Investigation of the association of idiopathic male infertility with polymorphisms in the methionine synthase (MTR) gene / 대한생식의학회지

OBJECTIVE: Spermatogenesis is a complex process that is regulated by a number of genes, some of which are involved in folate-dependent 1-carbon metabolism. Methionine synthase (encoded by MTR) is a key enzyme participating in this pathway. This study aimed to investigate the relationship of the MTR 2756A > G polymorphism with idiopathic male fertility in the Iranian population. METHODS: The participants of this study included 100 men with idiopathic infertility and 100 healthy men as the control group. Genotyping of MTR 2756A > G was performed using the polymerase chain reaction and restriction fragment length polymorphism technique. The obtained data were analyzed using SPSS ver. 20.0 with a level of confidence of p G single-nucleotide polymorphism is not a predisposing factor for idiopathic infertility in men.

Methionine synthase A2756G and reduced folate carrier1 A80G gene polymorphisms as maternal risk factors for Down syndrome in Egypt

Background: Polymorphisms of genes encoding enzymes involved in folate metabolism have long been hypothesized to be maternal risk factors for Down syndrome, however, results are conflicting and inconclusive

Aim of the study: To analyze the effect of methionine synthase [MTR] A2756G, and reduced folate carrier [RFC1] A80G gene polymorphisms on the maternal risk for DS

Patients: This study was conducted in the Medical Genetics Center, Ain-Shams University hospitals, on a total of 170 mothers of children, diagnosed with Down syndrome, who were attending the center. Eighty-five control mothers were also enrolled in the study

Methods: Genotype analyses were performed using PCR-RFLP to detect RFC1A80G and MTRA2756G gene polymorphisms in all case and control mothers

Results: Comparing RFC1A80G genotype frequency between both groups revealed, that the frequency of the AA genotype in case mothers [94.11%] is highly significantly [p< 0.001] greater than its frequency in control mothers [74.11%], with no significant difference between the two groups regarding GG genotype. Comparing RFC1 A80G allele frequency between the two groups revealed a high frequency of the A allele among case mothers [94.11%], which showed a highly statistically significant difference [p<0.001] from the control group [55.29%], meanwhile the G allele showed a low frequency of 5.88% in DS mothers compared to 22.35% in the control mothers, with a highly statistically significant difference [p<0.001] between the two groups. Regarding MTRA2756G polymorphism, it was found that the AA genotype predominated in the control group [65.88%] with a highly statistically significant difference [p< 0.001] from case mothers group [5.88%]. Comparing MTR allele frequency between the two groups revealed predominance of the G allele among mothers of DS children [76.47%]

Conclusion: Current results provide strong evidence that the MTRA2756G, and RFC1 80 A genotypes could be considered as maternal risk factors for DS in Egyptian mothers

An association study between gene polymorphism of the key enzyme's folacin metabolism pathway and plasmatic homocysteine levels in fertile woman / 中华预防医学杂志

<p><b>OBJECTIVE</b>The effect of the gene polymorphism for the key enzyme's folacin metabolism pathway on plasmatic homocysteine (Hcy) levels in fertile woman was observed.</p><p><b>METHODS</b>The subjects were from Shaoxing City, Jiangsu province in 2012, the selection criteria for the women of childbearing age were between 20-45 years old, with an average age of 28.2 (95%CI:27.8-28.6) years old. Sample collection continued uninterrupted lasted seven days, a total of 535 samples were collected, venous blood with EDTA addition or sodium citrate to anticoagulant. After separation, the blood cells and blood plasma were cryopreserved. DNA was extracted using spin column method. All the samples were selected for the gene polymorphism testing of the key enzyme's on folate metabolism and monitoring of plasmatic Hcy level.</p><p><b>RESULTS</b>Eight single nucleotide polymorphism (SNP) sites of methylenetetrahydrofolate reductase gene (MTHFR) , methionine synthase gene (MS) , synthetic methionine reductase gene (MSR) and cystathionine β synthase gene (CBS) were detected. It was found the genotype AA of the SNP sites-rs1801131 would result higher plasmatic Hcy levels (8.99 µmol/L) than the genotypes CC (7.81 µmol/L) and CA(8.38 µmol/L) (P < 0.01) . Similarly, the genotype TT of the SNP sites-rs1801133 was significantly responded to the increasing of Hcy levels (11.10 µmol/L) than the genotype CC (8.15 µmol/L) and CT (8.45 µmol/L), (P < 0.01) . The two sites of genotype combination of AA-TT could also result in the significant increase of Hcy levels (11.02 µmol/L) than other combined genotypes (genotypes CC-CC, CA-CC, CA-CT, AA-CC, AA-CT), especially the genotype CC-CC. And the risk factor was 1.41 (95CI:1.20-1.66) times over the genotype CC-CC.</p><p><b>CONCLUSION</b>The gene mutations of two SNP sites rs1801131 and rs1801133 in MTHFR would increase Hcy levels.</p>

