Methylenetetrahydrofolate Reductase 677CC Research Articles

Aberrant DNA methylation of the P16, MGMT, and hMLH1 genes in combination with the methylenetetrahydrofolate reductase C677T genetic polymorphism and folate intake in gastric cancer.

Epidemiological studies have indicated that folate metabolism is correlated with increased risk of gastric cancer. Since methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in folate metabolism, in this study, we examined whether polymorphisms and haplotypes of MTHFR are correlated with the risk of gastric cancer. The polymorphisms MTHFR C677T and MTHFR A1298C were genotyped by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) analysis in 285 patients and 570 healthy controls. Association analyses based on binary logistic regression were conducted to determine the odds ratio (OR) and its 95% confidence interval (95%CI) for each genotype. The MTHFR 677TT genotype was significantly related with a reduced risk of gastric cancer (OR = 0.60, 95%CI = 0.39-0.92) compared to the CC genotype. Similarly, the MTHFR 1298CC genotype was significantly associated with a decreased risk of cancer (OR = 0.52, 95%CI = 0.32- 0.81). Haplotype analysis showed that the TC haplotype was associated with a reduced risk of gastric cancer compared to the most common haplotype, CA (OR = 0.28, 95%CI = 0.12-0.60). Our results suggest that the MTHFR C677T and MTHFR A1298C polymorphisms are related to gastric cancer susceptibility in the Chinese population.

Role of 677C→T polymorphism a single substitution in methylenetetrahydrofolate reductase (MTHFR) gene in North Indian infertile men

Failure or severe difficulty in conceiving a child is surprisingly common, worldwide problem. Half of these cases are due to male factors with defects in sperm (1 in 15 men) being the single most common cause. Also about 60-75% of male infertility cases are idiopathic, since the molecular mechanisms underlying the defects remain unknown. DNA methylation is crucial for spermatogenesis and high methylenetetrahydrofolate reductase (MTHFR) activity in adult testis than other organs in mouse, signifies its critical role in spermatogenesis. According to recent findings there is a correlation of epigenetic regulation of several imprinted genes with disturbed spermatogenesis and fertility. Consequently any change in the MTHFR gene sequence can modify the spermatogenesis including transmission of infertility to the carriers. The aim of the study is to analyze the distribution of the single nucleotide polymorphism C677T in the MTHFR gene in 637 North Indian infertile patients and 364 fertile North Indian men as controls by using PCR-RFLP technique and Chi Square test for statistical analysis. The average MTHFR 677CC, 677CT, 677TT genotype frequencies of total infertile men were 70.17, 24.17, 5.65% in infertile men and 75.27, 21.7, 2.74% in controls, respectively. The average frequency of the MTHFR 677T allele was 17.73% in infertile men as compared to 13.59% in controls. The statistical difference was significant. Disease risk was found 2.27-folds increased in patients who were carrying T allele. We found an association of C677T polymorphism with male infertility and that it may be a genetic risk factor for male infertility in North Indian population.

Synergistic effect of MTHFR C677T and F2 G20210A polymorphisms on ischemic stroke

The predisposition to stroke might involve interactive effects among variants in several genes. We tested this hypothesis by examining the influence of polymorphisms in methylenetetrahydrofolate reductase (MTHFR) (C677T) and prothrombin (F2) (G20210A) as risk factors for stroke in Morocco. The polymerase chain reaction-restriction fragment length polymorphism methods were used to analyze DNA from 91 stroke patients and 182 controls. Association between the two polymorphisms and the risk of stroke was estimated by four-level models for the analysis of genetic interaction. Neither the MTHFR 677TT nor the F2 20210GA genotype showed any significant association compared to the MTHFR CC and F2 GG genotypes, respectively. An interactive effect between the MTHFR 677TT and F2 20210GA polymorphisms showed an increased risk of stroke. The odds ratios, in univariate and multivariate analysis, for the combined polymorphisms were 4.99 (95% CI, 1.75-14.2, P = 0.001) and 5.29 (95% CI, 1.63-17.1, P = 0.005), respectively.

