scholarly journals Investigation of Homocysteine-Pathway-Related Variants in Essential Hypertension

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Javed Y. Fowdar ◽  
Marta V. Lason ◽  
Attila L. Szvetko ◽  
Rodney A. Lea ◽  
Lyn R. Griffiths
Keyword(s):  
Essential Hypertension ◽  
Methylenetetrahydrofolate Reductase ◽  
Interaction Model ◽  
Mthfr A1298c ◽  
Methionine Synthase Reductase ◽  
Pathway Gene ◽  
Mtrr A66g ◽  
Increased Risk ◽  
Reductase Gene ◽  
Chi Square Analysis

Hyperhomocysteinemia (hHcy) has been associated with an increased risk of cardiovascular disease and stroke. Essential hypertension (EH), a polygenic condition, has also been associated with increased risk of cardiovascular related disorders. To investigate the role of the homocysteine (Hcy) metabolism pathway in hypertension we conducted a case-control association study of Hcy pathway gene variants in a cohort of Caucasian hypertensives and age- and sex-matched normotensives. We genotyped two polymorphisms in the methylenetetrahydrofolate reductase gene (MTHFR C677T and MTHFR A1298C), one polymorphism in the methionine synthase reductase gene (MTRR A66G), and one polymorphism in the methylenetetrahydrofolate dehydrogenase 1 gene (MTHFD1 G1958A) and assessed their association with hypertension using chi-square analysis. We also performed a multifactor dimensionality reduction (MDR) analysis to investigate any potential epistatic interactions among the four polymorphisms and EH. None of the four polymorphisms was significantly associated with EH and although we found a moderate synergistic interaction between MTHFR A1298C and MTRR A66G, the association of the interaction model with EH was not statistically significant (P=0.2367). Our findings therefore suggest no individual or interactive association between four prominent Hcy pathway markers and EH.

scholarly journals The impact of Folate Pathway Polymorphisms Combined to Nutritional Deficiency As a Maternal Predisposition Factor for Down Syndrome

2008 ◽  
Vol 25 (3) ◽  
pp. 149-157 ◽  
Author(s):  
C. B. Santos-Rebouças ◽  
J. C. Corrêa ◽  
A. Bonomo ◽  
N. Fintelman-Rodrigues ◽  
K. C. V. Moura ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Methylenetetrahydrofolate Reductase ◽  
Genetic Profile ◽  
Negative Effects ◽  
Methionine Synthase Reductase ◽  
Genotype Frequencies ◽  
Folate Pathway ◽  
Increased Risk ◽  
Reductase Gene ◽  
The Impact

Polymorphisms in genes encoding folate metabolizing enzymes have been linked to an increased risk of maternal chromosomal nondisjunction in several populations. With the purpose of evaluating this relationship, we compared the frequencies of 677C>T and 1298A>C polymorphisms in the methylenetetrahydrofolate reductase gene (MTHFR) and 66A>G in the methionine synthase reductase gene (MTRR) between 103 young mothers of Down syndrome (DS) individuals and 108 control mothers, whose offspring was karyotypically normal, correlating it with an estimative of folate and – related micronutrients levels intake. Maternal and paternal transmission frequencies ofMTHFR677T allele were also examined to access potential parent-of-origin effects. PCR-RFLP for genomic DNA was accomplished and allele/genotype frequencies differences were determined using the x2test, whereas pattern of transmission of theMTHFR677 allele was analyzed by transmission disequilibrium test. None of the polymorphisms seemed to be more frequent in case mothers than in controls, either individually or combined. The estimative of nutritional intake revealed that folate consumption median was inadequate in both groups, whereas methionine and zinc consumption medians were significantly greater in control mothers. It suggests that such interaction between genetic profile and environment could predispose this sub group of women to have a DS child. Additional studies focusing the interaction between nutritional intakes, biochemical data and folate pathway polymorphisms are needed to confirm the present results. The possibility of neutralize the biochemical negative effects of folate-related polymorphisms through oral supplementation could provide new targets for DS prevention.