Interaction between maternal 5,10-methylenetetrahydrofolate reductase C677T and methionine synthase A2756G gene variants to increase the risk of fetal neural tube defects in a Shanxi Han population / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The 5,10-methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS) are attractive candidates for screening for risk of neural tube defects (NTDs). The aim of the current study was to investigate maternal MTHFR and MS polymorphisms and the interaction between them and their influence on children with NTDs in the Shanxi Province of northern China.</p><p><b>METHODS</b>Fifty-one mothers who previously had children with NTDs constituted the case group and 51 age-matched mothers with children that were unaffected by any birth defects constituted the control group. All subjects were genotyped for MTHFR C677T and MS A2756G polymorphisms. SPSS 11.5 software package was used for all analyses.</p><p><b>RESULTS</b>There was a significant difference for MTHFR genotype distribution for one site (C677T) between the case and control groups. The T allele frequencies were significantly higher in the case group than in the control group (55.9% vs. 35.3%, P < 0.05). A lack of association was observed for the MS A2756G polymorphism. There was an interaction between the maternal MTHFR C677T genotype and MS A2756G genotype.</p><p><b>CONCLUSION</b>Genetic interaction between MTHFR and MS genes raises the probability of neural tube defects.</p>

Polymorphisms of homocysteine metabolism enzyme-related genes MS and MSR in Buyi, Dong and Miao ethnics from Guizhou / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To investigate polymorphisms of homocysteine metabolism enzyme-related genes methionine synthase (MS) and methionine synthase reductase (MSR) in Buyi, Dong, Miao ethnics from Guizhou.</p><p><b>METHODS</b>Genotypes of MS and MSR genes of healthy individuals from the three ethnic groups were determined with a TaqMan-MGB probe genotyping method and compared.</p><p><b>RESULTS</b>For Buyi, Dong and Miao ethnics from Guizhou, frequencies of MS gene 2756G allele were respectively 12.0%, 8.9% and 15.4%. However, no significant difference was found by statistics. Frequencies of MS A2756G alleles for the three ethnic groups are similar to those of Han Chinese from Beijing and Henan, Hui ethnics from Ningxia as well as European populations, but differ significantly from those of Japanese, Indians, Africans and Nigerians (P < 0.05). Frequencies of MSR gene 66 G allele were respectively 32.3%, 30.4% and 21.2% for Buyi, Dong and Miao ethnics. Miao is significantly lower than Buyi and Dong (P< 0.05). Frequencies of MSR gene A66G alleles for the three ethnic groups are similar to those of Han Chinese from Beijing and Guangdong, Japanese, Africans and Nigerians populations, but differ significantly from those of Indians and European (P< 0.05).</p><p><b>CONCLUSION</b>The distributions of MS gene A2756G and MSR gene A66G polymorphisms have differed significantly between the three ethnic groups and individuals from various regions.</p>

Association Study between Folate Pathway Gene Single Nucleotide Polymorphisms and Gastric Cancer in Koreans

