Objective: To investigate the contribution of polymorphic variation in genes involved in the folate-dependent homocysteine pathway in the aetiology of neural tube defects (NTD).
Design: Case-control association study.
Subjects: A total of 530 individuals from families affected by NTD, 645 maternal controls, and 602 healthy newborn controls from the northern UK.
Main outcome measures: Seven polymorphisms in six genes coding for proteins in the folate-dependent homocysteine pathway (MTHFR 677C→T, MTHFR 1298A→C, MTRR 66A→G, SHMT 1420C→T, CßS 844ins68, GCPII 1561C→T, RFC-1 80G→A). The impact of each polymorphism and the effect of gene–gene interactions (epistasis) upon risk of NTD were assessed using logistic regression analysis.
Results: The MTHFR 677C→T polymorphism was shown to represent a risk factor in NTD cases (CC v CT+TT odds ratio (OR) 2.03 [95% confidence interval (CI) 1.09, 3.79] p = 0.025) and the MTRR 66A→G polymorphism was shown to exert a protective effect in NTD cases (AA v AG+GG OR 0.31 [95% CI 0.10, 0.94] p = 0.04). When statistical tests for interaction were conducted, three genotype combinations in cases (MTRR/GCPII; MTHFR 677/CßS; MTHFR 677/MTRR) and one combination in case mothers (CßS/RFC-1) were shown to elevate NTD risk. Maternal–fetal interaction was also detected when offspring carried the MTHFR 677C→T variant and mothers carried the MTRR 66A→G variant, resulting in a significantly elevated risk of NTD.
Conclusion: Both independent genetic effects and gene–gene interaction were observed in relation to NTD risk. Multi-locus rather than single locus analysis might be preferable to gain an accurate assessment of genetic susceptibility to NTD.
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.
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.
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.
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.
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.
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.
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.
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.
Neural Tube Defects (NTDs) are among the most prevalent and most severe congenital malformations worldwide. Polymorphisms in key genes involving the folate pathway have been reported to be associated with the risk of NTDs. However, the results from these published studies are conflicting. We surveyed the literature (1996–2011) and performed a comprehensive meta-analysis to provide empirical evidence on the association.
Methods and Findings
We investigated the effects of 5 genetic variants from 47 study populations, for a total of 85 case-control comparisons MTHFR C677T (42 studies; 4374 cases, 7232 controls), MTHFR A1298C (22 studies; 2602 cases, 4070 controls), MTR A2756G (9 studies; 843 cases, 1006 controls), MTRR A66G (8 studies; 703 cases, 1572 controls), and RFC-1 A80G (4 studies; 1107 cases, 1585 controls). We found a convincing evidence of dominant effects of MTHFR C677T (OR 1.23; 95%CI 1.07–1.42) and suggestive evidence of RFC-1 A80G (OR 1.55; 95%CI 1.24–1.92). However, we found no significant effects of MTHFR A1298C, MTR A2756G, MTRR A66G in risk of NTDs in dominant, recessive or in allelic models.
Our meta-analysis strongly suggested a significant association of the variant MTHFR C677T and a suggestive association of RFC-1 A80G with increased risk of NTDs. However, other variants involved in folate pathway do not demonstrate any evidence for a significant marginal association on susceptibility to NTDs.
Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme for folate metabolism in humans; it is encoded by the MTHFR gene. Several studies have assessed the association between MTHFR C677T polymorphism and the risk of congenital heart defects (CHDs), while the results were inconsistent.
Methods and Findings
Multiple electronic databases were searched to identify relevant studies published up to July 22, 2012. Data from case-control and TDT studies were integrated in an allelic model using the Catmap and Metafor software. Twenty-nine publications were included in this meta-analysis. The overall meta-analysis showed significant association between MTHFR C677T polymorphism and CHDs risk in children with heterogeneity (Pheterogeneity = 0.000) and publication bias (Pegger = 0.039), but it turned into null after the trim-and-fill method was implemented (OR = 1.12, 95% CI = 0.95–1.31). Nevertheless, positive results were obtained after stratified by ethnicity and sample size in all subgroups except the mixed population. For mothers, there was significant association between the variant and CHDs without heterogeneity (Pheterogeneity = 0.150, OR = 1.16, 95% CI = 1.05–1.29) and publication bias (Pegger = 0.981). However, the results varied across each subgroup in the stratified analysis of ethnicity and sample size.