scholarly journals Effect of MTHFR A1298C and MTRR A66G genetic mutations on homocysteine levels in the Chinese population: a systematic review and meta-analysis

2017 ◽  
Vol 5 (4) ◽  
pp. 220-229 ◽  
Author(s):  
Jiancheng Wang ◽  
Nengtai Ouyang ◽  
Long Qu ◽  
Tengfei Lin ◽  
Xianglin Zhang ◽  
...  
Keyword(s):  
Chinese Population ◽  
Methylenetetrahydrofolate Reductase ◽  
Meta Analysis ◽  
Random Effect ◽  
Mthfr Gene ◽  
Folate Intake ◽  
Folic Acid Fortification ◽  
Mthfr A1298c ◽  
Methionine Synthase Reductase ◽  
Mtrr A66g

AbstractBackground and ObjectivesThe Chinese population typically has inadequate folate intake and no mandatory folic acid fortification. Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) are the two key regulatory enzymes in the folate/homocysteine (Hcy) metabolism. Hcy has been implicated in the pathogenesis of cardiovascular disease. We conducted a meta-analysis to assess whether the MTHFR gene A1298C and the MTRR gene A66G polymorphisms affect Hcy levels in the Chinese population.MethodsThis analysis included 13 studies with Hcy levels reported as one of the study measurements. Summary estimates of weighted mean differences and 95% confidence intervals (CIs) were obtained using random-effect models.ResultsOverall, there were no significant differences in Hcy concentrations between participants with the MTHFR 1298 CC (12 trials,n= 129), AA (n= 2166; β, −0.51 μmol/L; 95%CI: −2.14, 1.11;P= 0.53), or AC genotype (n= 958; β, 0.55 μmol/L; 95%CI: −0.72, 1.82;P= 0.40). Consistently, compared to those with the MTRR 66 GG genotype (6 trials,n= 156), similar Hcy concentrations were found in participants with the AA (n= 832; β, −0.43 μmol/L; 95%CI: −1.04, 0.17;P= 0.16) or AG (n=743; β, −0.57 μmol/L; 95%CI: −1.46, 0.31;P= 0.21) genotype. Similar results were observed for the dominant and recessive models.ConclusionsNeither the MTHFR A1298C polymorphism nor the MTRR A66G polymorphism affects Hcy levels in the Chinese population.

scholarly journals Haplotype analysis of the folate-related genes MTHFR, MTRR, and MTR and migraine with aura

Cephalalgia ◽  
2013 ◽  
Vol 33 (7) ◽  
pp. 469-482 ◽  
Author(s):  
Kathryn A Roecklein ◽  
Ann I Scher ◽  
Albert Smith ◽  
Tamara Harris ◽  
Gudny Eiriksdottir ◽  
...  
Keyword(s):  
Migraine With Aura ◽  
Multiple Testing ◽  
Haplotype Analysis ◽  
Methylenetetrahydrofolate Reductase ◽  
Population Based ◽  
Methionine Synthase ◽  
Association Testing ◽  
Methionine Synthase Reductase ◽  
Increased Risk ◽  
Genes Encoding

Aims The C677T variant in the methylenetetrahydrofolate reductase ( MTHFR; EC 1.5.1.20) enzyme, a key player in the folate metabolic pathway, has been associated with increased risk of migraine with aura. Other genes encoding molecular components of this pathway include methionine synthase ( MTR; EC 2.1.1.13) and methionine synthase reductase ( MTRR; EC 2.1.1.135) among others. We performed a haplotype analysis of migraine risk and MTHFR, MTR, and MTRR. Methods Study participants are from a random sub-sample participating in the population-based AGES-Reykjavik Study, including subjects with non-migraine headache ( n = 367), migraine without aura ( n = 85), migraine with aura ( n = 167), and no headache ( n = 1347). Haplotypes spanning each gene were constructed using Haploview. Association testing was performed on single SNP and haplotypes using logistic regression, controlling for demographic and cardiovascular risk factors and correcting for multiple testing. Results Haplotype analysis suggested an association between MTRR haplotypes and reduced risk of migraine with aura. All other associations were not significant after correcting for multiple testing. Conclusions These results suggest that MTRR variants may protect against migraine with aura in an older population.