Gastric cancer is ranked as the most common cancer in Koreans. A recent molecular biological study about the folate pathway gene revealed the correlation with a couple of cancer types. In the folate pathway, several genes are involved, including methylenetetrahydrofolate reductase (MTHFR), methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR), and methyltetrahydrofolate-homocysteine methyltransferase (MTR). The MTHFR gene has been reported several times for the correlation with gastric cancer risk. However, the association of the MTRR or MTR gene has not been reported to date. In this study, we investigated the association between the single nucleotide polymorphisms (SNPs) of the MTHFR, MTRR, and MTR genes and the risk of gastric cancer in Koreans. To identify the genetic association with gastric cancer, we selected 17 SNPs sites in folate pathway-associated genes of MTHFR, MTR, and MTRR and tested in 1,261 gastric cancer patients and 375 healthy controls. By genotype analysis, estimating odds ratios and 95% confidence intervals (CI), rs1801394 in the MTRR gene showed increased risk for gastric cacner, with statistical significance both in the codominant model (odds ratio [OR], 1.39; 95% CI, 1.04 to 1.85) and dominant model (OR, 1.34; 95% CI, 1.02 to 1.75). Especially, in the obese group (body mass index > or = 25 kg/m2), the codominant (OR, 9.08; 95% CI, 1.01 to 94.59) and recessive model (OR, 3.72; 95% CI, 0.92 to 16.59) showed dramatically increased risk (p < 0.05). In conclusion, rs1801394 in the MTRR gene is associated with gastric cancer risk, and its functional significance need to be validated.

Purification and activity evaluation of methionine synthase / 药学学报

Methionine synthase (MS, EC2.1.1.13), a key enzyme in the folate metabolism area catalyzing methyl transfer from N5-methyltetrahydrofolate to homocysteine to give tetrahydrofolate and methionine, takes a core position in folate cycle, one-carbon-unit transfer and sculpture amino acid pathways. Cobalamin-dependent methionine synthase was purified from rat liver. The enzyme was purified 609-fold to near homogeneity by batch chromatography on DE-52, anion-exchange chromatography on Q Sepharose Fast Flow and CHT-I hydroxyapatite column and was identified by SDS-PAGE and Western blotting. The enzyme activity was determined by spectrophotometric assay. In addition, the influencing factor and optimal reaction condition were performed. The steady state kinetic of rat liver methionine synthase was similar to that of other mammalian cobalamin-dependent methionine synthase which employed a Ping-Pong mechanism. The result indicated that cobalamin-dependent methionine synthase purified from rat liver is suitable for screening and studying methionine synthase specific inhibitors.

Genetic variation in genes involved in folate and drug metabolism in a south Indian population.

BACKGROUND: Genetic variations represented as single nucleotide polymorphisms (SNPs) vary across the world population. This genetic polymorphism (such as SNPs) plays an important role in pharmacogenomics. SNPs that affects cellular metabolism, by altering the enzyme activity, have an important role in therapeutic outcome. Allele frequencies in number of clinically relevant SNPs within south Indian populations are not yet known. Hence, we genotyped randomly selected unrelated south Indian subjects from different locations of south India representing the heterogeneous ethnic background of the population. MATERIALS AND METHODS: Common variants of MTHFD1, TYMS, SHMT1, MTR, MTRR, CBS and SULT1A1 gene polymorphisms were screened from healthy unrelated south Indian volunteers. Genotypes were determined using RFLP analysis of polymerase chain reaction-amplified products and confirmed by DNA sequencing. Chi-square test was performed to test for deviation from the Hardy-Weinberg equilibrium for each locus. RESULTS: Gene allele frequency for several polymorphisms in our study differed significantly between the populations of other nations reported for several of the SNPs. These results demonstrate that the populations in different geographic regions may have widely varying genetic allele frequencies for clinically relevant SNPs. CONCLUSION: The present study reports, for the first time, the frequency distribution of MTHFD1, TYMS, SHMT1, MTR, MTRR, CBS and SULTIA1 gene polymorphisms in a south Indian population. Population-specific genetic polymorphism studies will help in practicing pharmacogenomic principles in the clinics.