Methylenetetrahydrofolate reductase C677T and methionine synthase A2756G polymorphisms influence on leukocyte genomic DNA methylation level

Methionine synthase (MTR) and methylenetetrahydrofolate reductase (MTHFR) enzymes are involved in the metabolism of methyl groups, and thus have an important role in the maintenance of proper DNA methylation level. In our study we aimed to evaluate the effect of the polymorphism A2756G (rs1805087) in the MTR gene on the level of human leukocyte genomic DNA methylation. Since the well-studied polymorphism C677T (rs1801133) in the MTHFR gene has already been shown to affect DNA methylation, we aimed to analyze the effect of MTR A2756G independently of the MTHFR C677T polymorphism. For this purpose, we collected the groups of 80 subjects with the MTR 2756AA genotype and 80 subjects with the MTR 2756GG genotype, having equal numbers of individuals with the MTHFR 677CC and the MTHFR 677TT genotypes, and determined the level of DNA methylation in each group. Individuals homozygous for the mutant MTR 2756G allele showed higher DNA methylation level than those harboring the MTR 2756AA genotype (5.061±1.761% vs. 4.501±1.621%, P=0.0391). Individuals with wild-type MTHFR 677СC genotype displayed higher DNA methylation level than the subjects with mutant MTHFR 677TT genotype (5.103±1.767% vs. 4.323±1.525%, P=0.0034). Our data provide evidence that the MTR A2756G polymorphism increases the level of DNA methylation and confirm the previous reports that the MTHFR C677T polymorphism is associated with DNA hypomethylation.

The MTHFR C677T polymorphism and global DNA methylation in oral epithelial cells

DNA methylation is mediated by DNA methyltransferases (DNMTs) that add a methyl group to the 5′-carbon of cytosine. The enzyme methylenetetrahydrofolate reductase (MTHFR) catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate in the rate-limiting step of the cycle involving the methyl donor S-adenosyl-L-methionine (SAM). The MTHFR C677T polymorphism results in a thermolabile enzyme with reduced activity that is predicted to influence the DNA methylation status. In this study, we investigated the impact of the MTHFR C677T polymorphism on the global DNA methylation of oral epithelial cells obtained from 54 healthy subjects. There were no significant differences in global DNA methylation among the MTHFR CC, CT and TT genotypes (p = 0.75; Kruskal-Wallis test).

Association of methylenetetrahydrofolate reductase C677T and A1298C polymorphisms with colorectal cancer risk: A meta-analysis

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.

MTHFR polymorphisms and capecitabine-induced toxicity in patients with metastatic colorectal cancer

The availability of current chemotherapeutic options for metastatic colorectal cancer (mCRC) has increased survival, but it is also accompanied by considerable morbidity. Fluoropyrimidines are the mainstay of systemic therapy. Germline pharmacogenetic markers involved in 5-fluorouracil pharmacodynamics could provide individualized pretreatment tools for predicting toxicity. Research on methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and fluoropyrimidine treatment outcome has focused on intravenous 5-fluorouracil and has yielded inconclusive results. The literature on pharmacogenetics in capecitabine-based chemotherapy is scarce. Therefore, we analysed the association of MTHFR gene polymorphisms and the occurrence of serious toxicity of first-line capecitabine monotherapy and combination therapy. One hundred and twenty-seven patients treated with first-line monotherapy capecitabine and 141 patients on capecitabine-irinotecan combination therapy were recruited from the CAIRO trial, an open-label phase III randomized trial, comparing sequential versus combination chemotherapy with capecitabine, irinotecan and oxaliplatin in mCRC. All patients were genotyped for MTHFR 1298A>C and 677C>T polymorphisms and analysed in both cohorts separately for the association between the MTHFR genotype and incidence of grade 3-4 overall toxicity and specific adverse events, as well as efficacy parameters. MTHFR 1298A>C and 677C>T genotypes were not associated with grade 3-4 overall toxicity, febrile neutropenia or hand-foot syndrome. MTHFR 1298CC homozygotes showed a borderline significantly higher incidence of grade 3-4 diarrhoea compared with MTHFR 1298AC or AA individuals (25 vs. 5%, P=0.041) in the monotherapy cohort. No significant association was found between the MTHFR genotypes and efficacy parameters in either treatment cohort. MTHFR polymorphisms are not associated with toxicity or efficacy in mCRC patients treated with capecitabine-based chemotherapy.

