[Functional polymorphism sites in non-coding regions of folate metabolism-related genes in the reproductive-aged population of Hubei Province].

Objective: To investigate the distribution of the functional polymorphisms in the non-coding regions of folate metabolism-related genes in the reproductive-aged population of Hubei Province. METHODS: Using Sanger sequencing, we examined the polymorphisms of the genes MTR (rs28372871 and rs1131450), MTRR (rs326119) and CBS (rs2850144) in 790 subjects before and during pregnancy from April 2020 to March 2021. We compared the distributions of the four loci between different populations. RESULTS: The distributions of the four genotypes of rs28372871, rs1131450, rs326119 and rs2850144 all conformed to the Hardy-Weinberg equilibrium (HWE). Statistically significant differences were observed in the polymorphism distribution of rs28372871 between Hubei and Jiangsu (P < 0.05), in that of rs1131450 between Hubei and Shanghai (P < 0.05), and in that of rs2850144 between Hubei and Yazd, Iran (P < 0.01). CONCLUSIONS: This was the first investigation on the distribution of MTR, MTRR and CBS gene polymorphisms in the reproductive-aged population of Hubei Province. The effects of the functional loci in both encoding and non-coding regions of folate metabolism-related genes have to be comprehensively considered so as to formulate an appropriate folate-supplementary protocol.

Association between donor/recipient MTRR gene polymorphisms and the risk of new-onset neurological complications after liver transplantation.

Neurological complications are very common after liver transplantation. This study focuses on clinical risk factors and susceptibility gene polymorphisms of neurological complications after liver transplantation. A better predictive model is obtained. This study proves that MTRR is an independent susceptibility gene for neurological complications. Compared with the independent risk factor of abdominal infection, MTRR has a more advantageous value in predicting neurological complications after liver transplantation.

Relationship between genetic polymorphisms MTHFR (C677T, A1298C), MTR (A2756G) and MTRR (A66G) genes and multiple sclerosis: a case-control study.

Recent studies have reported elevated plasma homocysteine and reduced folate and vitamin B levels in patients with multiple sclerosis (MS). In this study, we aimed to investigate the association between MS and the following four DNA polymorphisms: MTR A[2756]G, MTHFR C[677]T, MTHFR A[1298]C and MTRR A[66]G. The DNA polymorphisms were genotyped in 80 patients with confirmed MS and 80 healthy control age- and gender-matched subjects using PCR-RFLP approach. Our results show that the frequency of the T/T genotype homozygotes for the MTHFR C[677]T polymorphism was significantly higher in patients than in controls (p = 0.04, OR: 3.16, 95% CI: 1.23-8.17). In turn, the A/A genotype of the MTHFR A[1298]C polymorphism was more frequent in controls than in patients (41.3% vs. 32.5%, p = 0.04). There were no differences in distribution of genotypes for the MTR A[66]G and MTR A[2756]C polymorphisms between patients with MS and controls (p > 0.05). Our findings suggested that the MTHFR C[677]T and MTHFR A[1298]C gene polymorphisms might be associated with MS as genetic factors influencing the risk of the disease.

Methionine Synthase Reductase-A66G and -C524T Single Nucleotide Polymorphisms and Prostate Cancer: A Case-Control Trial

Purpose: Some variations in the sequence of methionine synthase reductase (MTRR) gene can increase the risk of various cancers such as prostate cancer. The aim of this study was to investigate the association between prostate cancer and the MTRR A66G and C524T gene single nucleotide polymorphisms (SNPs) using an in silico analysis. Methods: In this case-control study, 218 Iranian men, including 108 men with prostate cancer and 110 prostate cancer-free men, were enrolled. The MTRR A66G and C524T genotyping was performed by PCR-RFLP. Some of the bioinformatics tools were employed for the evaluation of polymorphism on the molecular aspects of the MTRR. Results: With regard to the MTRR A66G polymorphism, the genotype AG (OR: 0.85, 95% CI: 0.47-1.54, p= 0.6014), genotype GG (OR: 0.89, 95% CI: 0.42-1.87, p= 0.7512), and allele G (OR: 0.92, 95% CI: 0.63-1.35, p= 0.6686) were not associated with prostate cancer risk. However, the data for C524T SNP showed that the genotype CT was associated with prostate cancer risk (OR: 1.92, 95% CI: 1.06-3.47, p= 0.0308). Further, carriers of the allele T (OR: 1.80, 95% CI: 1.04-3.13, p= 0.0358) were associated with high risk of prostate cancer. In addition, bioinformatics analysis revealed that C524T SNP could affect some molecular aspects of the protein structure, while having no effect on the mRNA structure. Conclusion: The MTRR C524T is a genetic risk factor for prostate cancer; however, the MTRR A66G is not suggested as a suitable biomarker for prostate cancer. To obtain more reliable results, further studies are recommended to use larger sample sizes and investigate the effects of environmental factors.