Association of genetic polymorphisms in methionine metabolism genes with X-linked adrenoleukodystrophy / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To investigate the association of the polymorphisms of methionine metabolism genes and the phenotype of X-linked adrenoleukodystrophy (X-ALD) and clinical severity.</p><p><b>METHODS</b>The clinical information of 120 X-ALD patients were analyzed and three genetic variants involved in the methionine metabolism, including cystathionine beta-synthase (CBS) c.844_855ins68, 5-methyltetrahydrofolate-homocysteine-S-methyltransferase (MTR) c.2756A to G, and transcobalamin 2 (TC2) c.776 C to G were analyzed by polymerase chain reaction and sequencing. The association between these polymorphisms and phenotype of X-ALD was studied.</p><p><b>RESULTS</b>The frequency of GG genotype of the TC2 c.776 C/G was higher in patients with central nervous system(CNS) demyelination than in controls (P= 0.012). However, the other two polymorphisms did not show any significant associations with the phenotypes.</p><p><b>CONCLUSION</b>The GG genotype of TC2 c.776 C/G may contribute to X-ALD phenotype.</p>

Associations of polymorphisms of methionine synthase A2756G and methionine synthase reductase G66A with the risks of coronary artery disease: a meta-analysis / 中华预防医学杂志

<p><b>OBJECTIVE</b>To evaluate the associations between polymorphisms of methionine synthase(MTR) A2756G and methionine synthase reductase(MTRR) G66A and risk of coronary artery disease.</p><p><b>METHODS</b>Literatures in Medline reporting the relationship between polymorphisms of MTR A2756G and MTRR G66A and risk of coronary artery disease from January 1990 to May 2010 were searched. A total of 14 relevant articles were selected and 13 of them met the criteria. A Meta-analysis was performed to estimate the pooled odds ratio (OR) to evaluate the relationship between polymorphisms of MTR A2756G and MTRR G66A and risk of coronary artery disease. All analyses were performed using the STATA statistical software.</p><p><b>RESULTS</b>Among the 13 studies, eight case-control studies containing 2143 cases of coronary artery disease and 2270 controls were included in the analysis of MTR A2756G and risk of coronary artery disease. Meanwhile, five case-control studies with 811 cases of coronary artery disease and 387 controls were included in the analysis of MTRR G66A and risk of coronary artery disease. In the analysis of MTRR G66A related to the risk of coronary artery disease, there were 246 GG carries, 397 AG carriers and 168 AA carriers in the group of coronary artery disease, against 102 GG carriers, 203 AG carriers and 82 AA carriers in the control group. Compared with the MTRR GG carriers, the risk of coronary artery disease decreased significantly by 27% (OR = 0.73, 95%CI: 0.54 - 0.99) and 25% (OR = 0.75, 95%CI: 0.56 - 1.00) (Egger's test t = -0.19, P = 0.862) in the MTRR 66 AG and AG/AA carriers, respectively, and also decreased in the MTRR AA carriers but significant difference was observed (OR = 0.84, 95%CI: 0.42 - 1.68). There was no significant association between coronary artery disease and MTR A2756G.</p><p><b>CONCLUSION</b>These results suggest that MTRR66 may play a role in coronary artery disease susceptibility. MTRR 66 A allele carries are associated with a statistically significant decreased risk of coronary artery disease susceptibility.</p>

