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1.  The Polymorphisms in Methylenetetrahydrofolate Reductase, Methionine Synthase, Methionine Synthase Reductase, and the Risk of Colorectal Cancer 
Polymorphisms in genes involved in folate metabolism may modulate the risk of colorectal cancer (CRC), but data from published studies are conflicting. The current meta-analysis was performed to address a more accurate estimation. A total of 41 (17,552 cases and 26,238 controls), 24(8,263 cases and 12,033 controls), 12(3,758 cases and 5,646 controls), and 13 (5,511 cases and 7,265 controls) studies were finally included for the association between methylenetetrahydrofolate reductase (MTHFR) C677T and A1289C, methione synthase reductase (MTRR) A66G, methionine synthase (MTR) A2756G polymorphisms and the risk of CRC, respectively. The data showed that the MTHFR 677T allele was significantly associated with reduced risk of CRC (OR = 0.93, 95%CI 0.90-0.96), while the MTRR 66G allele was significantly associated with increased risk of CRC (OR = 1.11, 95%CI 1.01-1.18). Sub-group analysis by ethnicity revealed that MTHFR C677T polymorphism was significantly associated with reduced risk of CRC in Asians (OR = 0.80, 95%CI 0.72-0.89) and Caucasians (OR = 0.84, 95%CI 0.76-0.93) in recessive genetic model, while the MTRR 66GG genotype was found to significantly increase the risk of CRC in Caucasians (GG vs. AA: OR = 1.18, 95%CI 1.03-1.36). No significant association was found between MTHFR A1298C and MTR A2756G polymorphisms and the risk of CRC. Cumulative meta-analysis showed no particular time trend existed in the summary estimate. Probability of publication bias was low across all comparisons illustrated by the funnel plots and Egger's test. Collectively, this meta-analysis suggested that MTHFR 677T allele might provide protection against CRC in worldwide populations, while MTRR 66G allele might increase the risk of CRC in Caucasians. Since potential confounders could not be ruled out completely, further studies were needed to confirm these results.
doi:10.7150/ijbs.4462
PMCID: PMC3372886  PMID: 22719222
Colorectal cancer; Methylenetetrahydrofolate reductase; Methione synthase reductase; Methionine synthase; Folate.
2.  Association between 5, 10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms and congenital heart disease: A meta-analysis☆ 
Meta Gene  2013;1:109-125.
Background
Inconsistent results were reported in recent literature regarding the association between methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphisms and the susceptibility of congenital heart disease (CHD). In this study, we performed a meta-analysis to investigate the associations by employing multiple analytical methods.
Methods
Literature search was performed and published articles were obtained from PubMed, Embase and CNKI databases based on the exclusion and inclusion criteria. Data were extracted from eligible studies and the crude odds ratios and their corresponding 95% confidence intervals (CIs) were calculated using random or fix effects model to evaluate the associations between the MTHFR C677T/A1298C polymorphisms and CHD development. Subgroup based analysis was performed by Hardy–Weinberg equilibrium, ethnicity, types of CHD, source of control and sample size.
Results
Twenty-four eligible studies were included in this meta-analysis. Significant association was found between fetal MTHFR C677T polymorphism and CHD development in all genetic models. The pooled ORs and 95% CIs in all genetic models indicated that MTHFR C677T polymorphism was significantly associated with CHD in Asian, but not Caucasian in subgroup analysis. The maternal MTHFR C677T polymorphism was not associated with CHD except for recessive model. Moreover, neither maternal nor fetal MTHFR A1298C polymorphism was associated with CHD.
Conclusion
The fetal MTHFR C677T polymorphism may increase the susceptibility to CHD. Fetal MTHFR C677T polymorphism was more likely to affect Asian fetus than Caucasian. The MTHFR A1298C polymorphism may not be a risk of congenital heart disease.
doi:10.1016/j.mgene.2013.09.009
PMCID: PMC4205024  PMID: 25606381
Congenital heart disease; MTHFR; Polymorphism; Association; Meta-analysis; Folic acid
3.  Association between MTHFR Polymorphisms and Acute Myeloid Leukemia Risk: A Meta-Analysis 
PLoS ONE  2014;9(2):e88823.
Previous observational studies investigating the association between methylenetetrahydrofolate reductase (MTHFR) polymorphisms and acute myeloid leukemia risk (AML) have yielded inconsistent results. The aim of this study is to derive a more precise estimation of the association between MTHFR (C677T and A1298C) polymorphisms and acute myeloid leukemia risk. PubMed and Embase databases were systematically searched to identify relevant studies from their inception to August 2013. Odds ratios (ORs) with 95% confidence intervals (CIs) were the metric of choice. Thirteen studies were selected for C677T polymorphism (1838 cases and 5318 controls) and 9 studies (1335 patients and 4295 controls) for A1298C polymorphism. Overall, pooled results showed that C677T polymorphism was not significant associated with AML risk(OR, 0.98–1.04; 95% CI, 0.86–0.92 to 1.09–1.25). Similar results were observed for the A1298C polymorphism and in subgroup analysis. All comparisons revealed no substantial heterogeneity nor did we detect evidence of publication bias. In summary, this meta-analysis provides evidence that MTHFR polymorphisms were not associated with AML risk. Further investigations are needed to offer better insight into the role of these polymorphisms in AML carcinogenesis.
doi:10.1371/journal.pone.0088823
PMCID: PMC3930602  PMID: 24586405
4.  The Association between MTHFR Gene Polymorphisms and Hepatocellular Carcinoma Risk: A Meta-Analysis 
PLoS ONE  2013;8(2):e56070.
Background
The association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and hepatocellular carcinoma (HCC) risk was inconsistent and underpowered. To clarify the effects of MTHFR gene polymorphisms on the risk of HCC, a meta-analysis of all available studies relating C677T and/or A1298C polymorphisms of MTHFR gene to the risk of HCC was conducted.
Methods
The authors searched PubMed, EMBASE, Cochrane Library, Web of Science, and Chinese Biomedical Literature database (CBM) for the period up to July 2012. Data were extracted by two independent authors and pooled odds ratio (OR) with 95% confidence interval (CI) was calculated. Metaregression and subgroup analyses were performed to identify the source of heterogeneity.
Results
Finally, 12 studies with 2,351 cases and 4,091 controls were included for C677T polymorphism and 6 studies with 1,333 cases and 1,878 controls were included for A1298C polymorphism. With respect to A1298C polymorphism, significantly decreased HCC risk was found in the overall population (CC vs. AA: OR = 0.660, 95%CI 0.460–0.946, P = 0.024; recessive model: OR = 0.667, 95%CI = 0.470–0.948, P = 0.024). In subgroup analyses, significantly decreased HCC risk was found in Asian population (CC vs. AA: OR = 0.647, 95%CI = 0.435–0.963; P = 0.032) and population-based studies (CC vs. AA: OR = 0.519, 95%CI = 0.327–0.823; P = 0.005). With respect to C677T polymorphism, no significant association with HCC risk was demonstrated in overall and stratified analyses.