Study on Relationships of Gene Polymorphism of MTRR and SLCO1B1 with Blood Concentration of MTX and HD-MTX- induced ADR in ALL Children / 中国药房

OBJECTIVE： To study the relationships of polymorphism of MTRR gene rs1801394 locus and SLCO1B1 gene rs11045879 locus with drug concentration of methotrexate （MTX） and high-dose MTX （HD-MTX）-induced ADR in acute lymphoblastic leukemia （ALL） children. METHODS： From Oct. 2015 to Sept. 2018， 70 ALL hospitalized children of Han nationality in Sichuan area who received HD-MTX treatment and were in consolidation chemotherapy were selected retrospectively from Sichuan People’s Hospital. The blood concentration of MTX at 48 and 72 hours after administration was measured by EMIT. The genetic typing of MTRR gene rs1801394 locus and SLCO1B1 gene rs11045879 locus were detected with real-time PCR. The relationships of the polymorphism of MTRR gene and SLCO1B1 gene with MTX blood concentration [dose-corrected concentration （c48 h/D，48 h）， the proportion of children with different concentration of MTX （≤0.1， ＞0.1 μmol/L）] and ADR （such as myelosuppression， liver function damage， gastrointestinal response， mucosal damage， rash， etc.） were analyzed. Binary Logistic regression analysis for the correlation of ADR with different influencing factors （gene polymor- phism， blood concentration of MTX， immunophenotyping， body mass index， etc.） was carried out by Wald method. RESULTS： Totally 31， 32， 7 children with MTRR gene AA， AG and GG genotype， while 23， 37， 10 children with SLCO1B1 gene TT， TC and CC genotype were detected. The distribution of each genotype in 70 children conformed to Hardy-Weinberg equilibrium （P＞0.05）. There was no significant difference in c48 h/D（48 h） of children and the proportion of children with different concentration of MTX （72 h） among difterent genotypes of MTRR and SLCO1B1 gene （P＞0.05）. There was statistical significance in the incidence of liver function injury in children with different genotypes of MTRR gene （P＜0.05）， and the AA genotype was significantly higher than the AG+GG genotype （P＜0.05）. There was no correlation of MTRR gene polymorphism with the incidence of other ADR， neither SLCO1B1 gene polymorphism with the incidence of ADR （P＞0.05）. The results of Binary Logistic regression analysis showed that liver function damage in ALL children was related to the gene polymorphism of MTRR； gastrointestinal reaction was related to whether the plasma concentration was more than 0.1 μmol/L at 72 h； mucosal damage was related to the immune type and BMI of children； the occurrence of skin allergy was correlated with body weight of children（P＜0.05）. CONCLUSIONS： Gene polymorphism of MTRR rs1801394 locus may associated with the occurrence of HD-HTX-induced liver function injury in ALL children， but its polymorphism and gene polymorphism of SLCO1B1 rs11045879 locus are not related to MTX blood concentration in ALL children.

Roles of penA and mtrR gene mutations in in vitro-induced resistance of Neisseria gonorrhoeae to ceftriaxone / 中华皮肤科杂志

Objective To investigate the roles of penA and mtrR gene mutations in resistance of Neisseria gonorrhoeae to ceftriaxone.Methods Standard strains of Neisseria gonorrhoeae (ATCC-49226),clinical strains of Neisseria gonorrhoeae with high sensitivity to ceftriaxone (2012-4052 and 2012-15361) and clinical strains of Neisseria gonorrhoeae with reduced sensitivity to ceftriaxone (2012-5616) were treated with ceftriaxone at subinhibitory concentration (50％ MIC),so as to induce the resistance to ceftriaxone.DNA was extracted from the primary strains before the treatment and daughter strains resistant to ceftriaxone after the treatment,followed by the amplification and DNA sequencing of the penA and mtrR genes.Results For strains 2012-5616 and ATCC-49226,ceftriaxone-resistant strains with MIC ≥ 1 mg/L were obtained after 26 and 28 passages,respectively.For strains 2012-4052 and 2012-15361,ceftriaxone-resistant strains with MIC ≥ 0.5 mg/L were obtained after 22 and 36 passages,respectively.Sequence analysis of the penA gene revealed that A501T and G542S mutations were identified in the induced resistant ATCC-49226 strains,but no new mutations were observed in the other 3 strains.All the 4 mutant strains showed penicillin-binding protein 2 (PBP2) of gene sequence type ⅩⅧ and no mosaic structure of the penA gene was found in the strains.Sequence analysis of the mtrR gene showed that the A39T mutation was found in the 2012-5616 and ATCC-49226 strains before and after the induction,as well as in the coding region of the mtrR gene in the induced resistant 2012-4052 strains.Conclusion The A501T and G542S mutations in the penA gene and A39T mutation in the mtrR gene may play a role in the resistance of Neisseria gonorrhoeae to ceftriaxone.