No association of the A2756G polymorphism of methionine synthase gene with nonsyndromic cleft lip with or without cleft palate / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To study the association of the A2756G polymorphism of the methionine synthase (MS) gene with nonsyndromic cleft lip with or without cleft palate (NSCL/P) in Chinese.</p><p><b>METHODS</b>Ninety-seven NSCL/P case-parent triads were selected as the case group. One hundred and four healthy subjects and their biological parents were selected as control group. For all subjects the A2756G polymorphism of the MS gene was examined by PCR-RFLP method.</p><p><b>RESULTS</b>There was no statistical difference in genotype and allele frequencies for MS A2756G variants among family members between case group and control group. The GG genotype was not detected in the offsprings and mothers. The odds ratio and confidence interval of genotype AG in offspring, father and mother were 1.78(0.74-4.34), 0.80(0.36-1.79) and 1.26(0.54-2.93) respectively. The odds ratio and confidence interval of allele G in offspring, father and mother were 1.70(0.78-3.73), 0.88(0.49-1.75), and 1.23(0.59-2.60) respectively. The G allele did not increase the risk of NSCL/P. Transmission disequilibrium test (TDT) analysis yielded no evidence of linkage disequilibrium (chi-square=0.034,P>0.05). The results of haplotype-based haplotype relative risk (HHRR) analysis (chi-square=0.03,P>0.05) and family-based association tests (FBAT) (Z=0.186, P>0.05) failed to show association between the MS A2756G variant and the risk of NSCL/P.</p><p><b>CONCLUSION</b>The A2756G polymorphism of the MS gene was not associated with NSCL/P in Chinese in the present study.</p>

Plasma homocysteine and gene polymorphisms associated with the risk of hyperlipidemia in northern Chinese subjects / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>To examine the relationship between occurrence of hyperlipidemia, plasma homocysteine and polymorphisms of methylenetetra hydrofolate reductase (MTHFR) gene and methionine synthase (MS) gene.</p><p><b>METHODS</b>A total of 192 hyperlipidemia patients were selected and divided into hypercholesterolemia group, hypertriglyceridemia group, and combined hyperlipidemia group. Another 208 normal individuals were selected as control. Total plasma homocysteine (tHcy) concentration was measured by high-performance liquid chromatography (HPLC). Lipid profiles were measured for all subjects. The polymorphisms of MTHFR gene C677T and MS gene A2756G were analyzed by PCR-RFLP.</p><p><b>RESULTS</b>The tHcy concentration in the combined hyperlipidemia patients was significantly higher than that in the control (15.95 micromol/L vs 13.43 micromol/L, P < 0.05). The prevalence of hyperhomocysteinemia (HHcy) in the combined hyperlipidemia group was significantly higher than that in the control (42.2% vs. 23.0%, P = 0.015), with the odds ratio (OR) of 3.339 (95% CI: 1.260-8.849). The hyperlipidemia patients with HHcy had a higher concentration of total cholesterol (TC) than that in the normal tHcy patients (5.67 +/- 0.95 mmol/L vs. 5.47 +/- 0.92 mmol/L, P=0.034). There was no significant difference in genotype or allele frequencies of MTHFR C677T between the hyperlipidemic and control groups. The hyperlipidemia patients with MTHFR CT/TT genotype had a higher concentration of triglyceride (TG) than those with CC genotype (2.24 +/- 1.75 mmol/L vs 1.87 +/- 0.95 mmol/L, P < 0.05). Individuals with CT/TT genotype had a higher concentration of tHcy than those with 677CC genotype both in the hyperlipidemia group (12.61 +/- 1.24 micromol/L vs. 11.20 +/- 1.37 micromol/L, P < 0.05) and in the control group (14.04 +/- 1.48 micromol/L vs. 12.61 +/- 1.24 micromol/L, P < 0.05). The percentage of MS 2756 GG/AG genotype in the combined hyperlipidemia group was significantly higher than that in the control (26.7% vs. 13.0%, P = 0.012), with the OR of 3.121 (95% CI: 1.288-7.651). The hyperlipidemia patients with MS 2756AG/GG genotype had a higher concentration of TC (5.87 +/- 0.89 mmol/L vs. 5.46 +/- 0.93 mmol/L, P < 0.05) and LDL-C (3.29 +/- 0.81 mmol/L vs. 2.94 +/- 0.85 mmol/L, P < 0.05) than those with AA genotype. However, individuals with 2756AG/GG genotype showed no significant difference in tHcy among those with AA genotype.</p><p><b>CONCLUSION</b>HHcy and MS A2756G mutation may be the risk factors for combined hyperlipidemia. Further study is needed to confirm the role of HHcy and MS A2756G mutation in the development of hyperlipidemia.</p>