Conclusions
We concluded that MTHFR A1298C polymorphism may play a protective role in the carcinogenesis of HCC. Further large and well-designed studies are needed to confirm this association.
doi:10.1371/journal.pone.0056070
PMCID: PMC3573065  PMID: 23457501
5.  Methylenetetrahydrofolate Reductase C677T Polymorphism and Type 2 Diabetes Mellitus in Chinese Population: A Meta-Analysis of 29 Case-Control Studies 
PLoS ONE  2014;9(7):e102443.
Background
Methylenetetrahydrofolate reductase (MTHFR), a key enzyme in folate metabolism, had significant effects on the homocysteine levels. The common functional MTHFR C677T polymorphism had been extensively researched. Several studies had evaluated the relationship between MTHFR C677T polymorphism and type 2 diabetes mellitus (T2DM), but the results were still controversial in the Chinese Han population. This meta-analysis was conducted to evaluate the relationship between MTHFR C677T polymorphism and T2DM in the Chinese Han population.
Methods
We searched the relevant studies in multiple electronic databases, which published up to December 2013. We reviewed and extracted data from all the included studies on the relationship between MTHFR C677T polymorphism and T2DM in the Chinese Han population. The odds ratios (ORs) and their 95% confidence intervals (95%CIs) were used to evaluate the relationship. Fixed-effects and random-effects meta-analysis were used to pool ORs by the heterogeneity. Publication bias and sensitivity analysis were also examined.
Results
29 studies were finally included in our meta-analysis, which contained 4656 individuals with T2DM and 2127 healthy controls. There was a significant relationship between MTHFR C677T polymorphism and T2DM under dominant (OR: 1.70, 95% CI: 1.42–2.02), recessive (OR: 1.48, 95% CI: 1.21–1.80), homozygous (OR: 1.89, 95% CI: 1.47–2.42), heterozygous (OR: 1.58, 95% CI: 1.33–1.87), and additive (OR: 1.46, 95% CI: 1.28–1.68) genetic model in a random-effects model. Subgroup analysis also reached similar results. Sensitivity analysis indicated that the overall result were dependable.
Conclusions
There was a significant relationship between MTHFR C677T polymorphism and T2DM in the Chinese Han population. The results of our meta-analysis suggested that MTHFR 677T allele might be a risk genetic factor of T2DM in the Chinese Han population.
doi:10.1371/journal.pone.0102443
PMCID: PMC4105552  PMID: 25047451
6.  Association Between MTHFR Polymorphisms and Congenital Heart Disease: A Meta-analysis based on 9,329 cases and 15,076 controls 
Scientific Reports  2014;4:7311.
The aim of our study was to evaluate the association between polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene and the risk for congenital heart disease (CHD). Electronic literature databases were searched to identify eligible studies published before Jun, 2014. The association was assessed by the odds ratio (OR) with a 95% confidence interval (CI). The publication bias was explored using Begg's test. Sensitivity analysis was performed to evaluate the stability of the crude results. A total of 35 studies were included in this meta-analysis. For the MTHFR C677T polymorphism, we detected significant association in all genetic models for Asian children and the maternal population. Significant association was also detected in T vs. C for a Caucasian paediatric population (OR = 1.163, 95% CI: 1.008–1.342) and in both T vs. C (OR = 1.125, 95% CI: 1.043–1.214) and the dominant model (OR = 1.216, 95% CI:b1.096–1.348) for a Caucasian maternal population. For the MTHFR A1298C polymorphism, the association was detected in CC vs. AC for the Caucasian paediatric population (OR = 1.484, 95% CI: 1.035–2.128). Our results support the MTHFR -677T allele as a susceptibility factor for CHD in the Asian maternal population and the -1298C allele as a risk factor in the Caucasian paediatric population.
doi:10.1038/srep07311
PMCID: PMC4255188  PMID: 25472587
7.  Homocysteine and Coronary Heart Disease: Meta-analysis of MTHFR Case-Control Studies, Avoiding Publication Bias 
PLoS Medicine  2012;9(2):e1001177.
Robert Clarke and colleagues conduct a meta-analysis of unpublished datasets to examine the causal relationship between elevation of homocysteine levels in the blood and the risk of coronary heart disease. Their data suggest that an increase in homocysteine levels is not likely to result in an increase in risk of coronary heart disease.
Background
Moderately elevated blood levels of homocysteine are weakly correlated with coronary heart disease (CHD) risk, but causality remains uncertain. When folate levels are low, the TT genotype of the common C677T polymorphism (rs1801133) of the methylene tetrahydrofolate reductase gene (MTHFR) appreciably increases homocysteine levels, so “Mendelian randomization” studies using this variant as an instrumental variable could help test causality.
Methods and Findings
Nineteen unpublished datasets were obtained (total 48,175 CHD cases and 67,961 controls) in which multiple genetic variants had been measured, including MTHFR C677T. These datasets did not include measurements of blood homocysteine, but homocysteine levels would be expected to be about 20% higher with TT than with CC genotype in the populations studied. In meta-analyses of these unpublished datasets, the case-control CHD odds ratio (OR) and 95% CI comparing TT versus CC homozygotes was 1.02 (0.98–1.07; p = 0.28) overall, and 1.01 (0.95–1.07) in unsupplemented low-folate populations. By contrast, in a slightly updated meta-analysis of the 86 published studies (28,617 CHD cases and 41,857 controls), the OR was 1.15 (1.09–1.21), significantly discrepant (p = 0.001) with the OR in the unpublished datasets. Within the meta-analysis of published studies, the OR was 1.12 (1.04–1.21) in the 14 larger studies (those with variance of log OR<0.05; total 13,119 cases) and 1.18 (1.09–1.28) in the 72 smaller ones (total 15,498 cases).
Conclusions
The CI for the overall result from large unpublished datasets shows lifelong moderate homocysteine elevation has little or no effect on CHD. The discrepant overall result from previously published studies reflects publication bias or methodological problems.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Coronary heart disease (CHD) is the leading cause of death among adults in developed countries. With age, fatty deposits (atherosclerotic plaques) coat the walls of the coronary arteries, the blood vessels that supply the heart with oxygen and nutrients. The resultant restriction of the heart's blood supply causes shortness of breath, angina (chest pains that are usually relieved by rest), and sometimes fatal heart attacks. Many established risk factors for CHD, including smoking, physical inactivity, being overweight, and eating a fat-rich diet, can be modified by lifestyle changes. Another possible modifiable risk factor for CHD is a high blood level of the amino acid homocysteine. Methylene tetrahydofolate reductase, which is encoded by the MTHFR gene, uses folate to break down and remove homocysteine so fortification of cereals with folate can reduce population homocysteine blood levels. Pooled results from prospective observational studies that have looked for an association between homocysteine levels and later development of CHD suggest that the reduction in homocysteine levels that can be achieved by folate supplementation is associated with an 11% lower CHD risk.