scholarly journals Association Between MTHFR Polymorphisms and the Risk of Essential Hypertension: An Updated Meta-analysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Hao Meng ◽  
Shaoyan Huang ◽  
Yali Yang ◽  
Xiaofeng He ◽  
Liping Fei ◽  
...  
Keyword(s):  
Sensitivity Analysis ◽  
Essential Hypertension ◽  
Methylenetetrahydrofolate Reductase ◽  
Meta Analysis ◽  
Mthfr C677t ◽  
Cochrane Library ◽  
Mthfr Polymorphisms ◽  
Southeast Asians ◽  
Increased Risk ◽  
Meta Analyses

Background: Since the 1990s, there have been a lot of research on single-nucleotide polymorphism (SNP) and different diseases, including many studies on 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism and essential hypertension (EH). Nevertheless, their conclusions were controversial. So far, six previous meta-analyses discussed the internal relationship between the MTHFR polymorphism and EH, respectively. However, they did not evaluate the credibility of the positive associations. To build on previous meta-analyses, we updated the literature by including previously included papers as well as nine new articles, improved the inclusion criteria by also considering the quality of the papers, and applied new statistical techniques to assess the observed associations. Objectives: This study aims to explore the degree of risk correlation between two MTHFR polymorphisms and EH. Methods: PubMed, EMBASE, the Cochrane Library, CNKI, and Wan Fang electronic databases were searched to identify relevant studies. We evaluated the relation between the MTHFR C677T (rs1801133) and A1298C (rs1801131) polymorphisms and EH by calculating the odds ratios (OR) as well as 95% confidence intervals (CI). Here we used subgroup analysis, sensitivity analysis, cumulative meta-analysis, assessment of publication bias, meta-regression meta, False-positive report probability (FPRP), Bayesian false discovery probability (BFDP), and Venice criterion. Results: Overall, harboring the variant of MTHFR C677T was associated with an increased risk of EH in the overall populations, East Asians, Southeast Asians, South Asians, Caucasians/Europeans, and Africans. After the sensitivity analysis, positive results were found only in the overall population (TT vs. CC: OR = 1.14, 95% CI: 1.00–1.30, Ph = 0.032, I2 = 39.8%; TT + TC vs. CC: OR = 1.15, 95% CI: 1.01–1.29, Ph = 0.040, I2 = 38.1%; T vs. C: OR = 1.14, 95% CI: 1.04–1.25, Ph = 0.005, I2 = 50.2%) and Asian population (TC vs. CC: OR = 1.14, 95% CI: 1.01–1.28, Ph = 0.265, I2 = 16.8%; TT + TC vs. CC: OR = 1.17, 95% CI: 1.04–1.30, Ph = 0.105, I2 = 32.9%; T vs. C: OR = 1.10, 95% CI: 1.02–1.19, Ph = 0.018, I2 = 48.6%). However, after further statistical assessment by FPRP, BFDP, and Venice criteria, the positive associations reported here could be deemed to be false-positives and present only weak evidence for a causal relationship. In addition, when we performed pooled analysis and sensitivity analysis on MTHFR A1298C; all the results were negative. Conclusion: The positive relationships between MTHFR C677T and A1298C polymorphisms with the susceptibility to present with hypertension were not robust enough to withstand statistical interrogation by FPRP, BFDP, and Venice criteria. Therefore, these SNPs are probably not important in EH etiology.