Polymorphisms of 5, 10-Methylentetrahydrofolate Reductase (MTHFR C677T) and Methionine Synthase Reductase (MTRR A66G) as Maternal Risk Factors for Fetal Aneuploidy

PURPOSE: Aneuploidy is the cause of diseases such as Down syndrome or Edward syndrome and, more generally, is a major cause of mental retardation and fetal loss. The purpose of this study was to evaluate the association between MTHFR (C677T) or MTRR (A66G) polymorphisms and fetal aneuploidy. MATERIALS AND METHODS: Data was collected from 37 women who had a fetus with aneuploidy (cases) and 78 women who had previously delivered at least two healthy children without aneuploidy and did not have a history of miscarriage or abnormal pregnancy (controls). The MTHFR (C677T) or MTRR (A66G) polymorphisms were analyzed by PCR-restriction fragment length polymorphism assay. RESULTS: The frequencies of the MTHFR 677 CC, CT, and TT genotypes were 30.7%, 48.7%, and 20.6% in the control group and 37.8%, 48.6%, and 13.5% in the case group, respectively. There were no significant differences in genotype frequencies between the two groups. For the MTRR A66G polymorphism, the frequencies of the AA, AG and GG genotypes were 50%, 46.1%, and 3.9% in the control group and 13.5%, 81.1%, and 5.4% in case group, respectively. The frequency of the MTRR AG mutant was significantly increased in the case group, with an odds ratio of 6.5 (95% CI: 2.3-18.6, P<0.05). CONCLUSION: The results of this study suggest that mother carriers with the MTRR G allele have an increased risk of fetal aneuploidy, while the MTHFR T allele is not associated with increased risk of fetal aneuploidy. The MTRR A66G polymorphism may be a risk factor for producing a child with chromosomal aneuploidy.

Synergistic effect of methyltetrahydrofolate reductase [MTHFR] C677T and a1298C polymorphism as risk modifiers of pediatric acute lymphoblastic leukemia

ALL is the most common pediatric cancer. The causes of the majority of pediatric acute leukemia are unknown and are likely to involve an interaction between genetic and environmental factors. Therefore, unfavourable gene-environmental interactions might be involved in the genesis of ALL. The aim of this work was to evaluate, in a case-control study, whether the common polymorphisms in 5, 10-methylenetetrahydro-folate reductase [MTHFR] namely [C677T and A1298C] and methionine synthase [MS] [A2756G] genes may play a role in altering susceptibility to pediatric ALL as individual genes and in combination. DNA of 88 ALL patients [age <18 years] and 311 healthy control subjects was analyzed for the polymorphisms of MTHFR and MS genes using PCR-RFLP method. The frequencies of the wild types of MTHFR 677CC, MTHFR 1298AA and MS 2756AA, the homozygous genotypes of MTHFR 677TT, MTHFR 1298CC and MS 2756GG and heterozygous genotypes of MTHFR 677CT and MS 2756AG showed no statistically significant differences between patients and controls. The frequency of the MTHFR 1298AC heterozygous genotype was 25% among patients compared to 45.0% among controls; the difference was found to be statistically significant [p value =0.001, O.R=0.382 and 95% C.1=0.222-0.658]. The frequency of the MTHFR 1298AC heterozygous genotype plus 1298CC homozygous genotype was 34% among patients compared to 54.3% among controls and the difference was statistically significant [p value=0.001]. A synergistic effect of 677CT and 298AC [CTAC] was observed, [p value=0.002] with 3.65 fold protection [OR 0.273 and 95% C.1=0.155-0.9] compared to 2.6 folds for MTHFR 1298AC alone. This protective effect of CTAC polymorphism was abolished when combined with MS 2756AA or AG. The present study provided further evidence for the protective role of MTHFR 1298AC mutant alleles in acute lymphoblastic leukemia in children [2.6 fold protection]. This suggests that folate and methionine metabolism play an important role in the pathogenesis of pediatric ALL. In contrast to the main bulk of literature, we did not find any protective role of either MTHFR C677T or MS A2756G polymorphisms. This may reflect the ethnic variation in both the polymorphism frequencies, variation in plasma level of folate in addition to the possible role of gene-environment interaction mainly dietary availability of folate. The synergistic effect of MTHFR 1298AC and 677CT and its abolishment by MS 2756AA or AG further emphasizes that the interaction of genes, rather than the polymorphism in any single one, determines risk susceptibility to disease