Why Was This Study Done?
Prospective observational studies cannot prove that high homocysteine levels cause CHD because of confounding, the potential presence of other unknown shared characteristics that really cause CHD. However, an approach called “Mendelian randomization” can test whether high blood homocysteine causes CHD. A common genetic variant of the MTHFR gene—the C677T polymorphism—reduces MTHFR efficiency so TT homozygotes (individuals in whom both copies of the MTHFR gene have the nucleotide thymine at position 677; the human genome contains two copies of most genes) have 25% higher blood homocysteine levels than CC homozygotes. In meta-analyses (statistical pooling of the results of several studies) of published Mendelian randomized studies, TT homozygotes have a higher CHD risk than CC homozygotes. Because gene variants are inherited randomly, they are not subject to confounding, so this result suggests that high blood homocysteine causes CHD. But what if only Mendelian randomization studies that found an association have been published? Such publication bias would affect this aggregate result. Here, the researchers investigate the association of the MTHFR C677T polymorphism with CHD in unpublished datasets that have analyzed this polymorphism incidentally during other genetic studies.
What Did the Researchers Do and Find?
The researchers obtained 19 unpublished datasets that contained data on the MTHFR C677T polymorphism in thousands of people with and without CHD. Meta-analysis of these datasets indicates that the excess CHD risk in TT homozygotes compared to CC homozygotes was 2% (much lower than predicted from the prospective observational studies), a nonsignificant difference (that is, it could have occurred by chance). When the probable folate status of the study populations (based on when national folic acid fortification legislation came into effect) was taken into account, there was still no evidence that TT homozygotes had an excess CHD risk. By contrast, in an updated meta-analysis of 86 published studies of the association of the polymorphism with CHD, the excess CHD risk in TT homozygotes compared to CC homozygotes was 15%. Finally, in a meta-analysis of randomized trials on the use of vitamin B supplements for homocysteine reduction, folate supplementation had no significant effect on the 5-year incidence of CHD.
What Do These Findings Mean?
These analyses of unpublished datasets are consistent with lifelong moderate elevation of homocysteine levels having no significant effect on CHD risk. In other words, these findings indicate that circulating homocysteine levels within the normal range are not causally related to CHD risk. The meta-analysis of the randomized trials of folate supplementation also supports this conclusion. So why is there a discrepancy between these findings and those of meta-analyses of published Mendelian randomization studies? The discrepancy is too large to be dismissed as a chance finding, suggest the researchers, but could be the result of publication bias—some studies might have been prioritized for publication because of the positive nature of their results whereas the unpublished datasets used in this study would not have been affected by any failure to publish null results. Overall, these findings reveal a serious example of publication bias and argue against the use of folate supplements as a means of reducing CHD risk.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001177.
The American Heart Association provides information about CHD and tips on keeping the heart healthy; it also provides information on homocysteine, folic acid, and CHD, general information on supplements and heart health, and personal stories about CHD
The UK National Health Service Choices website provides information about CHD, including personal stories about CHD
Information is available from the British Heart Foundation on heart disease and keeping the heart healthy
The US National Heart Lung and Blood Institute also provides information on CHD (in English and Spanish)
MedlinePlus provides links to many other sources of information on CHD (in English and Spanish)
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001177
PMCID: PMC3283559  PMID: 22363213
8.  Associations of MTHFR Gene Polymorphisms with Hypertension and Hypertension in Pregnancy: A Meta-Analysis from 114 Studies with 15411 Cases and 21970 Controls 
PLoS ONE  2014;9(2):e87497.
Background
Several epidemiological studies have investigated the associations of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms with hypertension (H) or hypertension in pregnancy (HIP). However, the results were controversial. We therefore performed a comprehensive meta-analysis to provide empirical evidences on the associations.
Methodologies
The English and Chinese databases were systematically searched to identify relevant studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the associations. Meta-regression, subgroup analysis, sensitivity analysis, cumulative meta-analysis and assessment of publication bias were performed in our study.
Principal Findings
A total of 114 studies with 15411 cases and 21970 controls were included, 111 studies with 15094 cases and 21633 controls for the C677T polymorphism and 21 with 2533 cases and 2976 controls for the A1298C polymorphism. Overall, the C677T polymorphism was significantly associated with H and HIP (H & HIP: OR = 1.26, 95% CI = 1.17–1.34; H: OR = 1.36, 95% CI = 1.20–1.53; HIP: OR = 1.21, 95% CI = 1.08–1.32). Stratified analysis by ethnicity revealed a significant association among East Asians and Caucasians, but not among Latinos, Black Africans, and Indians and Sri Lankans. In the stratified analyses according to source of controls, genotyping method, sample size and study quality, significant associations were observed in all the subgroups, with the exception of population based subgroup in H studies and large sample size and “others” genotyping method subgroups in HIP studies. For the A1298C polymorphism, no significant association was observed either in overall or subgroup analysis under all genetic models.
Conclusions
This meta-analysis suggests that the MTHFR C677T rather than A1298C polymorphism may be associated with H & HIP, especially among East Asians and Caucasians.
doi:10.1371/journal.pone.0087497
PMCID: PMC3914818  PMID: 24505291
9.  Association of the Maternal MTHFR C677T Polymorphism with Susceptibility to Neural Tube Defects in Offsprings: Evidence from 25 Case-Control Studies 
PLoS ONE  2012;7(10):e41689.
Background
Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in folate metabolism and is involved in DNA methylation, DNA synthesis, and DNA repair. In addition, it is a possible risk factor in neural tube defects (NTDs). The association of the C677T polymorphism in the MTHFR gene and NTD susceptibility has been widely demonstrated, but the results remain inconclusive. In this study, we performed a meta-analysis with 2429 cases and 3570 controls to investigate the effect of the MTHFR C677T polymorphism on NTDs.
Methods
An electronic search of PubMed and Embase database for papers on the MTHFR C677T polymorphism and NTD risk was performed. All data were analysed with STATA (version 11). Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association. Sensitivity analysis, test of heterogeneity, cumulative meta-analysis, and assessment of bias were performed in our meta-analysis.