Both infant and maternal MTHFR C677T polymorphisms may contribute to the risk of CHDs.
This study was designed to investigate an association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and the risk of lung cancer in a Korean population.
We conducted a large-scale, case-control study involving 3938 patients with newly diagnosed lung cancer and 1700 healthy controls. Genotyping was performed with peripheral blood DNA for MTHFR C677T polymorphisms. Statistical significance was estimated by logistic regression analysis.
The MTHFR C677T frequencies of CC, CT, and TT genotypes were 34.5%, 48.5%, and 17% among lung cancer patients, and 31.8%, 50.7%, and 17.5% in the controls, respectively. The MTHFR 677CT and TT genotype showed a weak protection against lung cancer compared with the homozygous CC genotype, although the results did not reach statistical significance. The age- and gender-adjusted odds ratio (OR) of overall lung cancer was 0.90 (95% confidence interval (CI), 0.77-1.04) for MTHFR 677 CT and 0.88 (95% CI, 0.71-1.07) for MTHFR 677TT. However, after stratification analysis by histological type, the MTHFR 677CT genotype showed a significantly decreased risk for squamous cell carcinoma (age- and gender-adjusted OR, 0.78; 95% CI, 0.64-0.96). The combination of 677 TT homozygous with 677 CT heterozygous also appeared to have a protection effect on the risk of squamous cell carcinoma. We observed no significant interaction between the MTHFR C677T polymorphism and age and gender or smoking habit.
This is the first reported study focusing on the association between MTHFR C677T polymorphisms and the risk of lung cancer in a Korean population. The T allele was found to provide a weak protective association with lung squamous cell carcinoma.
Methylenetetrahydrofolate reductase (MTHFR) gene mutations have been implicated as risk factors for neural tube defects (NTDs). The best-characterized MTHFR genetic mutation 677C→T is associated with a 2–4 fold increased risk of NTD if patient is homozygous for this mutation. This risk factor is modulated by folate levels in the body. A second mutation in the MTHFR gene is an A→C transition at position 1298. The 1298A→C mutation is also a risk factor for NTD, but with a smaller relative risk than 677C→T mutation. Under conditions of low folate intake or high folate requirements, such as pregnancy, this mutation could become of clinical importance. We present a case report with MTHFR genetic mutation, who presented with recurrent familial pregnancy losses due to anencephaly/NTDs.
Folate; methylenetetrahydrofolate reductase gene mutation; neural tube defects
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 tumour cells.
Material and methods
We evaluated these two common polymorphisms and breast cancer risk association in an Iranian sporadic breast cancer population-based case-control study of 294 breast cancer cases and 306 controls using a PCR-RFLP-based assay.
Analyses of affected and controls show that homozygote genotype MTHFR 677CC has the highest frequency in both groups (28.3% in patients and 25.3% in control group). Genotype MTHFR 677CT and genotype MTHFR 1298AC were found to be statistically significant risk factors in our population (odds ratio: 1.6, 95% CI: 1.019-2.513, p = 0.041; and odds ratio: 2.575, 95% CI: 1.590-4.158, p = 0.001 respectively).
We can conclude based on the results of our study that a significant association between breast cancer and C677T and A1298C polymorphism might exist.
MTHFR gene; polymorphism; breast cancer; PCR-RFLP; susceptibility factor
Women with polycystic ovary syndrome (PCOS) are prone for coronary artery disease (CAD), and hyperhomocysteinemia is an independent risk factor for CAD. MTHFR deficiency is the most common cause of hyperhomocysteinemia, thereby provoking a possible association between PCOS and MTHFR C677T polymorphism.
The aim of this study was to investigate an association of MTHFR C677T polymorphism with PCOS.
SETTINGS AND DESIGN:
92 women with PCOS (Rotterdam criteria) and 95 age-matched controls were compared with respect to MTHFR C677T polymorphism. The 2 genotypes (CC and CT) obtained were compared with clinical and laboratory parameters in women with PCOS.