Association between genetic polymorphisms in folate metabolic enzyme genes and colorectal cancer: a nested case-control study / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To investigate the interrelationship of genetic polymorphisms in folate metabolic enzymes (MTHFRC677T, MTHFRA1298C, MTRA2756G and MTRRA66G) and their combinative effects with colorectal cancer (CRC).</p><p><b>METHODS</b>A nested case-control study was designed and carried out. 140 CRC patients and 343 control subjects were included in this study. Polymorphisms of folate metabolic enzyme genes were genotyped by PCR-restriction fragment length polymorphism method. Risk of CRC was estimated by unconditional logistic model, and P value for interaction was calculated by likelihood test.</p><p><b>RESULTS</b>The allele of MTR2756G showed a positive association with CRC (OR = 2.04, 95% CI = 1.22 - 3.40). Those with MTHFR1298AA and MTR 2756AG/GG genotypes had an elevated risk with CRC (OR = 2.57, 95% CI, 1.42 -4.65), and their combinative effect showed a significant association with CRC (P = 0.04).</p><p><b>CONCLUSION</b>MTR2756G allele may be a risk factor of CRC, and interaction may exsit between polymorphisms of MTHFRA1298C and MTRA2756G. Further studies with larger sample and in different ethnic groups are needed.</p>

Study on the association of polymorphisms in homocysteine metabolism related enzymes with deep venous thrombosis / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To explore the significance of gene mutation of methylenetetrahydrofolate reductase (MTHFR) C677T, methionine synthase (MS) 2756 AG and cystathionine beta-synthase (CBS) 844ins68 in the development of deep venous thrombosis.</p><p><b>METHODS</b>One hundred and three cases of deep venous thrombosis (DVT group) and 250 healthy subjects (control group) were recruited in the study. The polymorphisms of MTHFR C677T, MS A2756G and CBS 844ins68 were detected by PCR-restriction fragment length polymorphism(PCR-RFLP).</p><p><b>RESULTS</b>The prevalences of TT genotypes of MTHFR (C677T) between DVT group and normal control group had significant difference (27.2% vs 17.2%, P< 0.05), the prevalence of AG genotypes of MS A2756G in the DVT group was less than that in the control group (9.7% vs 19.2%, P< 0.05). The prevalence of 677T-2756A haplotype in the DVT group was higher than that in the control group (P< 0.05), the prevalence of 677C-2756A haplotype in the DVT group was less than that in the control group (P< 0.05). There were no significant differences in the prevalences of CBS 844ins68 mutation.</p><p><b>CONCLUSION</b>The homozygote of MTHFR C677T (TT) may be a risk factor of DVT. MS A2756 G(AG) genotypes may reduce the development of DVT. The 677T-2756A haplotype may be a risk factor of DVT. The 677C-2756A haplotype may be a protective factor of DVT. The prevalence of gene mutation of CBS 844ins68 might vary with different ethnic group or geographic regions.</p>

Study on the relations between genetic polymorphisms in methylenetetrahydrofolate reductase, methionine synthase and the risk of pancreatic cancer / 中华流行病学杂志