Results
A significant association between the MTHFR C677T polymorphism and NTD susceptibility was revealed in our meta-analysis ( TT versus CC: OR  = 2.022, 95% CI: 1.508, 2.712; CT+TT versus CC: OR  = 1.303, 95% CI: 1.089, 1.558; TT versus CC+CT: OR  = 1.716, 95% CI: 1.448, 2.033; 2TT+CT versus 2CC+CT: OR  = 1.330, 95% CI: 1.160, 1.525). Moreover, an increased NTD risk was found after stratification of the MTHFR C677T variant data by ethnicity and source of controls.
Conclusion
The results suggested the maternal MTHFR C677T polymorphism is a genetic risk factor for NTDs. Further functional studies to investigate folate-related gene polymorphisms, periconceptional multivitamin supplements, complex interactions, and the development of NTDs are warranted.
doi:10.1371/journal.pone.0041689
PMCID: PMC3463537  PMID: 23056169
10.  Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and susceptibility to pediatric acute lymphoblastic leukemia in a German study population 
BMC Medical Genetics  2005;6:23.
Background
Methylenetetrahydrofolate reductase (MTHFR) has a major impact on the regulation of the folic acid pathway due to conversion of 5,10-methylenetetrahydrofolate (methylene-THF) to 5-methyl-THF. Two common polymorphisms (677C>T and 1298A>C) in the gene coding for MTHFR have been shown to reduce MTHFR enzyme activity and were associated with the susceptibility to different disorders, including vascular disease, neural tube defects and lymphoid malignancies. Studies on the role of these polymorphisms in the susceptibility to acute lymphoblastic leukemia (ALL) led to discrepant results.
Methods
We retrospectively evaluated the association of the MTHFR 677C>T and 1298A>C polymorphisms with pediatric ALL by genotyping a study sample of 443 ALL patients consecutively enrolled onto the German multicenter trial ALL-BFM 2000 and 379 healthy controls. We calculated odds ratios of MTHFR genotypes based on the MTHFR 677C>T and 1298A>C polymorphisms to examine if one or both of these polymorphisms are associated with pediatric ALL.
Results
No significant associations between specific MTHFR variants or combinations of variants and risk of ALL were observed neither in the total patient group nor in analyses stratified by gender, age at diagnosis, DNA index, immunophenotype, or TEL/AML1 rearrangement.
Conclusion
Our findings suggest that the MTHFR 677C>T and 1298A>C gene variants do not have a major influence on the susceptibility to pediatric ALL in the German population.
doi:10.1186/1471-2350-6-23
PMCID: PMC1164414  PMID: 15921520
11.  Folate Pathway Polymorphisms Predict Deficits in Attention and Processing Speed after Childhood Leukemia Therapy 
Pediatric blood & cancer  2011;57(3):454-460.
Background
Neurocognitive impairment occurs in 20%-40% of childhood acute lymphoblastic leukemia (ALL) survivors, possibly mediated by folate depletion and homocysteine elevation following methotrexate treatment. We evaluated the relationship between folate pathway polymorphisms and neurocognitive impairment after childhood ALL chemotherapy.
Procedure
Seventy-two childhood ALL survivors treated with chemotherapy alone underwent a neurocognitive battery consisting of: Trail Making Tests A (TMTA) and B (TMTB), Grooved Pegboard Test Dominant-Hand and Nondominant-Hand, Digit Span subtest, and Verbal Fluency Test. We performed genotyping for: 10-methylenetetrahydrofolate reductase (MTHFR 677C>T and MTHFR 1298A>C), serine hydroxymethyltransferase (SHMT 1420C>T), methionine synthase (MS 2756 A>G), methionine synthase reductase (MTRR 66A>G), and thymidylate synthase (TSER). Student's two sample t-test and analysis of covariance were used to compare test scores by genotype.
Results
General impairment on the neurocognitive battery was related to MTHFR 1298A>C (p=0.03) and MS 2756A>G (p=0.05). Specifically, survivors with MTHFR 1298AC/CC genotypes scored, on average, 13 points lower on TMTB than those with MTHFR 1298AA genotype (p=0.001). The MS 2756AA genotype was associated with a 12.2 point lower mean TMTA score, compared to MS 2756 AG/GG genotypes (p=0.01). The TSER 2R/3R and 3R/3R genotypes were associated with an 11.4 point lower mean score on TMTB, compared to the TSER 2R/2R genotype (p=0.03). Survivors with >6 folate pathway risk alleles demonstrated a 9.5 point lower mean TMTA score (p=0.06) and 14.5 point lower TMTB score (p=0.002) than survivors with <6 risk alleles.
Conclusions
Folate pathway polymorphisms are associated with deficits in attention and processing speed after childhood ALL therapy.
doi:10.1002/pbc.23162
PMCID: PMC3134130  PMID: 21618410
folate; leukemia; neurocognitive; survivor
12.  Functional Inference of Methylenetetrahydrofolate Reductase Gene Polymorphisms on Enzyme Stability as a Potential Risk Factor for Down Syndrome in Croatia 
Disease markers  2010;28(5):293-298.
Understanding the biochemical structure and function of the methylenetetrahydrofolate reductase gene (MTHFR) provides new evidence in elucidating the risk of having a child with Down syndrome (DS) in association with two common MTHFR polymorphisms, C677T and A1298C. The aim of this study was to evaluate the risk for DS according to the presence of MTHFR C677T and A1298C polymorphisms as well as the stability of the enzyme configuration. This study included mothers from Croatia with a liveborn DS child (n = 102) or DS pregnancy (n = 9) and mothers with a healthy child (n = 141). MTHFR C677T and A1298C polymorphisms were assessed by PCR-RFLP. Allele/genotype frequencies differences were determined using χ2 test. Odds ratio and the 95% confidence intervals were calculated to evaluate the effects of different alleles/genotypes. No statistically significant differences were found between the frequencies of allele/genotype or genotype combinations of the MTHFR C677T and A1298C polymorphisms in the case and the control groups. Additionally, the observed frequencies of the stable (677CC/1298AA, 677CC/1298AC, 677CC/1298CC) and unstable (677CT/1298AA, 677CT/1298AC, 677TT/1298AA) enzyme configurations were not significantly different. We found no evidence to support the possibility that MTHFR polymorphisms and the stability of the enzyme configurations were associated with risk of having a child with DS in Croatian population.