MATERIALS AND METHODS:
In a case-control study, clinical, biochemical, hormonal and genetic analysis (PCR-RFLP of peripheral leucocytes) was carried out on all women with PCOS as well as controls.
Student “t” test for quantitative and Chi-square test for nominal variables was used. For estimation of risk, odds ratio and 95% confidence interval were calculated.
The odds ratio of bearing a heterozygous genotype (CT) was 1.32 in women with PCOS as compared to controls (P = 0.48). No homozygous mutation (TT) was found in the study population. Serum cholesterol was more in heterozygous (CT) genotype (215.48 ± 25.56 mg/dl) as compared to normal (CC) genotype (203.29 ± 16.35 mg/dl) in women with PCOS (P = 0.01). Similarly, serum triglyceride was more in heterozygous (CT) genotype (95.86 ± 37.34 mg/dl) as compared to normal (CC) genotype (82.36 ± 20.88 mg/dl) in women with PCOS (P = 0.04).
Although not statistically significant, there is a slightly higher prevalence of heterozygous (CT) genotype in women with PCOS. MTHFR C677T polymorphism when present may confer an increased susceptibility to develop hyperlipidemia in women with PCOS. More prospective studies are needed to confirm whether this hyperlipidemia due to MTHFR C677T polymorphism clinically manifests into CAD in long term in women with PCOS.
CAD; coronary artery disease; hyperlipidemia; MTHFR C677T polymorphism; PCOS; polycystic ovary syndrome
Inadequate folate status due to either genetic variation or nutritional deficiencies has been associated with an increased risk of congenital malformations including orofacial clefting, limb, cardiac and neural tube defects. Few epidemiologic studies have examined the association between limb reduction defects (LRDs) and folate-related genetic polymorphisms other than MTHFR 677C→T. We conducted a case–parental analysis of 148 families who participated in the National Birth Defects Prevention Study (NBDPS) to examine the association between nonsyndromic transverse and longitudinal LRDs with five single nucleotide polymorphisms (SNPs) in genes encoding for enzymes in folate and methionine pathways. Log-linear Poisson regression, adapted for analysis of case–parental data, assuming an additive genetic model was used to estimate genetic relative risks and 95% confidence intervals for the association between LRDs and each SNP. Among women who did not take multivitamin supplements, the MTHFR 677T variant acts via the offspring’s genome to increase the risk of LRDs. No association between LRDs and any fetal SNP was found among women who used multivitamin supplements. These results suggest the possibility that initiating folic acid supplementation prior to pregnancy may reduce the risk of having a LRD-affected pregnancy, especially in women whose offspring inherit one or two copies of the MTHFR 677T variant.
Folic acid; homocysteine; MTHFR; polymorphisms; case-parental analysis
Migraine is a common disorder that often coexists with depression. While a functional polymorphism in methyleneterahydrofolate reductase gene (MTHFR C677T) has been implicated in depression; the evidence to support an association of MTHFR with migraine has been inconclusive. We aim to investigate the effect of this variant on propensity for migraine and to perform a systematic review and meta-analysis of studies of MTHFR and migraine to date.
Individuals with migraine (n = 447) were selected from the Depression Case Control (DeCC) study to investigate the association between migraine and MTHFR C677T single nucleotide polymorphism (SNP) rs1801133 using an additive model compared to non-migraineurs adjusting for depression status. A meta-analysis was performed and included 15 studies of MTHFR and migraine.
MTHFR C677T polymorphism was associated with migraine with aura (MA) (OR 1.31, 95% CI 1.01-1.70, p = 0.039) that remained significant after adjusting for age, sex and depression status. A meta-analysis of 15 case-control studies showed that T allele homozygosity is significantly associated with MA (OR = 1.42; 95% CI, 1.10-1.82) and total migraine (OR = 1.37; 95% CI, 1.07-1.76), but not migraine without aura (OR = 1.16; 95% CI, 0.36-3.76). In studies of non-Caucasian population, the TT genotype was associated with total migraine (OR= 3.46; 95% CI, 1.22-9.82), whereas in studies of Caucasians this variant was associated with MA only (OR = 1.28; 95% CI, 1.002-1.63).
MTHFR C677T is associated with MA in individuals selected for depression study. A meta-analysis of 15 studies supports this association and demonstrated effects across ethnic groups.