MTRR rs326119 polymorphism is associated with plasma concentrations of homocysteine and cobalamin, but not with congenital heart disease or coronary atherosclerosis in Brazilian patients.

BACKGROUND: Differences in the distribution of the MTRR rs326119 polymorphism (c.56 + 781 A > C) between patients with congenital heart disease (CHD) and controls have been described in Chinese individuals. The association is thought to be due to deregulation of homocysteine-cobalamin pathways. This has not been replicated in other populations. The primary objective of this study was to assess the influence of the MTRR rs326119 polymorphism on biochemical parameters of vitamin B12 metabolism, coronary lesions, and congenital heart disease in Brazilian subjects. METHODS: We selected 722 patients with CHD, 1432 patients who underwent coronary angiography, and 156 blood donors. Genotyping for the MTRR polymorphism was evaluated by high-resolution melting analysis, and biochemical tests of vitamin B12 metabolism were measured. RESULTS: Subjects carrying the AC or CC genotypes had higher homocysteine concentrations (9.7 ± 0.4 µmol/L and 10.1 ± 0.6 µmol/L) and lower cobalamin concentrations (260.5 ± 13.3 pmol/L and 275.6 ± 19.9 pmol/L) compared with the subjects carrying the AA genotype (8.7 ± 0.5 µmol/L and 304.8 ± 14.7 pmol/L), respectively. A multiple linear regression model also identified a significant association between the number of C variant alleles with the concentrations of homocysteine and cobalamin. Nonetheless, the allelic and genotypic distributions for MTRR rs326119 were not associated with CHD or coronary atherosclerosis in the studied samples. CONCLUSION: Our findings indicate that the MTRR rs326119 variant might be a genetic marker associated with homocysteine and cobalamin concentrations, but not a strong risk factor for CHD or coronary atherosclerosis in the Brazilian population.

Effect of MTHFR A1298C and MTRR A66G Genetic Mutations on Homocysteine Levels in the Chinese Population: A Systematic Review and Meta-analysis.

BACKGROUND AND OBJECTIVES: The Chinese population typically has inadequate folate intake and no mandatory folic acid fortification. Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) are the two key regulatory enzymes in the folate/homocysteine (Hcy) metabolism. Hcy has been implicated in the pathogenesis of cardiovascular disease. We conducted a meta-analysis to assess whether the MTHFR gene A1298C and the MTRR gene A66G polymorphisms affect Hcy levels in the Chinese population. METHODS: This analysis included 13 studies with Hcy levels reported as one of the study measurements. Summary estimates of weighted mean differences and 95% confidence intervals (CIs) were obtained using random-effect models. RESULTS: Overall, there were no significant differences in Hcy concentrations between participants with the MTHFR 1298 CC (12 trials, n = 129), AA (n = 2166; ß, -0.51 µmol/L; 95%CI: -2.14, 1.11; P = 0.53), or AC genotype (n = 958; ß, 0.55 µmol/L; 95%CI: -0.72, 1.82; P = 0.40). Consistently, compared to those with the MTRR 66 GG genotype (6 trials, n = 156), similar Hcy concentrations were found in participants with the AA (n = 832; ß, -0.43 µmol/L; 95%CI: -1.04, 0.17; P = 0.16) or AG (n =743; ß, -0.57 µmol/L; 95%CI: -1.46, 0.31; P = 0.21) genotype. Similar results were observed for the dominant and recessive models. CONCLUSIONS: Neither the MTHFR A1298C polymorphism nor the MTRR A66G polymorphism affects Hcy levels in the Chinese population.

