Abstract
Folate deficiency is strongly associated with cardiovascular disease. We aimed to explore the joint effect of the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C, methionine synthase (MTR) A2756G, and methionine synthase reductase (MTRR) A66G polymorphisms on folate deficiency in a Chinese hypertensive population. A total of 480 subjects aged 28–75 were enrolled in this study from September 2005–December 2005 from six hospitals in different Chinese regions. Known genotypes were detected by PCR-RFLP methods and serum folate was measured by chemiluminescence immunoassay. Our results showed that MTHFR 677TT and MTR 2756AG + GG were independently associated with a higher risk of folate deficiency (TT vs. CC + CT, p < 0.001 and AG + GG vs. AA p = 0.030, respectively). However, the MTHFR A1298C mutation may confer protection by elevating the serum folate level (p = 0.025). Furthermore, patients carrying two or more risk genotypes showed higher odds of folate deficiency than null risk genotype carriers, especially those carrying four risk genotypes. These findings were verified by generalized multifactor dimensionality reduction (p = 0.0107) and a cumulative effects model (p = 0.001). The results of this study have shown that interactions among homocysteine metabolism gene polymorphisms lead to dramatic elevations in the folate deficiency risk.
Highlights
A large-scale randomized clinical trial confirmed the benefits of folate therapy on the risk of first stroke [1]
After exclusion of 12 subjects who lacked data on methylenetetrahydrofolate reductase (MTHFR) A1298C, MTR A2756G or folate, a total of 468 subjects were included in our final analysis
Four polymorphisms (MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) in this population showed no deviation in genotype distribution from expected Hardy-Weinberg equilibrium (p values of 0.711, 0.380, 0.862 and 0.393, respectively)
Summary
A large-scale randomized clinical trial confirmed the benefits of folate therapy on the risk of first stroke [1]. A previous meta-analysis has shown that the effect of the MTHFR C677T variant on the homocysteine concentration is modified by folate status [2]. Hyperhomocysteinemia and the MTHFR 677TT genotype are considered risk factors for cardiovascular diseases (CVDs) [2,3,4,5]. Some mutations may result in an elevation in the plasma homocysteine concentration and a reduction in the folate concentration [6,7,8,9,10,11], thereby exacerbating the risks of several complicated diseases [6,12]. Other studies have demonstrated that high-dose folate intervention therapy [13] or dietary folate supplementation [8] may increase the serum folate level and simultaneously reduce the prevalence of hyperhomocysteinemia and hypertension
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