doi:10.3233/DMA-2010-0704
PMCID: PMC3833613  PMID: 20592453
Down syndrome; enzyme configuration; MTHFR; polymorphisms
13.  Risk association of meningiomas with MTHFR C677T and GSTs polymorphisms: a meta-analysis 
Previous studies have shown that the single nucleotide polymorphisms (SNPs) in Methylenetetrahydrofolate reductase (MTHFR) and Glutathione S-transferases (GSTs, including GSTM1, GSTT1) genes play an important role in determining the response of an individual to environmental pathogenesis and significantly relate to incidences of various human tumors, including brain tumors. However, these genes’ polymorphisms on meningioma risk remains poorly understood. The relevant inferences from previous studies are hindered by their limited statistical power and conflicting results. The aim of this meta-analysis is to provide a relatively comprehensive account of the association between these polymorphisms and human meningioma risk. A literature search for eligible studies published before January 1, 2014 was conducted in PubMed, Embase, Web of Science, Cochrane Library, and CNKI databases. Pooled odds ratios (OR) with their corresponding 95% confidence intervals (95% CI) were used to evaluate the strength of the association under a fixed or random effect model according to heterogeneity test results. Heterogeneity and publication bias were evaluated. All statistical analyses were conducted by using the software of STATA 12.0 (STATA Corporation, College Station, TX, USA). For MTHFR C677T (dbSNP: rs1801133) (C T) polymorphism, 9 individual case-control studies from six publications with 1,615 cases and 1,909 controls were obtained. For GSTM1 null polymorphism, there were 4 studies with 417 cases and 1,735 controls. For GSTT1 null polymorphism, there were 4 studies with 405 cases and 1,622 controls. The combined results for the MTHFR C677T show that carriers of the CT genotype may be associated with a higher meningioma risk (OR = 1.20, 95% CI 1.05-1.38, P = 0.009). Stratified analyses show that Caucasians have significantly higher risk if they carry the CT genotype of MTHFR (OR = 1.31, 95% CI 1.05-1.63, P = 0.02). Risk of Caucasians carrying TT + CT genotype is also significantly higher (OR = 1.27, 95% CI 1.02-1.58, P = 0.03). Risk of Caucasians carrying TT genotype is not significantly different compared to control population (OR = 0.96, 95% CI 0.69-1.34, P = 0.82). All of the enrolled studies about GSTM1/GSTT1 are on Caucasians. The pooled ORGSTM1 and ORGSTT1 were not significant in Caucasian population. These results indicate SNPs of MTHFR C677T are related to meningioma risk with ethnic differences. Caucasians carrying CT genotype of MTHFR C677T have significantly higher meningioma susceptibility. SNPs of GSTM1/GSTT1 are not related to meningioma risk.
PMCID: PMC4276156  PMID: 25550898
MTHFR; GSTM1; GSTT1; meningioma; gene polymorphism; meta-analysis
14.  Association of 677 C>T (rs1801133) and 1298 A>C (rs1801131) Polymorphisms in the MTHFR Gene and Breast Cancer Susceptibility: A Meta-Analysis Based on 57 Individual Studies 
PLoS ONE  2014;9(6):e71290.
Objective
The 677 C>T and 1298 A>C polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene have been widely reported and considered to have a significant effect on breast cancer risk, but the results are inconsistent. A meta-analysis based on 57 eligible studies was carried out to clarify the role of MTHFR gene polymorphisms in breast cancer.
Methods and Results
Eligible articles were identified by searching databases including PubMed, Web of Science, EMBASE, CNKI and CBM for the period up to August 2012. Finally, a total of 57 studies were included in this meta-analysis. Crude ORs with 95% CIs were used to assess the association between the MTHFR polymorphisms and breast cancer risk. The pooled ORs were performed with additive model, dominant model and recessive model, respectively. Subgroup analysis was also performed by ethnicity. The statistical heterogeneity across studies was examined with χ2-based Q-test. A meta-analysis was performed using the Stata 12.0 software. Overall, the 677 C allele was significantly associated with breast cancer risk (OR = 0.942, 95%CI = 0.898 to 0.988) when compared with the 677 T allele in the additive model, and the same results were also revealed under other genetic models. Simultaneously, the 1298 A allele was not associated with the breast cancer susceptibility when compared with the 1298 C allele (OR = 0.993, 95%CI = 0.978 to 1.009). Furthermore, analyses under the dominant, recessive and the allele contrast model yielded similar results.
Conclusions
The results of this meta-analysis suggest that 677 C>T polymorphism in the MTHFR gene may contribute to breast cancer development. However, the 1298 A>C polymorphism is not significantly associated with increased risks of breast cancer.
doi:10.1371/journal.pone.0071290
PMCID: PMC4063741  PMID: 24945727
15.  Meta-analysis on MTHFR polymorphism and lung cancer susceptibility in East Asian populations 
Biomedical Reports  2013;1(3):440-446.
Lung cancer is the most frequently occurring type of cancer worldwide and the leading cause of cancer mortality. Environmental and genetic factors play important roles in lung carcinogenesis. The aim of this meta-analysis was to investigate the association between methylenetetrahydrofolate reductase (MTHFR) polymorphism and the risk of lung cancer in East Asian populations. Related articles were identified through searching literature databases, such as PubMed, EMBASE, Web of Science, Chinese Biomedicine and CNKI. The odds ratio (OR) values in those studies were incorporated by meta-analysis to assess lung cancer susceptibility associated with the MTHFR mutation genotype. The MTHFR C677TT genotype exhibited a significantly increased risk of lung cancer compared to the MTHFR 677CC/CT genotype (OR=1.24; 95% CI, 1.01–1.52). No relationship was identified between the other MTHFR C677T genetic models and the risk of lung cancer and there was no significantly increased risk of lung cancer in A1298C genetic models. In a subgroup of hospital-based controls, according to the source of controls, the C677TT genotype exhibited a significantly increased risk of lung cancer, compared to the C677CC genotype (OR=3.01; 95% CI, 1.07–8.46). In the stratified analysis, the study indicated that the MTHFR 677TT genotype was associated with a significant increase in the risk of lung squamous carcinoma (OR=1.53; 95% CI, 1.09–2.14), whereas no association was observed between the MTHFR C677TT genotype and the risk of lung adenocarcinoma. No association was observed between MTHFR C677TT polymorphism and the risk of lung cancer when smoking was considered. In conclusion, the meta-analysis results suggested that MTHFR C677T polymorphisms exhibit a significantly increased risk of lung cancer and that the MTHFR 677TT genotype is associated with a significantly increased risk of lung squamous carcinoma.
doi:10.3892/br.2013.68
PMCID: PMC3917083  PMID: 24648965
lung cancer; methylenetetrahydrofolate reductase; polymorphisms; meta-analysis
16.  Methylenetetrahydrofolate Reductase (MTHFR) Polymorphisms and Susceptibility for Cervical Lesions: A Meta-Analysis 
PLoS ONE  2012;7(12):e52381.
Background
The association between the methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphisms and the susceptibility to cervical lesions was unclear. This study was designed to investigate their precise association using a large-scale meta-analysis.