Folate has been hypothesized to influence carcinogenesis due to its dual role in DNA methylation, which regulates gene expression, and synthesis of purine and thymidylate, which is vital for DNA repair. Thus, we examined ovarian cancer risk in relation to two functional polymorphisms (C677T and A1298C) in the MTHFR gene.
We genotyped the C677T (rs1801133) and A1298C (rs1801131) MTHFR polymorphisms in 1642 cases and 2068 controls from three studies, the New England Case Control Study (NEC), Nurses’ Health Study (NHS), and Mayo Clinic Ovarian Cancer Case Control Study (MAY).
Overall, we observed no association between either SNP and ovarian cancer risk (pooled C677T ptrend = 0.59 and A1298C ptrend = 0.58). Significant associations (C677T ptrend=0.001, A1298C ptrend=0.02) between these MTHFR SNPs and serous ovarian cancer risk were observed in the NEC study, but were not replicated in the NHS and MAY studies.
MTHFR SNPs C677T and A1298C are not associated with ovarian cancer risk. Our results highlight the need for validation of genetic findings.
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.
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).
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).
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.
The methylenetetrahydrofolate reductase (MTHFR) enzyme catalyzes the reduction of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate and methyl donors. The methyl donors are required for the conversion of homocysteine to methionine. Mutation of MTHFR 677 C > T disrupts its thermostability therefore leads to defective enzyme activities and dysregulation of homocysteine levels.
This case-control study (n = 367) was conducted to investigate the correlation of the MTHFR gene polymorphism [NM_005957] and psoriasis vulgaris amongst the Malaysian population. Overnight fasting blood samples were collected from a subgroup of consented psoriasis vulgaris patients and matched controls (n = 84) for the quantification of homocysteine, vitamin B12 and folic acid levels.
There was no significant increase of the MTHFR 677 C > T mutation in patients with psoriasis vulgaris compared with controls (χ2 = 0.733, p = 0.392). No significant association between homocysteine levels and MTHFR gene polymorphism in cases and controls were observed (F = 0.91, df = 3, 80, p = 0.44). However, homocysteine levels in cases were negatively correlated with vitamin B12 (r = -0.173) and folic acid (r = -0.345) levels. Vitamin B12 and folic acid levels in cases were also negatively correlated (r = -0.164).
Our results indicate that there was no significant association between the MTHFR gene polymorphism and psoriasis vulgaris in the Malaysian population. There was no significant increase of the plasma homocysteine level in the psoriasis patients compared to the controls.
This study was designed to investigate an association between the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and the risk of gastric and colorectal cancer in the Korean population.
We conducted a population-based large-scale case-control study involving 2,213 patients with newly diagnosed gastric cancer, 1,829 patients with newly diagnosed colorectal cancer, and 1,700 healthy controls. Genotyping was performed with peripheral blood DNA for MTHFR C677T polymorphisms. The statistical significance was estimated by logistic regression analysis.
The MTHFR C677T frequencies of CC, CT, and TT genotypes were 35.2%, 47.5%, and 17.3% among stomach cancer, 34%, 50.5%, and 15.5% in colorectal cancer, and 31.8%, 50.7%, and 17.5% in the controls, respectively. The MTHFR 677TT genotype showed a weak opposite association with colorectal cancer compared to the homozygous CC genotype [adjusted age and sex odds ratio (OR) = 0.792, 95% confidence interval (CI) = 0.638-0.984, P = 0.035]. Subjects with the MTHFR 677CT showed a significantly reduced risk of gastric cancer compared whose with the 677CC genotype (age- and sex-adjusted OR = 0.810; 95% CI = 0.696-0.942, P = 0.006). We also observed no significant interactions between the MTHFR C677T polymorphism and smoking or drinking in the risk of gastric and colorectal cancer.
The T allele was found to provide a weak protective association with gastric cancer and colorectal cancer.
The C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene has been hypothesized to increase breast cancer risk. However, results have been inconsistent, and few studies have reported the association by menopausal status or by intakes of nutrients participating in one-carbon metabolism. Our aims were to investigate whether MTHFR C677T was associated with postmenopausal breast cancer risk and whether this relation was modified by intakes of folate, methionine, vitamins B2, B6, and B12, and alcohol.