<p><b>OBJECTIVE</b>To determine whether genetic polymorphisms in methylenetetrahydrofolate reductase (MTHFR C677T and A1298C), methionine synthase (MS A2756G) were associated with the risks of pancreatic cancer.</p><p><b>METHODS</b>A hospital-based, case-control study consisting of 101 incident pancreatic cancer cases and 337 controls matched on age, sex and race was conducted to investigate the association between polymorphism in MTHFR and MS, and susceptibility to pancreatic cancer. Genotypes of MTHFR C677T, A1298C and MS A2756G were analyzed by polymerase chain reasction-restriction fragment length polymorphism methods.</p><p><b>RESULTS</b>It was found that multivariate-adjusted odds ratio (ORs; 95% confidence interval) for MTHFR-677CT and 677TT compared with 677CC were 2.17 (1.26 - 3.85) and 3.53 (1.85 - 6.84) respectively, which was in a manner of allele-dose relationship. However, no significant association between the A1298C genotype alone and the risk of cancer was observed which seemed that this polymorphism had a combined effect with the C677T polymorphism. A significant gene-environment interaction was observed between C677T polymorphism and cigarette smoking or alcohol intake. Subjects with variant genotypes who smoked > 17 pack-years had highest risk for developing the cancer, with the OR of 5.58 (2.53 - 12.30). Similarly, the OR (3.27, 1.51 - 7.23) for subjects with variant genotypes of alcohol drinker was significantly higher than that for subjects either having the variant genotype or being drinkers. No association was found between MS A2756G polymorphism and risk of pancreatic cancer in the study.</p><p><b>CONCLUSION</b>These findings supported the hypothesis that genetic polymorphisms in MTHFR C677T might contribute to the risk of developing pancreatic cancer.</p>

Polymorphism of methionine synthase gene in nuclear families of congenital heart disease / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>To investigate the relation of methionine synthase (MS) gene variation with congenital heart disease (CHD) phenotype.</p><p><b>METHODS</b>One hundred and ninety three CHD patients (94 males and 99 females) and their biological parents (nuclear families) in Liaoning Province were selected as the case group, and another 104 normal persons (60 males and 44 females) and their parents without family history of birth defects as the control group. For all subjects the polymorphism of MS gene A2756G locus was examined by PCR-RFLP method.</p><p><b>RESULTS</b>In offspring of the control group the frequencies of MS genotype (+/-) and allele (+) were 10.7% and 5.3%, without existence of homozygote. The MS genotype distribution and allele frequencies of CHD patients and their mothers were not significantly different from the control (P > 0.05). The frequency of allele (+) in case fathers (5.0%) was apparently lower than that in the control (9.1%, P = 0.060), and the odds ratio (OR) was 0.53 (95% CI: 0.25-1.09). There was no difference in parents' genotype combination between the two groups, and in genotype distribution among different types of CHD. Analysis of genetic transmission indicated that mutation allele (+) existed transmission disequilibrium in CHD nuclear families. The percentage of allele (+) transmitted from parents was lower than that allele (-) with OR 0.26 (95% CI: 0.11-0.60).</p><p><b>CONCLUSION</b>MS gene variation in parents is associated with occurrence of CHD in offspring, and mutation allele (+) in parents may be related with the decrease of CHD risk in offspring.</p>

Correlation analysis between plasma homocysteine level and polymorphism of homocysteine metabolism related enzymes in ischemic cerebrovascular or cardiovascular diseases / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate the changes of plasma homocysteine (Hcy) level in patients with ischemic cerebrovascular or cardiovascular disease and analyze the relationship between plasma Hcy levels and the mutations in Hcy metabolism related enzymes, including methylene tetrahydrofolate reductase (MTHFR) C677T, cystathionine beta-synthetase (CBS) 844ins68 and methionine synthetase (MS) A2756G.</p><p><b>METHODS</b>By using the HPLC-FLD method, the plasma total homocysteine (tHcy) concentration was determined in 86 patients with cerebral infarction, 66 with myocardial infarction and 80 healthy controls. The association of plasma tHcy levels with cardiovascular or cerebrovascular disease and mutations of MTHFR C677T, CBS 844 ins 68 and MS A2756G were evaluated by statistic methods.</p><p><b>RESULTS</b>In the patient groups, the plasma tHcy concentrations increased significantly as compared with healthy controls. The individuals homozygous for MTHFR C677T mutation had significantly higher plasma Hcy levels.</p><p><b>CONCLUSION</b>Hyperhomocysteinemia is an important risk factor for ischemic cerebrovascular and cardiovascular disease. The homozygosity of MTHFR C677T may contribute to the increase of plasma Hcy and vascular damage.</p>