Methylenetetrahydrofolate reductase C677T polymorphism predicts response and time to progression to gemcitabine-based chemotherapy for advanced non-small cell lung cancer in a Chinese Han population

The aim of this study was to evaluate the association between the methylenetetrahydrofolate reductase (MTHFR) C677T excision repair cross-complementation group 1 (ERCC1) genetic polymorphisms and the clinical efficacy of gemcitabine-based chemotherapy in advanced non-small cell lung cancer (NSCLC). A total of 135 chemonaive patients with unresectable advanced NSCLC were treated with gemcitabine/platinum regimens. The polymorphisms of MTHFR C677T, ERCC1 C8092A, and ERCC1 C118T were genotyped using the TaqMan methods. The overall response rate was 28.9%. Patients with MTHFR CC genotype had a higher rate of objective response than patients with variant genotype (TT or CT) (41.2% versus 19.1%, P=0.01). Median time to progression (TTP) of patients with MTHFR CC genotype was longer than that of patients with variant genotype (7.6 months versus 5.0 months, P=0.003). No significant associations were obtained between ERCC1 C118T and C8092A polymorphisms and both response and survival. Our data suggest the value of MTHFR C677T polymorphism as a possible predictive marker of response and TTP in advanced NSCLC patients treated with gemcitabine/platinum.

Diet Folate, DNA Methylation and Polymorphisms in Methylenetetrahydrofolate Reductase in Association with the Susceptibility to Gastric Cancer

Methylenetetrahydrofolate reductase (MTHFR) has been reported to be associated with DNA methylation, an epigenetic feature frequently found in gastric cancer. We conducted a case-control study to explore the association of MTHFR C677T polymorphisms with gastric cancer risk and its relation with the DNA methylation of COX-2, MGMT, and hMLH1 genes. Genotyping of P16, MGMT and HMLH1 was determined by methylation-specific PCR after sodium bisulfate modification of DNA, and genotyping of MTHFR C677T was conducted by TaqMan assays using the ABI Prism 7911HT Sequence Detection System. Folate intake was calculated with the aid of a questionnaire. Compared with the MTHFR 677CC genotype, the TT genotype was significantly associated with 2.08 fold risk of gastric cancer when adjusting for potential risk factors. Individuals who had an intake of folate above 310 μg/day showed protective effects against gastric cancer risk. The effect of MTHFR C677T polymorphisms on the risk of gastric cancer was modified by folate intake and methylation status of MGMT (P for interaction <0.05).

Methylenetetrahydrofolate reductase and methionine synthase reductase gene polymorphisms in ethnic Han women from Linyi

To explore the distribution of genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) 677C/T, 1298A/C and methionine synthase reductase (MTRR) 66A/G among ethnic Han females from Linyi, and to correlate it with serum level of homocysteine (Hcy). A cross-sectional study was carried out. Oral epithelial cell samples were collected from 825 subjects. MTHFR and MTRR gene polymorphisms were determined with a Taqman-Minor Groove Binder (MGB) method. Distribution of gene polymorphisms was analyzed and compared with others regions of China including Weifang, Zhengzhou, Deyang and Hainan. A biochemical assay was also carried out to determine the total Hcy in plasma of 281 subjects. The reductase activity of MTHFR was classified into decreased and stable groups according to genetic polymorphism of MTHFR. Correlation between MTHFR groups and total Hcy level were also explored. (1) The frequencies of MTHFR677CC, CT and TT genotypes of the selected subjects were 16.7%, 48.3% and 35.0%, respectively. The frequencies of MTHFR 1298AA, AC and CC genotypes were 76.0%, 21.6% and 2.4%, respectively. And those of MTRR 66AA, AG and GG genotypes were 54.7%, 39.4% and 5.9%, respectively. For the selected subjects, their frequency of MTHFR 677TT genotype was higher than that of Deyang and Hainan (P< 0.01), whilst the frequency of MTHFR 1298CC genotype was lower than that of Deyang and Hainan (P < 0.01), and the frequency of MTRR 66 GG genotype was lower than that of Hainan (P< 0.01). (2) The Hcy level for those with decreased MTHFR activity was significantly higher than those with stable MTHFR activity (P< 0.05). MTHFR gene 677C/T, 1298A/C and MTRR 66A/G polymorphisms in ethnic Han women from Linyi have differed significantly from other regions of China. Decreased MTHFR activity caused by genetic polymorphisms is a risk factor for raised Hcy level.