Interaction between Polymorphisms MTHFR C677T and MTRR A66G and Vitamin Levels in Pregnant Women.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3687-3687
Author(s):  
Elvira M. Guerra-Shinohara ◽  
Patricia R. Barbosa ◽  
Luiz F. Sampaio-Neto ◽  
Rosario D. Hirata ◽  
Mario H. Hirata ◽  
...  
Keyword(s):  
High Risk ◽  
Pregnant Women ◽  
Mthfr C677t ◽  
Serum Levels ◽  
Serum Folate ◽  
P Value ◽  
Methionine Synthase Reductase ◽  
Mtrr A66g ◽  
Increased Risk ◽  
677T Allele

Abstract In the homocysteine metabolic pathway, several key enzymes, including methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR), have been implicated in abnormal homocysteine accumulation in the presence of rare alleles. In previous study, we showed that lower maternal Cbl levels were associated with higher tHcy and lower S-adenosylmethionine/S-adenosylhomocysteine ratio in pregnant women and their neonates.The aim of this study is to investigate whether MTHFR and MTRR polymorphisms are involved in the risk for elevated total homocysteine (tHcy) and its interaction with low cobalamin (Cbl) or serum folate (SF) levels. Genotypes for polymorphisms MTHFR C677T and MTRR A66G were determined by PCR-FLRP. The serum levels of Cbl, SF and tHcy were determined in 377 pregnant women (37–42 weeks of gestational age), and cutoff values for Cbl and SF were considered the first quartile (low values). Four models of univariate logistic regression analyses were used (Table 1). Pregnant women with MTHFR 677T allele have high risk for elevated tHcy that is increased when 677T allele is associated with low Cbl. Increased risk for elevated tHcy is also met when MTRR 66G allele and low Cbl levels were associated. Women with low SF and common MTHFR and MTRR alleles have high risk for elevated tHcy, that is increased when in association with 677T allele or with 66G allele. Interaction between MTHFR C677T and MTRR A66G polymorphisms and vitamins levels in pregnant women Dependent variables Comparation levels (N) P value Odd Ratios 95% CI P for trend: (a) P<0.001; (b) P<0.001; (c) P=0.067; (d) P<0.001 tHcy>8.3μmol/L MTHFR 677CC genotype and Cbl> 115.8 pmol/L (ref) (136) a 1.00 MTHFR 677CC genotype and≤Cbl 115.8 pmol/L (45) 0.298 1.57 0.67 – 3.63 MTHFR 677CT and 677TT genotypes and Cbl>115.8 pmol/L (145) 0.015 2.09 1.16 – 3.77 MTHFR 677CT and 677TT genotypes and≤Cbl 115.8 pmol/L (48) 0.001 4.63 2.22 – 9.65 tHcy>8.3μmol/L MTHFR 677CC genotype and SF > 10.9 nmol/L (ref) (148) b 1.00 MTHFR 677CC genotype and≤SF 10.9 nmol/L (33) 0.008 3.20 1.35 – 7.59 MTHFR 677CT and 677TT genotypes and SF > 10.9 nmol/L (133) 0.035 1.95 1.05 – 3.61 MTHFR 677CT and 677TT genotypes and≤SF 10.9 nmol/L (59) 0.001 6.62 3.31 – 13.26 tHcy>8.3μmol/L MTRR 66AA genotype and Cbl> 115.8 pmol/L (ref) (96) c 1.00 MTRR 66AA genotype and ≤Cbl 115.8 pmol/L (23) 0.222 1.90 0.68 – 5.29 MTRR 66AG and 66GG genotypes and Cbl>115.8 pmol/L (183) 0.418 1.29 0.70 – 2.39 MTRR 66AG and 66GG genotypes and ≤Cbl 115.8 pmol/L (69) 0.013 2.46 1.21 – 5.01 tHcy>8.3μmol/L MTRR 66AA genotype and SF > 10.9 nmol/L (ref) (92) d 1.00 MTRR 66AA genotype and ≤SF 10.9 nmol/L (27) 0.006 3.83 1.47 – 9.96 MTRR 66AG and 66GG genotypes and SF > 10.9 nmol/L (186) 0.399 1.34 0.68 – 2.63 MTRR 66AG and 66GG genotypes and≤SF 10.9 nmol/L (65) 0.001 4.78 2.26 – 10.10 In conclusion, the interaction between MTHFR and MTRR polymorphisms and low folate and cobalamin serum levels may explain the increased risk for elevated tHcy found in pregnant women.

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