We studied 318 incident breast cancer cases and 647 age- and race-matched controls participating in a nested case-control study of postmenopausal women within the VITamins And Lifestyle (VITAL) cohort. Genotyping was conducted for MTHFR C677T and dietary and supplemental intakes were ascertained from a validated questionnaire. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression.
We observed a 62% increased risk of breast cancer among postmenopausal women with the TT genotype (OR = 1.62; 95% CI: 1.05 to 2.48). Women with a higher number of variant T alleles had higher risk of breast cancer (P for trend = 0.04). Evidence of effect-modification by intakes of some B vitamins was observed. The most pronounced MTHFR-breast cancer risks were observed among women with the lowest intakes of dietary folate (P for interaction = 0.02) and total (diet plus supplemental) vitamin B6 (P for interaction = 0.01), with no significant increased risks among women with higher intakes.
This study provides support that the MTHFR 677TT genotype is associated with a moderate increase in risk of postmenopausal breast cancer and that this risk may be attenuated with high intakes of some one-carbon associated nutrients.
To asses he association between intake of folate and B vitamins and the incidence of spontaneous abortion (SA) according to the maternal methylenetetrahydrofolate reductase (MTHFR) polymorphisms (677 C>T and 1298 A>C).
Material and Methods
We conducted a nested case-control study within a perinatal cohort of women recruited in the state of Morelos, Mexico. Twenty-three women with SA were compared to 74 women whose pregnancy survived beyond week 20th. Intake of folate and B vitamins respectively, was estimated using a validated food frequency questionnaire. Maternal MTHFR polymorphisms were determined by PCR-RFLP and serum homocysteine levels by HPLC.
Carriers of MTHFR 677TT and 1298AC genotypes respectively showed an increased risk of SA (OR 677TT vs. CC/CT=5.0; 95% CI: 1.2, 20.9 and OR 1298 AC vs. AA=5.5; 95% CI: 1.1, 26.6).
Our results support the role of MTHFR polymorphisms as a risk factor for SA, regardless of dietary intake of B vitamins.
MTHFR; 677 C>T and 1298 A>C polymorphisms; spontaneous abortion; Mexico
MTHFR 677C>T polymorphism is a genetic alteration in an enzyme involved in folate metabolism, but its effect on host susceptibility to cervical cancer is still uncertain. The aim of this study was to investigate the association between MTHFR 677C>T polymorphism and cervical cancer by performing a meta-analysis.
Pubmed, Embase, Web of Science, and the Chinese Biomedical Database (CBM) databases were searched for case–control studies investigating the association between MTHFR 677C>T polymorphism and cervical cancer. Odds ratios (OR) and 95% confidence intervals (95%CI) were used to assess this possible association.
11 studies with a total of 1898 cervical cancer cases and 2678 controls were included. Meta-analyses of a total 11 studies showed no association between MTHFR 677C>T polymorphism and cervical cancer using all five genetic models (All P values > 0.05). However, subgroup analyses showed the odds of the homozygous TT genotype were much less in cervical cancer cases than in controls in Europeans, which implied an association between the homozygous TT genotype and cervical cancer in Europeans (For TT versus CC, fixed-effects OR = 0.65, 95%CI 0.45-0.93, P = 0.020, I2 = 0.0%). The odds for the homozygous TT genotype were greater in cervical cancer cases than in controls in East Asians, which also implied an association between the homozygous TT genotype and cervical cancer in East Asians (For TT versus CC, random-effects OR = 1.66, 95%CI 1.05-2.62, P = 0.029, I2 = 52.6%; For TT versus CT/CC, random-effects OR = 1.55, 95%CI 1.09-2.22, P = 0.016, I2 = 42.4%). Both subgroup analyses and meta-regression analyses suggested ethnicity was the major source of heterogeneity. Publication bias was not evident.
This meta-analysis supports an association between MTHFR 677C>T polymorphism and cervical cancer, and the effect of this association may be race specific. Further studies with large sample sizes and careful design are needed to identify this association more comprehensively.