MTHFR C677T AND MTR A2756G POLYMORPHISMS AND THE HOMOCYSTEINE LOWERING EFFICACY OF DIFFERENT DOSES OF FOLIC ACID IN HYPERTENSIVE CHINESE ADULTS

ObjectivesThis study aimed to investigate if the homocysteine-lowering efficacy of two commonly used physiological doses (0.4 mg/d and 0.8 mg/d) of folic acid (FA) can be modified by individual methylenetetrahydrofolate...

Influence of Methylenetetrahydrofolate Reductase C677T Gene Polymorphisms in Algerian Infertile Men with Azoospermia or Severe Oligozoospermia

The C677T allele of the methylenetetrahydrofolate reductase (MTHFR) gene has been suggested to represent a risk factor for male infertility. To confirm this association, the distribution of the single-nucleotide polymorphism C677T was investigated in idiopathic infertile Algerian patients with nonobstructive azoospermia (NOA) or severe oligoasthenoteratozoospermia (OAT). A case-control study was carried out, including 74 idiopathic infertile Algerian patients with NOA (n=46) or severe OAT (n=28) and 84 fertile men as controls. Polymorphism C677T was studied by polymerase chain reaction-restriction fragment length polymorphism, and the results were statistically analyzed. The frequency of genotypes MTHFR 677CC, 677CT, and 677TT in idiopathic infertile men with NOA was 43.48%, 41.30%, and 15.22%; 39.29%, 50%, and 10.71% regarding the severe oligozoospermic men; and 42.86%, 45.24%, and 11.90% in the control group. The data suggest that the C677T MTHFR polymorphism is not a risk factor for idiopathic male subfertility in an Algerian population.

Abstract 3128: Diet folate, DNA methylation and genetic polymorphisms of MTHFR C677T in esophageal squamous cell carcinoma

Abstract Background: To explore the role of aberrant hypermethylation of cancer related genes in the esophageal squamous cell carcinoma (ESCC) as well as its relation to dietary folate intake and MTHFR C677T polymorphism, we conducted a molecular epidemiological study in the Chinese population. Methods: This study was conducted in Yangzhong County, an island located on the middle of Yangtze River in the southeast part of Jiangsu Province, China. Totally, 125 ESCC patients having undergone esophagectomy between January 2005 and March 2006 in the Yangzhong People's Hospital were recruited and followed. Face-to-face interviews were conducted by trained investigators using a structured questionnaire. A food frequency questionnaire was used to estimate the dietary intake. For patients having undergone surgery, tissues in the center of the cancer lesion and remote normal appearing esophagus were excised. The methylation at the promoter region of P16, MGMT and hMLH1 was determined by methylation specific PCR. The effects of diet folate, aberrant DNA methylation of selected genes and methylenetetrahydrofolate reductase (MTHFR) C677T genetic polymorphisms were analyzed. Results: The aberrant CpG island hypermethylation of P16, MGMT and hMLH1 gene could be found in cancer tissues with frequency of about 88.0%, 27.2% and 3.2% respectively, and in remote normal appearing esophageal tissues with frequency of about 36.8%, 11.2% and 0.0% respectively. MGMT gene showed a higher proportion of hypermethylation in cancer tissues while P16 gene showed a higher proportion of hypermethylation in remote normal appearing esophageal tissues in patients with lymph node metastasis. A significant association was found between MTHFR C677T genetic polymorphism and CpG island methylation status of MGMT gene. After adjustment for potential confounders, individuals carrying CT or TT genotype have higher frequency of hypermethylation in MGMT gene in cancer tissues with odds ratio 3.34 (95% CI:1.07-10.39) and 3.83 (95% CI:1.13-12.94) respectively. Based on the follow-up data, our analysis showed an inverse association between diet folate intake and the risk of death after esophagectomy. The median survival time was 2.92 years for low folate consumption, 3.18 years for moderate folate consumption and over 4.59 years for high folate consumption. After adjusting for potential confounders, the hazard ratios (95% confidence interval) were 0.72(0.36-1.46) for moderate and 0.39(0.20-0.78) for high folate intake, respectively. This preventive effect was more evident in patients carrying MTHFR 677CC genotype. Conclusions: This study indicated the aberrant CpG island hypermethylation of cancer related genes were associated with ESCC and might be a promising biomarker in diagnosis. Diet folate intake may have benefits on the prognosis of ESCC after esophagectomy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3128. doi:1538-7445.AM2012-3128