Genetic Variants in Folate and Cobalamin Metabolism-Related Genes in Nonsyndromic Cleft Lip and/or Palate

The aim of this study was to evaluate the association of the polymorphisms in TCN2 (rs1801198) gene and in MTRR (rs1801394) gene with nonsyndromic cleft lip and/or palate (NSCL/P) in a Brazilian population. Genomic DNA was extracted from buccal cells. The polymorphisms in TCN2 (rs1801198) and MTRR (rs1801394) genes were genotyped by carrying out real-time PCR and Taqman assay. Chi-square test was used to determine the association between genotype and allele frequencies with NSCL/P and NSCL/P subgroups (cleft lip only, cleft lip and palate, and cleft palate only). Eight hundred and sixty seven unrelated individuals (401 cases with NSCL/P and 466 individuals without cleft) were evaluated. Genotype distributions of TCN2 and MTRR polymorphisms were in Hardy-Weinberg equilibrium. The TCN2 polymorphic genotype GG was identified in 16.7% of the NSCL/P group and in 14.1% of the non-cleft group (p>0.05). Similarly, the frequency of MTRR genotype (GG) was similar in NSCL/P group (15.5%) and control group (17.8%) (p>0.05). Multivariate analysis showed an association between MTRR and the subgroup that the mother smoked during pregnancy (p=0.039). Our findings did not demonstrate an association between TCN2 polymorphisms and NSCL/P, however suggests an association between MTRR and NSCL/P etiology.

Resumo O objetivo desse estudo foi avaliar a associação entre os polimorfismos no gene TCN2 (rs1801198) e no gene MTRR (rs1801394) com fissura de lábio e/ou palato não sindrômica (NSFL/P) em uma população brasileira. DNA genômico foi extraído de células bucais. Os polimorfismos nos genes TCN2 (rs1801198) e MTRR (rs1801394) foram genotipados através do PCR em tempo real pelo método Taqman. O teste do qui-quadrado foi utilizado para determinar a associação entre a frequência alélica e genotípica e NSFL/P e nos subtipos (fissura de lábio, fissura de lábio com palato e fissura de palato). Oitocentos e sessenta e sete indivíduos não aparentados (401 casos com NSFL/P e 466 indivíduos sem fissura) foram avaliados. A distribuição dos genótipos dos polimorfismos de TCN2 e MTRR estavam em equilíbrio de Hardy-Weinberg. O genótipo polimórfico GG do gene TCN2 foi identificado em 16,7% do grupo com NSFL/P e em 14,1% do grupo sem fissura (p>0,05). Da mesma forma, a freqüência do genótipo GG do gene MTRR foi bastante semelhante entre o grupo com NSFL/P (15,5%) e o grupo controle (17,8%). A análise multivariada mostrou associação entre o gene MTRR e o subgrupo que apresentou tabagismo materno durante a gestação (p=0,039). Nossos resultados mostraram que não há associação entre os polimorfismos nos genes TCN2 e NSFL/P, entretanto sugerem uma associação entre MTRR e a etiologia de NSFL/P.

Association between genetic polymorphisms in folate-related enzyme genes and infertile men with non-obstructive azoospermia.

Polymorphisms in the genes encoding enzymes in the folate metabolism pathway have been associated with male infertility and chromosome abnormalities. The aim of this study was to analyze the distribution of the methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), and methionine synthase reductase (MTRR) polymorphisms in fertile men and infertile men with non-obstructive azoospermia (NOA). A case-control study comprising 85 infertile men with NOA and 246 fertile men as controls was carried out. MTHFR c.677C > T (rs1801133), MTHFR c.1298A > C (rs1801131), MTR c.2756A > G (rs1805087), and MTRR c.66A > G (rs1801394) polymorphisms were determined using the polymerase chain reaction restriction fragment length polymorphism technique. There were significant differences in AC + CC genotype (OR = 1.9, 95% CI = 1.1-3.2) and C allele frequencies (OR = 1.8, 95% CI = 1.2-2.8) of MTHFR c.1298A > C polymorphism between NOA patients and controls after applying the Bonferroni correction. Moreover, the 1298AC genotype, 1298AC + CC genotype, and 1298C allele frequencies were statistically significant in NOA with chromosomal abnormalities and/or a Y chromosome deletion compared to the controls (AC genotype: OR = 3.0; AC + CC genotype: OR = 3.0; C allele: OR = 2.3). Considering the other polymorphisms, no differences were found between cases and controls. Our findings suggest the MTHFR c.1298A > C polymorphism is associated with an increased risk of male infertility, i.e., NOA.