Methods
The previous 16 studies were identified by searching PubMed, Embase and CBM databases. The crude odds ratios and their corresponding 95% confidence intervals (CIs) were used to estimate the association between the MTHFR C677T/A1298C polymorphisms and the susceptibility to the cervical lesions. The subgroup analyses were made on the following: pathological history, geographic region, ethnicity, source of controls and source of DNA for genotyping.
Results
Neither of the polymorphisms had a significant association with the susceptibility to the cervical lesions in all genetic models. Similar results were found in the subgroup analyses. No association was found between the MTHFR C677T polymorphism and the cervical lesions in the Asia or the America populations though a significant inverse association was found in the Europe population (additive model: P = 0.006, OR = 0.83, 95% CI = 0.72–0.95; CT vs. CC: P = 0.05, OR = 0.83, 95% CI = 0.69–1.00; TT vs. CC: P = 0.05, OR = 0.73, 95% CI = 0.53–1.00). Interestingly, women with the MTHFR A1298C polymorphisms had a marginally increased susceptibility to invasive cancer (ICC) when compared with no carriers but no statistically significant difference in the dominant model (P = 0.06, OR = 1.21, 95% CI = 0.99–1.49) and AC vs. AA (P = 0.09, OR = 1.21, 95% CI = 0.97–1.51).
Conclusions
The MTHFR C677T and A1298C polymorphisms may not increase the susceptibility to cervical lesions. However, the meta-analysis reveals a negative association between the MTHFR C677T polymorphisms and the cervical lesions, especially in the European populations. The marginal association between the MTHFR A1298C polymorphisms and the susceptibility to cervical cancer requires a further study.
doi:10.1371/journal.pone.0052381
PMCID: PMC3528671  PMID: 23285018
17.  Association of methylenetetrahydrofolate reductase C677T and A1298C polymorphisms with colorectal cancer risk: A meta-analysis 
Biomedical Reports  2013;1(5):781-791.
Colorectal cancer (CRC) is one of the most common types of cancer worldwide and a leading cause of cancer-related mortality. This meta-analysis was conducted to determine the effect of methylenetetrahydrofolate reductase (MTHFR) mutants on the risk of CRC. A literature search was conducted on PubMed, Medline and the China National Knowledge Infrastructure (CNKI) databases. Eligible studies were collected based on rigorous criteria of inclusion. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by the fixed- or random-effects model. After all the studies were pooled, the OR of CRC for individuals carrying the MTHFR 677TT genotype, compared to the CC genotype, was 0.89 (95% CI: 0.82–0.97). When analyzed by ethnicity, Asians with the MTHFR 1298CC genotype exhibited a decreased risk of CRC (OR=0.69; 95% CI: 0.54–0.89). In a mixed population, a significantly reduced risk of CRC was observed among carriers of the 677TT (OR=0.86; 95% CI: 0.76–0.96) and the 1298CC (OR=0.82; 95% CI: 0.69–0.98) genotypes, compared to the wild-type homozygous genotype. In the subgroup of colon cancer, the OR of 677TT vs. CC+CT was 0.83 (95% CI: 0.72–0.96) and the OR of 1298CC vs. AA+AC was 0.81 (95% CI: 0.69–0.96). In the rectal cancer subgroup, the OR of 677TT vs. CC+CT was 0.86 (95% CI: 0.77–0.97). Therefore, this meta-analysis suggested that the MTHFR 677T and 1298C alleles were associated with a low risk of CRC.
doi:10.3892/br.2013.134
PMCID: PMC3917732  PMID: 24649029
methylenetetrahydrofolate reductase; polymorphism; colorectal cancer; meta-analysis
18.  Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and gastric cancer susceptibility 
World Journal of Gastroenterology : WJG  2014;20(32):11429-11438.
AIM: To identify the association between methylenetetrahydrofolate reductase (MTHFR) polymorphisms and gastric cancer (GC) susceptibility.
METHODS: Systematic searches were performed on the electronic databases PubMed, ISI, Web of knowledge, CNKI and Wanfang, as well as manual searching of the references of the identified articles. A total of 26 papers were included in this meta-analysis. Overall and subgroup analyses were performed. Odds ratio (OR) and 95%CI were used to evaluate the associations between MTHFR polymorphisms and GC risk. The I2 statistics were used to evaluate between-study heterogeneity. Sensitivity analysis was also performed.
RESULTS: Increased risk was found for the MTHFR C677T polymorphism under four genetic models (TT + CT vs CC: OR = 1.23, P = 0.002; T vs C: OR = 1.15, P = 0.001; TT vs CC: OR = 1.37, P = 0.0005; TT vs CT + CC: OR = 1.17, P = 0.0008). Subgroup analysis by ethnicity suggested that C677T polymorphism conferred a risk of GC in eastern but not in western populations. Stratification by tumor site showed an association between the C677T polymorphism and gastric cardia cancer and non-cardia GC in the worldwide population and in eastern populations. Regardless of comparisons with controls or diffuse-type GC, a positive association was found for the C677T polymorphism and an increased risk of intestinal-type GC in the whole population and in western populations. With regard to the A1298C polymorphism, we found that genotype CC was significantly decreased and conferred protection against GC in eastern populations (CC vs AA: OR = 0.44, P = 0.03; CC vs AC + AA: OR = 0.46, P = 0.04).
CONCLUSION: MTHFR C677T polymorphism is a risk factor for GC, and the A1298C polymorphism may be a protective factor against GC in eastern populations.
doi:10.3748/wjg.v20.i32.11429
PMCID: PMC4145786  PMID: 25170232
Methylenetetrahydrofolate reductase; Polymorphism; Gastric cancer; Meta-analysis
19.  MTHFR Genetic Polymorphism As a Risk Factor in Egyptian Mothers with Down Syndrome Children 
Disease markers  2007;24(1):19-26.