Folate Intake and Methylenetetrahydrofolate Reductase Gene Polymorphisms as Predictive and Prognostic Biomarkers for Ovarian Cancer Risk

Folic acid and methylenetetrahydrofolate reductase (MTHFR) may affect the development of human cancer. However, few studies have evaluated folate intake and MTHFR in susceptibility to and prognosis of patients with ovarian cancer. We conducted a prospective case-control study in 215 ovarian cancer patients and 218 controls (all Chinese) between Jan. 2004 and Jan. 2007. MTHFR C677T genotyping was done by PCR-RFLP. All patients were followed up until Dec. 2010. We found a 2.43-fold increased risk of ovarian cancer among MTHFR 677TT carriers, and a decreased risk of ovarian cancer in individuals with high folate intake (OR = 0.54, 95% CI = 0.32–0.94). Cox regression survival analysis showed that among the ovarian cancer patients, those carrying the 677TT genotype had a higher risk of death (HR = 2.17, 95% CI = 1.20–4.79), while high folate intake was associated with a lower risk of death (HR = 0.43, 95% CI = 0.33–0.88). Moreover, MTHFR 677CC carriers with higher folate intake showed a lower risk of death from ovarian cancer (HR = 0.32, 95% CI = 0.27–0.82). In summary, high folate intake may lessen susceptibility and improve the prognosis of ovarian cancer patients, while the MTHFR 677TT genotype appears to increase ovarian cancer risk and worsen its prognosis in a Chinese population.

MTHFR C677T and MTR A2756G polymorphisms and the homocysteine lowering efficacy of different doses of folic acid in hypertensive Chinese adults

BackgroundThis study aimed to investigate if the homocysteine-lowering efficacy of two commonly used physiological doses (0.4 mg/d and 0.8 mg/d) of folic acid (FA) can be modified by individual methylenetetrahydrofolate reductase (MTHFR) C677T and/or methionine synthase (MTR) A2756G polymorphisms in hypertensive Chinese adults.MethodsA total of 480 subjects with mild or moderate essential hypertension were randomly assigned to three treatment groups: 1) enalapril only (10 mg, control group); 2) enalapril-FA tablet [10:0.4 mg (10 mg enalapril combined with 0.4 mg of FA), low FA group]; and 3) enalapril-FA tablet (10:0.8 mg, high FA group), once daily for 8 weeks.ResultsAfter 4 or 8 weeks of treatment, homocysteine concentrations were reduced across all genotypes and FA dosage groups, except in subjects with MTR 2756AG /GG genotype in the low FA group at week 4. However, compared to subjects with MTHFR 677CC genotype, homocysteine concentrations remained higher in subjects with CT or TT genotype in the low FA group (P < 0.05 for either of these genotypes) and TT genotype in the high FA group (P < 0.05). Furthermore, subjects with TT genotype showed a greater homocysteine-lowering response than did subjects with CC genotype in the high FA group (mean percent reduction of homocysteine at week 8: CC 10.8% vs. TT: 22.0%, P = 0.005), but not in the low FA group (CC 9.9% vs. TT 11.2%, P = 0.989).ConclusionsThis study demonstrated that MTHFR C677T polymorphism can not only affect homocysteine concentration at baseline and post-FA treatment, but also can modify therapeutic responses to various dosages of FA supplementation.