MTHFR; Single nucleotide polymorphism; Cervical cancer; Meta-analysis
We designed a case-control study to determine the plasma homocysteine (Hcy) level and evaluate the potential role of the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism in colorectal cancer (CRC). Total Hcy was quantified using the fluorescence polarization immunoassay (FPIA) on the IMx analyzer. Genomic DNA was analyzed by the real-time polymerase chain reaction (RT-PCR). The plasma levels of Hcy in the CRC group (12.63±3.11 μmol/l) were significantly higher compared with those in the control group (10.87±2.42 μmol/l; P<0.05). The frequency of the MTHFR 677TT genotype in CRC patients was markedly high. The MTHFR 677TT genotype was significantly correlated with an increased risk of CRC (odds ratio, 1.671; 95% confidence interval, 1.094–2.553; P=0.018). This study suggests that the MTHFR C677T polymorphism indicates susceptibility to CRC and is correlated with CRC pathogenesis, suggesting that the homozygous variant MTHFR C677T polymorphism is a candidate risk factor for CRC.
methylenetetrahydrofolate reductase; polymorphism; homocysteine; colorectal cancer
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.
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.
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.
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.
Common genetic SNPs in two genes, encoding catechol-O-methyltransferase (COMT) and methylenetetrahydrofolate reductase (MTHFR), which are interconnected with COMT gene regulation, have been reported to contribute to schizophrenia risk. In this study, we evaluated the association between functional polymorphisms in COMT and MTHFR and schizophrenia risk with a case-control study in a Korean population.
We performed a case-control study by genotyping analysis using 360 cases and 348 controls in Korean subjects to determine the association between functional polymorphisms in COMT and MTHFR and schizophrenia risk.
Four functional SNPs in COMT (Val158Met and rs165599) and MTHFR (C677T and A1298C) were genotyped by primer extension assay. None of the genotype distributions for the four SNPs was significantly different between cases and controls. Stratified analysis did not show any significant gender difference for any polymorphism. In addition, we found no evidence of a gene-gene interaction in the analysis of combined genotypes.
Our results suggest no significant association between the selected functional polymorphisms of COMT or MTHFR in Korean schizophrenia subjects. However, further studies are required to confirm our findings in a larger number of subjects.
Catechol-O-methyltransferase; Schizophrenia; Methylenetetrahydrofolate reductase; Polymorphism
The methylenetetrahydrofolate reductase (MTHFR) gene polymorphism C677T is suspected to be a risk factor for psychiatric disorders, but it remains inconclusive whether the MTHFR polymorphism C677T is imputed to vulnerability to schizophrenia and bipolar disorder.
We prompted impetus to appraise this polymorphism in an Iranian population. Therefore, 90 patients with bipolar disorder type I (BID), 66 patients with schizophrenia diagnosed according to DSM-IV criteria, and 94 unrelated controls with no history of psychiatric disorders were recruited for this study. Genotype distribution and allelic frequencies of C677T polymorphism were investigated.
We found no robust differences between patients with BID and schizophrenia with control participants either for allele frequencies or genotype distribution of MTHFR C677T polymorphism. However, a trend toward an increased risk for T allele was observed in the BID patients [with odds ratio (OR) of 1.28(CI 95%: 0.8-1.31), p>0.05].
However, the present and some previous studies failed to elucidate possible interaction between MTHFR C677T polymorphism and vulnerability to schizophrenia and bipolar disorder; still some associations have been revealed in performed meta-analyses that warrant further studies.
Bipolar disorder; Methylenetetrahydrofolate reductase; Polymorphism; Schizophrenia
Little is known about the contribution of polymorphisms in the methylenetetrahydrofolate reductase gene (MTHFR) and the folate metabolism pathway in rectal cancer alone. Data were from participants in a case-control study conducted in Northern California and Utah (751 cases and 979 controls). We examined independent associations and interactions of folate, B vitamins, methionine, alcohol, and MTHFR polymorphisms (MTHFR C677T and A1298C) with rectal cancer. Dietary folate intake was associated with a reduction in rectal cancer OR 0.66, 95% CI 0.48-0.92 (>475 mcg day compared to < = 322 mcg) as was a combination of nutrient intakes contributing to higher methyl donor status (OR 0.79, 95% CI 0.66-0.95). Risk was reduced among women with the 677 TT genotype (OR 0.54, 95% CI 0.30-0.9), but not men (OR 1.11, 95% CI 0.70-1.76) and with the 1298 CC genotype in combined gender analysis (OR 0.67, 95% CI 0.46-0.98). These data are consistent with a protective effect of increasing dietary folate against rectal cancer and suggest a protective role of the MTHFR 677 TT genotype in women and 1298 CC in men and women. Folate intake, low methyl donor status, and MTHFR polymorphisms may play independent roles in the etiology of rectal cancer.