Recent reports linking Down syndrome (DS) to maternal polymorphisms at the methylenetetrahydrofolate reductase (MTHFR) gene locus have generated great interest among investigators in the field. The present study aimed at evaluation of MTHFR 677C/T and 1298A/C polymorphisms in the MTHFR gene as maternal risk factors for DS. Forty two mothers of proven DS outcomes and forty eight control mothers with normal offspring were included. Complete medical and nutritional histories for all mothers were taken with special emphasis on folate intake. Folic acid intake from food or vitamin supplements was significantly low (below the Recommended Daily Allowance) in the group of case mothers compared to control mothers. Frequencies of MTHFR 677T and MTHFR 1298C alleles were significantly higher among case mothers (32.1% and 57.1%, respectively) compared to control mothers (18.7% and 32.3%, respectively). Heterozygous and homozygous genotype frequencies of MTHFR at position 677 (CT and TT) were higher among case mothers than controls (40.5% versus 25% and 11.9% versus 6.2%, respectively) with an odds ratio of 2.34 (95% confidence interval [CI] 0.93–5.89) and 2.75 (95% CI 0.95–12.77), respectively. Interestingly, the homozygous genotype frequency (CC) at position 1298 was significantly higher in case mothers than in controls (33.3% versus 2.1% respectively) with an odds ratio of 31.5 (95% CI 3.51 to 282.33) indicating that this polymorphism may have more genetic impact than 677 polymorphism. Heterozygous genotype (AC) did not show significant difference between the two groups. We here report on the first pilot study of the possible genetic association between DS and MTHFR 1298A/C genotypes among Egyptians. Further extended studies are recommended to confirm the present work.
doi:10.1155/2008/214027
PMCID: PMC3850629  PMID: 18057532
Methylenetetrahydrofolate reductase (MTHFR); Down syndrome; polymorphism; MTHFR 677C/T polymorphism; MTHFR 1298A/C polymorphism; Egyptian
20.  No Association of Functional Polymorphisms in Methlylenetetrahydrofolate Reductase and the Risk and Minor Physical Anomalies of Schizophrenia in Korean Population 
Journal of Korean Medical Science  2011;26(10):1356-1363.
Methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in folate metabolism, plays an important role in DNA methylation. It has been suggested that abnormal DNA methylation contributes to the pathogenesis of schizophrenia and congenital anomalies. The previous findings regarding the genetic relationship between MTHFR and schizophrenia are controversial. This study investigated the association of the two functional polymorphisms of MTHFR, C677T and A1298C, with the risk for schizophrenia. Furthermore, we conducted an updated meta-analysis on the two polymorphisms. In addition, we investigated the relationship between the polymorphisms and minor physical anomaly (MPA), which may represent neurodevelopmental aberrations in 201 schizophrenia patients and 350 normal control subjects. There was no significant association between either of the two polymorphisms and the risk of schizophrenia (chi-square = 0.001, df = 1, P = 0.971 for C677T; chi-square = 1.319, df = 1, P = 0.251 for A1298C). However, in meta-analysis, the C677T polymorphism showed a significant association in the combined and Asian populations (OR = 1.13, P = 0.005; OR = 1.21, P = 0.011, respectively) but not in the Korean and Caucasian populations alone. Neither polymorphism was associated with MPAs measured by the Waldrop scale (chi-square = 2.513, df = 2, P = 0.285). In conclusion, the present findings suggest that in the Korean population, the MTHFR polymorphisms are unlikely to be associated with the risk for schizophrenia and neurodevelopmental abnormalities related to schizophrenia.
doi:10.3346/jkms.2011.26.10.1356
PMCID: PMC3192349  PMID: 22022190
Case-Control Studies; Polymorphism, Genetic; Korean; Meta-Analysis; Methylenetetrahydrofolate Reductase; Schizophrenia
21.  MTHFR A1298C and C677T gene polymorphisms and susceptibility to chronic myeloid leukemia in Egypt 
Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating the intracellular folate metabolism which plays an important role in carcinogenesis through DNA methylation. We aimed to evaluate the association between MTHFR A1298C and C677T polymorphisms and the risks of chronic myeloid leukemia (CML). Eighty-five patients with CML and a control group containing 100 healthy, age and sex matched individuals were examined for MTHFR C677T and A1298C polymorphisms using polymerase chain reaction-restriction fragment-length (PCR-RFLP) method. The frequency of 677TT genotype in patients with CML was significantly higher compared to controls (OR = 2.513, 95% CI: 0.722-4.086, P = 0.025). No such association was shown for heterozygous 677CT (OR = 1.010, 95% CI: 0.460-2.218, P = 0.981). Moreover, for A1298C genotype, a statistically significant higher frequency of 1298CC was also detected in CML patients compared to control group (OR = 1.1816, 95% CI: 0.952-3.573, P = 0.036), 0.036). No such statistical significance was demonstrable for heterozygote 1298AC (OR = 1.046, 95% CI: 0.740-1.759, P = 0.092). In addition, patients with joint 677CT/1298AC or 677TT/1298CC genotypes showed an association with increased risk of CML (OR = 1.849, 95% CI: 0.935-2.540, P = 0.024; OR = 1.915, 95% CI: 1.202-3.845, P = 0.020 respectively). .A statistically significant increased risk of resistant to therapy was observed with 677CT and 1298AC genotypes (P = 0.001, P = 0.002 respectively). We conclude that both MTHFR 677TT and 1298CC polymorphisms have been associated with risk of CML and both 677CT and 1298AC genotypes are associated with higher risk of resistant to therapy.
PMCID: PMC4069873  PMID: 24966971
MTHFR; CML; polymorphism
22.  Associations Between Two Polymorphisms in the Methylenetetrahydrofolate Reductase Gene and Placental Abruption 
Objective
Heritable thrombophilias have been implicated as a potential etiology of abruption via vascular disruption at the uteroplacental interface. Polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene have been linked to vascular complications outside of pregnancy, including stroke. Given the underlying thrombotic nature of abruption, we hypothesized that polymorphisms in the MTHFR gene are associated with abruption.
Study design
We examined 2 variants in MTHFR: 677C→T and 1298A→C in genomic DNA extracted from maternal blood from the New Jersey-Placental Abruption Study, an ongoing, multicenter case-control study. We identified 195 women with a clinical diagnosis of abruption (cases), and 189 controls matched on race/ethnicity and parity. We assessed allele and genotype frequencies, and their associations with abruption risk after adjusting for confounders through multivariable logistic regression analysis.
Results
The wild-type allele (C) frequency of the 677C→T variant of MTHFR among cases and controls was 69.0% and 64.3%, respectively, and the wild-type allele (A) of the 1298A→C variant was 75.9% and 79.4%, respectively. Distributions of the 677C→T alleles among controls violated the Hardy-Weinberg equilibrium (P=0.007), while those of the 1298A→C alleles were in equilibrium (P=0.825). In comparison to the wild-type genotype (C/C), the homozygous mutant form (T/T) of 677C→T was not associated with abruption (OR 0.60, 95% confidence interval (CI) 0.33, 1.18). Similarly, the homozygous mutant form (C/C) of the 1298A→C polymorphism was equally distributed between cases and controls (OR 2.28, 95% CI 0.82, 6.35). Plasma homocysteine and vitamin B12, but not folate, concentrations were elevated in cases compared to controls among women with the wild-type genotype of MTHFR 677C→T (P=0.039 for homocysteine; P=0.048 for B12 and P=0.224 for folate, respectively).