Sequence Variation of the Methylene Tetrahydrofolate Reductase Gene (677C&gt;T and 1298 A&gt;C) and Traditional Risk Factors in a South Indian Population

Methylene tetrahydrofolate reductase (MTHFR) plays a significant role in the metabolism of methionine. MTHFR deficiency is an autosomal recessive trait that could be a significant risk factor for a number of defects, for example, vascular events, due to lower dietary folate intake among South Indians. To find the incidence of 677 C>T and 1298 A>C in MTHFR gene single nucleotide polymorphisms (SNPs) among the south Indian population, polymerase chain reaction and restriction fragment length polymorphism were employed among 152 patients with myocardial infarction and 167 controls. The MTHFR 677CT genotype was found among 35 (22.4%) cases and 08 (4.8%) controls, the MTHFR 677CC allele was found among 115 (73.7%) cases and 159 (94.6%) controls. Also, the analysis of the MTHFR 1298A>C SNP identified the MTHFR 1298CC genotype among 16 (10.3%) cases and 01 (0.6%) control, the MTHFR 1298AC genotype was found in 56 (35.9%) cases and 27 (16.2%) controls, and the MTHFR 1298AA genotype was observed in 80 (51.3%) cases and 139 (82.6%) controls. The C vs. A allele also showed significantly higher frequency among the patients in comparison with the controls (p<0.0001). The results of this study indicate that the MTHFR A1298C SNP is more prevalent among south Indians compared with the MTHFR C677T SNP, suggesting a possible role of MTHFR A1298C in the pathogenesis of heart diseases.

An enhanced risk of basal cell carcinoma is associated with particular polymorphisms in the VDR and MTHFR genes

Vitamin D and folate are influenced by ultraviolet radiation (UVR), and both are implicated in skin carcinogenesis. Polymorphisms in the genes involved in the metabolism of these two compounds may alter the risk of basal cell carcinoma (BCC). To assess the frequency of four polymorphisms in the gene encoding the vitamin D receptor (VDR) (FokI, BsmI, TaqI and ApaI) and two in the gene encoding methylenetetrahydrofolate reductase (MTHFR) (677C/T and 1286A/C) in 142 patients of Polish origin with BCC and the same number of controls. The expression of VDR and MTHFR proteins in the skin, and the vitamin D status of a subset of patients and controls were also measured. The polymorphisms were assayed by PCR-RFLP, the VDR and MTHFR proteins by immunoblotting and vitamin D status as 25-hydroxyvitamin D (25(OH)D) level in the serum by RIA. The presence of the TT genotype in the FokI VDR polymorphism resulted in a >10-fold higher risk of BCC development. The CT genotype in 677C/T MTHFR polymorphism and CC genotype in 1286A/C MTHFR polymorphism also significantly increased the risk of BCC development. The expression of the VDR and MTHFR proteins was significantly higher in BCCs of the patients than in the healthy skin of the controls. The median serum level of 25(OH)D was significantly higher in the control group compared with the patients with BCC. Certain VDR and MTHFR gene polymorphisms increase the risk of BCC development in individuals of Polish origin.

Polymorphisms of the Methylene Tetrahydrofolate Reductase and Susceptibility to Acute Lymphoblastic Leukemia in Children

Background: Correlation between epigenetic factors and their effects on hematopoietic cells has led to a study of 2 common functional polymorphisms (C677T and A1298C) of 5,10methylene tetrahydrofolate reductase (MTHFR) enzyme. The aim of this study was to assess the individual and/or combined roles of these 2 polymorphisms in pediatric acute lymphoblastic leukemia (ALL). Methods: Using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analyses, we studied the frequencies of the C677T and A1298C MTHFR genotypes in 103 pediatric ALL patients and 160 age-sex matched controls. We calculated the odds ratio (OR) of MTHFR genotypes to determine if 1 or both of these polymorphisms may be associated with childhood ALL. Results: The T allele frequency for MTHFR 677C>T was 22.2% and 18.45% in controls and cases, respectively. The C allele frequency for MTHFR 1298 A>C was 40.65% and 40.72% in controls and cases, respectively. The OR for MTHFR 677CT was 1.08 (95%CI 0.58-1.95) and OR for MTHFR 677TT was 0.25 (95%CI 0.05-10.24). The OR for MTHFR 1298 AC was 0.57 (0.95% CI 0.57-1.95) and for MTHFR CC was 0.96 (0.95% CI 0.37-2.45). The OR for the combined heterozygous status (677CT and 1298AC) was 1.08 (95% CI 0.41-2.82). Conclusion: Our findings suggest that the MTHFR C677T and A1298C gene variants lack a major influence on the susceptibility for pediatric ALL. Another result was that the C allele frequency for MTHFR 1298 A>C was significantly higher than those reported for most Asian and European populations. The C677T prevalence seems to be similar to those reported in most Asian populations.

