, hematological variables, and lifestyle characteristics in 327 elderly Korean men (age range 40-81 yr; mean, 51.87). This study shows that mutation of the MTHFR gene may be a risk for hyperuricemia. The mean uric acid levels for the C/C, C/T and T/T genotypes were 5.54, 5.91 and 6.33 mg/dL, respectively (p=0.000). The T/T genotype was significantly more frequent in subjects with high uric acid levels (p=0.003). Thus, this mutation of the MTHFR gene is implied by the study results to be a risk factor of hyperuricemia in elderly Korean men. However, the relationship between the MTHFRmutation and uric acid metabolism remains unclear. Therefore, further studies are necessary to explain the associated between the MTHFR mutation and elevated uric acid levels, and to examine potential relationships between it and conventional cardiovascular risk factors.

Keywords: Methylenetetrahydrofolate Reductase (NADPH2), Uric Acid, Hyperuricemia, Cardiovascular Diseases, Risk Factors

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INTRODUCTION

Methylene tetrahydrofolate reductase (MTHFR) is a cytoplasmic enzyme of which gene located on chromosome 1p36.3 in man. MTHFR catalyze the reduction of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the primary methyl donor for the methylation of homocysteine to methionine. Severe deficiency of MTHFR causes an increase in homocysteine levels and is associated with developmental delay, neurological abnormalities and vascular complications (1-4). 

The C677T MTHFR mutation involves the substitution of an alanine residue for a valine, which results in a substantial reduction in its thermolabile enzymatic activity. With two copies of the TT variant, serum MTHFR activity is reduced to 30% of that of wild-type (CC), whereas the serum activity of CT heterozygotes is 65% of the wild-type (5). Therefore, the C677T MTHFR mutation is being viewed as a possible genetic contributor to hyper-homocysteinemia.

A direct relation between plasma homocysteine levels and serum uric acid was observed in patients with atherosclerosis and in control subjects (6-10). These findings indicate that the association between the two biochemical variables is indeed strong in the presence of homozygosity for thermolabile MTHFR. This could imply a greater availability of 5, 10-methylenetetrahydrofolate, substrate of the MTHFR reaction, for other metabolic uses, such as the de novo synthesis of purines via 10-formyltetrahydrofolate, with consequent overproduction of uric acid.

Hyperuricemia is commonly associated with other known risk factors for cardiovascular disease, such as obesity, hyperlipidemia, and hypertension, and in large epidemiological surveys, such as the Framingham study, it has been related to the occurrence of myocardial infarction. Yet, these associations are not fully understood.

Therefore, we studied a population of Korean elderly males, in order to investigate the relationships between the C677T MTHFR mutation and serum uric acid, and with other variables traditionally associated with cardiovascular risk.

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Serum uric acid is usually considered a marker of renal dysfunction, and a risk factor of renal disease progression. In addition, more recent studies suggest that elevated serum uric acid predict cardiovascular disease and cerebrovascular accidents (15-21). Although uric acid was thought to be an inert endproduct of purine metabolism, and without physiological significance, except in gouty diathesis.

Possible mechanisms underlying these associations may be presented. First, adenosine originating from S-adenosyl-homocysteine, and preferentially incorporated into a precursor pool for uric acid, would link the syntheses of homocysteine and uric acid (9). Second, in subjects with the T/T genotype, renovascular atherosclerosis or the complications of systemic vascular disease may reduce the renal clearance of uric acid, resulting in elevated serum uric acid (10). Therefore, the MTHFR mutation may be a risk factor that is involved in multiple metabolic pathways related to vascular diseases.

However, it remains a matter of debate as to whether uric acid is an independent predictor of mortality in patients with cardiovascular disease, or whether it represents only an indirect marker of adverse outcome by reflecting the association between uric acid and other cardiovascular risk factors

In this study, by comparing serum uric acid levels with the C677T MTHFR mutation, and with other variables by univariate analysis and multiple regression analysis. Five factors were found to be associated with hyperuricemia: the C677T MTHFR mutation, diastolic blood pressure, creatinine, triglycerides, and BMI. Compared with these factors, itself, may contribute less to hyperuricemia, because it showed a lower standard partial regression coefficient to serum uric acid.

To prevent cardiovascular disorders in those who carry the C677T MTHFR mutation, supplementation with folate, vitamin B6 and vitamin B12 has been recommended (22), because inter-individual variation in homocysteine levels are related to other biological traits. The regulation of homocyteine is an example of a nutritional/genetic interaction, in which dietary habits (i.e. the intake of folic acid) play an important role, in addition, to strategies aimed at lowering serum uric acid levels, such as weight control and reducing the intake of foods containing purines.

The present study shows that mutation of the MTHFR gene may be a risk factor for hyperuricemia in the Korean elderly population. In addition, the study identifies four other factors associated with hyperuricemia. Thus, we propose the probable need for a medical management strategy for those who are homozygous for the C677T MTHFR mutation, and the need for additional longitudinal study to determine the mechanism and role of uric acid as a risk factor of cardiovascular disease.