Conclusions
In this population, neither heterozygosity nor homozygosity for the 677C→T and 1298A→C variants in MTHFR was associated with placental abruption.
doi:10.1016/j.ajog.2007.06.046
PMCID: PMC2084064  PMID: 17904970
Placental abruption; MTHFR; linkage disequilibrium; case-control; DNA
23.  Association of MTHFR gene polymorphisms with breast cancer survival 
BMC Cancer  2006;6:257.
Background
Two functional single nucleotide polymorphisms (SNPs) in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, C677T and A1298C, lead to decreased enzyme activity and affect chemosensitivity of tumor cells. We investigated whether these MTHFR SNPs were associated with breast cancer survival in African-American and Caucasian women.
Methods
African-American (n = 143) and Caucasian (n = 105) women, who had incident breast cancer with surgery, were recruited between 1993 and 2003 from the greater Baltimore area, Maryland, USA. Kaplan-Meier survival and multivariate Cox proportional hazards regression analyses were used to examine the relationship between MTHFR SNPs and disease-specific survival.
Results
We observed opposite effects of the MTHFR polymorphisms A1298C and C677T on breast cancer survival. Carriers of the variant allele at codon 1298 (A/C or C/C) had reduced survival when compared to homozygous carriers of the common A allele [Hazard ratio (HR) = 2.05; 95% confidence interval (CI), 1.05–4.00]. In contrast, breast cancer patients with the variant allele at codon 677 (C/T or T/T) had improved survival, albeit not statistically significant, when compared to individuals with the common C/C genotype (HR = 0.65; 95% CI, 0.31–1.35). The effects were stronger in patients with estrogen receptor-negative tumors (HR = 2.70; 95% CI, 1.17–6.23 for A/C or C/C versus A/A at codon 1298; HR = 0.36; 95% CI, 0.12–1.04 for C/T or T/T versus C/C at codon 677). Interactions between the two MTHFR genotypes and race/ethnicity on breast cancer survival were also observed (A1298C, pinteraction = 0.088; C677T, pinteraction = 0.026).
Conclusion
We found that the MTHFR SNPs, C677T and A1298C, were associated with breast cancer survival. The variant alleles had opposite effects on disease outcome in the study population. Race/ethnicity modified the association between the two SNPs and breast cancer survival.
doi:10.1186/1471-2407-6-257
PMCID: PMC1634868  PMID: 17069650
24.  Methylenetetrahydrofolate reductase C677T gene polymorphism and essential hypertension: A meta-analysis of 10,415 subjects 
Biomedical Reports  2014;2(5):699-708.
The methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism has been suggested to be associated with the risk of essential hypertension (EH), however, results remain inconclusive. To investigate this association, the present meta-analysis of 27 studies including 5,418 cases and 4,997 controls was performed. The pooled odds ratio (OR) and its corresponding 95% confidence interval were calculated using the random-effects model. A significant association between the MTHFR C677T gene polymorphism and EH was found under the allelic (OR, 1.32; 95% CI, 1.20–1.45; P=0.000), dominant (OR, 1.39; 95% CI, 1.25–1.55; P=0.000), recessive (OR, 1.38; 95% CI, 1.18–1.62; P=0.000), homozygote (OR, 1.59; 95% CI, 1.32–1.92; P=0.000), and heterozygote (OR, 1.32; 95% CI, 1.20–1.45; P=0.000) genetic models. A strong association was also revealed in subgroups, including Asian, Caucasian and Chinese. The Japanese subgroup did not show any significant association under all models. Meta-regression analyses suggested that the study design was a potential source of heterogeneity, whereas the subgroup analysis additionally indicated that the population origin may also be an explanation. Another subgroup analysis revealed that hospital-based studies have a stronger association than population-based studies, however, the former suffered a greater heterogeneity. Funnel plot and Egger’s test manifested no evidence of publication bias. In conclusion, the present study supports the evidence for the association between the MTHFR C677T gene polymorphism and EH in the whole population, as well as in subgroups, such as Asian, Caucasian and Chinese. The carriers of the 677T allele are susceptible to EH.
doi:10.3892/br.2014.302
PMCID: PMC4106611  PMID: 25054014
methylenetetrahydrofolate reductase; meta-analysis; essential hypertension; gene polymorphism
25.  Methylenetetrahydrofolate reductase polymorphisms and interaction with smoking and alcohol consumption in lung cancer risk: a case-control study in a Japanese population 
BMC Cancer  2011;11:459.
Background
Cigarette smoking is an established risk factor of lung cancer development while the current epidemiological evidence is suggestive of an increased lung cancer risk associated with alcohol consumption. Dietary folate, which is present in a wide range of fresh fruits and vegetables, may be a micronutrient that has a beneficial impact on lung carcinogenesis. Methylenetetrahydrofolate reductase (MTHFR) plays a crucial role in regulating folate metabolism, which affects both DNA synthesis/repair and methylation. We examined if smoking or alcohol consumption modify associations between MTHFR polymorphisms and lung cancer risk.
Methods
We evaluated the role of the MTHFR C677T (rs1801133) and A1298C (rs1801131) polymorphisms in a case-control study comprised of 462 lung cancer cases and 379 controls in a Japanese population. Logistic regression was used to assess the adjusted odds ratios (OR) and 95% confidence intervals (95% CI).
Results
The TT genotype of the C677T polymorphism was significantly associated with an increased risk of lung cancer (OR = 2.27, 95% CI = 1.42 - 3.62, P < 0.01) while the A1298C polymorphism was not associated with lung cancer risk. The minor alleles of both polymorphisms behaved in a recessive fashion. The highest risks were seen for 677TT-carriers with a history of smoking or excessive drinking (OR = 6.16, 95% CI = 3.48 - 10.9 for smoking; OR = 3.09, 95% CI = 1.64 - 5.81 for drinking) compared with C-carriers without a history of smoking or excessive drinking, but no interactions were seen. The 1298CC genotype was only associated with increased risk among non-smokers (P < 0.05), and smoking was only associated with increased risks among 1298A-carriers (P < 0.01), but no significant interaction was seen. There was a synergistic interaction between the A1298C polymorphism and drinking (P < 0.05). The highest risk was seen for the CC-carriers with excessive drinking (OR = 7.24, 95% CI = 1.89 - 27.7) compared with the A-carriers without excessive drinking).
Conclusions
The C677T polymorphism was significantly associated with lung cancer risk. Although the A1298C polymorphism was not associated with lung cancer risk, a significant interaction with drinking was observed. Future studies incorporating data on folate intake may undoubtedly lead to a more thorough understanding of the role of the MTHFR polymorphisms in lung cancer development.
doi:10.1186/1471-2407-11-459
PMCID: PMC3213117  PMID: 22024018

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