Methylenetetrahydrofolate Reductase (MTHFR) Gene C677T, A1298C and G1793A Polymorphisms: Association with Risk for Clear Cell Renal Cell Carcinoma and Tumour Behaviour in Men

AimsMethylenetetrahydrofolate reductase (MTHFR) plays a crucial role in regulating folate metabolism, which affects DNA synthesis and methylation. This study investigated whether MTHFR C677T, A1298C and G1793A polymorphisms modified clear cell renal cell carcinoma (CCRCC) risk independently as well as in combination with serum total homocysteine (Hcy) and folate levels. Materials and methodsA case–control study of 152 cases (men) and 304 age-matched healthy controls was conducted in one geographical area of Iran. Genotyping of MTHFR gene polymorphisms was carried out using a polymerase chain reaction restriction fragment length polymorphism technique. Serum levels of total Hcy, folate and vitamin B12 were also determined. ResultsThe MTHFR 677T and 1298C allele frequencies were 42.8 and 47.4% in cases, compared with 33.7 and 33.1% in controls. After controlling for confounding factors, a significant increase in CCRCC risk was found among carriers of the 677CT genotype compared with those with the 677CC genotype (odds ratio 2.21, 95% confidence interval 1.31–3.76), with a significant trend (P=0.014). Statistically significant odds ratios were also found in patients homozygous for MTHFR C677T, who have a 1.58-fold higher risk of developing CCRCC (95% confidence interval=1.21–2.44; P=0.024). Compared with the MTHFR 677CC genotype, the odds ratio (95% confidence interval) for the MTHFR 677TT genotype was 6.18 (95% confidence interval=4.75–8.34) for stage IV cancer and 4.68 (95% confidence interval=2.72–6.54) for grade 3 CCRCC (both P=0.0001). After adjustment for selected variants, the MTHFR 1298AC genotype showed a significantly increased risk of CCRCC compared with the wild-type (odds ratio=3.71, 95% confidence interval=2.22–5.33; P=0.001), and the 1298C allele carrier showed a positive association with the risk of CCRCC compared with the wild-type (odds ratio=3.9, 95% confidence interval=2.55–6.02; P=0.001). Furthermore, subjects carrying at least one copy of the variant allele showed a 4.4 times increased risk of developing CCRCC than their control counterparts (odds ratio=4.40, 95% confidence interval=2.41–6.72; P=0.0001). There was not a significant interaction between MTHFR polymorphisms and serum levels of total Hcy and folate in increasing the risk of CCRCC. ConclusionsOur results provide evidence that the MTHFR polymorphisms might contribute to increased CCRCC risk in men.

Maternal depressed mood during pregnancy, MTHFR C677T genotype, and vitamin B12 status

Depression occurs in ~15% of pregnant women, and 1/3 are taking selective serotonin reuptake inhibitors (SSRIs) as antidepressants. Disturbances in methyl metabolism have been found in adults with depression. A variant (C677T) in the gene for methylenetetrahydrofolate reductase (MTHFR), an enzyme in methyl metabolism, is also associated with depression. However, the role of methyl metabolism and the MTHFR C677T variant in depression during pregnancy is unknown. We investigated if disturbances in methyl metabolism are associated with maternal depressed mood during pregnancy. Pregnant women (n=176) with the MTHFR 677TT genotype had greater depressed mood (Edinburgh Postnatal Depression Scale, EPDS; and Symptom Questionnaires, SQ) in the 2nd trimester and 5–6 days postpartum (P&lt;0.05) than women with the MTHFR 677CC genotype. In a subset of women, serum vitamin B12 levels at delivery correlated with infant vitamin B12 levels at birth (P&lt;0.01). Serum vitamin B12 levels were lower in infants and their mothers at birth who had depression compared to infants and their mothers without depression or those with depression and treated with SSRIs (P&lt;0.01). These findings suggest that the MTHFR 677TT genotype and low serum vitamin B12 levels are associated with depressed mood during pregnancy and may contribute to the pathology of depression during pregnancy.Grant Funding Source: Interdisciplinary Women's Reproductive Health Research Training Program, and Canadian Institutes of Health Research.