Diet; Pteroylpolyglutamic Acids; Rectal Neoplasms; Polymorphism; Genetic
AIMS AND OBJECTIVE:
Evaluation of C677T polymorphisms of the methylenetetra hydrofolate reductase (MTHFR) gene and its association with level of serum homocysteine, folate, and vitamin B12 as possible maternal risk factors for Down syndrome.
This was a case–control study.
MATERIAL AND METHODS
Fifty-two mothers (mean age 27.6 years) with babies having free trisomy 21 of North Indian ethnicity and 52 control nonlactating mothers (mean age 24.9 years) of same ethnicity attending services of genetic lab for bloodletting for other causes were enrolled after informed written consent. Fasting blood was collected and was used for determination of plasma homocysteine, vitamin B12, and folate (serum and RBC), and for PCR amplification of the MTHFR gene.
The prevalence of MTHFR C677T polymorphism in north Indian mothers of babies with trisomy 21 Down syndrome was 15.38% compared to 5.88 % in controls. The difference between two groups was not statistically significant (P = 0.124). Low serum folate was demonstrated in 34.62% of cases vs. 11.54% in controls, which was significant (P = 0.005). Low RBC folate was found in 30.7% of cases versus 11.53% in controls, which was not significant (P = 0.059), when analyzed independently. But on multiple regression analysis the difference was statistically significant. Low serum vitamin B12 was found in 42.31% of cases versus 34.62% in controls, which was not significant (P = 0.118). The mean serum homocysteine in cases was 10.35 ± 0.68 while controls were 9.02 ± 0.535.
Serum levels of folate were low in cases. The RBC folate levels were comparable in both groups. However the combined serum folate and RBC folate were low in cases compared to control groups. Homocysteine levels in our study were higher in Down syndrome mothers compared to controls; however high-serum level of Homocysteine had no association with MTHFR polymorphism. No association of serum vitamin B12 with MTHFR polymorphism in occurrence of Down syndrome births was found. Peri- or preconceptional folate supplementation may therefore lead to a decline in DS births, if supported by larger studies.
Down syndrome; methylenetetra hydrofolate reductase gene; serum and RBC folate; serum homocysteine; serum vitamin B12
Methionine synthase (MTR) and 5,10-methylenetetrahydrofolate reductase (MTHFR) are the main regulatory enzymes for homocysteine metabolism. The present case-control study was conducted to determine whether there is an association between the MTR 2756A > G or MTHFR 677C > T polymorphism and plasma homocysteine concentration in Korean subjects with ischemic stroke.
Materials and Methods
DNA samples of 237 patients who had an ischemic stroke and 223 age and sex-matched controls were studied. MTR 2756A > G and MTHFR 677C > T genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).
Frequencies of mutant alleles for MTR and MTHFR polymorphisms were not significantly different between the controls and cases. The patient group, however, had significantly higher homocysteine concentrations of the MTR 2756AA and MTHFR 677TT genotypes than the control group (p = 0.04 for MTR, p = 0.01 for MTHFR). The combined MTR 2756AA and MTHFR 677TT genotype (p = 0.04) and the homocysteine concentrations of the patient group were also higher than those of the controls. In addition, the genotype distribution was significant in the MTHFR 677TT genotype (p = 0.008) and combined MTR 2756AA and MTHFR 677TT genotype (p = 0.03), which divided the groups into the top 20% and bottom 20% based on their homocysteine levels.
The results of the present study demonstrate that the MTR 2756A > G and MTHFR 677C > T polymorphisms interact with elevated total homocysteine (tHcy) levels, leading to an increased risk of ischemic stroke.
Methylenetetrahydrofolate reductase (MTHFR); methionine synthase (MTR); ischemic stroke; hyperhomocysteinemia; polymorphism