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Association of C677T (rs1081133) and A1298C (rs1801131) Methylenetetrahydrofolate Reductase Variants with Breast Cancer Susceptibility Among Asians: A Systematic Review and Meta-Analysis.
Rezaee, M, Akbari, H, Momeni-Moghaddam, MA, Moazzen, F, Salahi, S, Jahankhah, R, Tahmasebi, S
Biochemical genetics. 2021;(2):367-397
Abstract
This systematic review and meta-analysis were conducted to investigate the association between methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms with breast cancer (BC) in Asians. Systematic searches were conducted in PubMed, EMBASE, Web of Science, and Scopus by May 2020. Inter-study heterogeneity was also assessed with a Q test, along with I2 statistics. Random-effects models were applied to pooled crude ORs with corresponding 95% CIs for the genetic models. A total of 1097 identified results, along with 36 qualified studies were included: for MTHFR C677T polymorphism, a total of 36 studies was comprised of 11,261 cases and 13,318 controls and for MTHFR A1298C polymorphism, a number of 19 studies contained 7424 cases and 8204 controls. Likewise, for C677T polymorphism, an increased risk of BC was seen for the allelic (OR 1.21, 95% CI 1.09-1.33, P < 0.01, I2 = 78.9%), dominant (OR 1.17, 95% CI 1.05-1.30, P < 0.01, I2 = 71.8%), recessive (OR 1.43, 95% CI 1.23-1.67, P < 0.01, I2 = 55.8%), and homozygous models (OR 1.48, 95% CI 1.25-1.75, P < 0.01, I2 59.9%) among BC patients compared to controls. Also, in terms of A1298C polymorphism, an association was found between the allelic (OR 1.15, 95% CI 1.04-1.28, P < 0.01, I2 70.4%) and homozygous models (OR 1.38, 95% CI 1.15-1.66, P < 0.01, I2 44.2%) with the risk of BC. In conclusion, findings revealed that MTHFR C677T variant might be a factor that predisposes BC in Asians. Furthermore, it was found that A1298C variant acts as a BC risk factor, particularly in a Western Asia population.
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A meta-analysis on associations of FTO, MTHFR and TCF7L2 polymorphisms with polycystic ovary syndrome.
Wang, X, Wang, K, Yan, J, Wu, M
Genomics. 2020;(2):1516-1521
Abstract
BACKGROUND We aimed to better clarify the relationship between FTO/MTHFR/TCF7L2 polymorphisms and PCOS in a larger combined population by performing a meta-analysis. METHODS Eligible articles were retrieved from Pubmed, Embase, Web of Science and CNKI. Review Manager Version was used to perform statistical analyses. RESULTS Forty-six studies were included for this meta-analysis. FTO rs9939609 polymorphism was found to be significantly associated with PCOS under dominant, recessive, over-dominant and allele comparisons, MTHFR rs1801131 polymorphism was found to be significantly associated with PCOS under recessive and allele comparisons, and MTHFR rs1801133 polymorphism was also found to be significantly associated with PCOS under dominant, recessive and allele comparisons in general population. In subgroup analyses, we found that positive results were mainly driven by the Asians. CONCLUSIONS Collectively, this meta-analysis proved that FTO rs9939609, MTHFR rs1801131 and MTHFR rs1801133 polymorphisms may serve as predisposing factors of PCOS, especially for Asians.
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Assessment of the relationship between methylenetetrahydrofolate reductase polymorphism and acute lymphoblastic leukemia: Evidence from an updated meta-analysis.
Frikha, R
Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners. 2020;(7):1598-1610
Abstract
OBJECTIVE The methylenetetrahydrofolate reductase gene C677T polymorphism is closely related to the acute lymphoblastic leukemia. Several case-control studies have investigated this association; however, no conclusions could be drawn. A comprehensive updated meta-analysis is established to explain these contradictions and clarify the overall impact of this variant on the susceptibility to acute lymphoblastic leukemia. METHODS Electronic searches were conducted to select published studies prior to June 2018. Pooled odds ratios and stratification analysis were performed under different genetic comparison models, age, and ethnicity. RESULTS Totally, 66 case-control studies including 9619 acute lymphoblastic leukemia cases and 17,396 controls were selected. Our analyses showed that methylenetetrahydrofolate reductase C677T polymorphism was protective mainly in Asian and European countries, under all genetic models and regardless of age, but leukemogenic in mixed population. CONCLUSION Thus, C677T polymorphism may be a promising acute lymphoblastic leukemia biomarker, but they should be interpreted with caution considering other factors such as folic acid intake, gene-gene and gene-environment interactions.
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Association between gene polymorphism of folate metabolism and recurrent spontaneous abortion in Asia: A Meta-analysis.
Zhao, X, Zhao, Y, Ping, Y, Chen, L, Feng, X
Medicine. 2020;(40):e21962
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Abstract
To evaluate the association between gene polymorphisms of MTHFR (C677T, A1298C) and MTRR (A66G), and the recurrent spontaneous abortion (RSA) risk in Asia.Related case-control studies were collected, selected, and screened. A meta-analysis was conducted by Stata 12.0 software to assess the association between polymorphisms of target genes and RSA.Altogether 30 studies examining the relationship between genetic polymorphism of folate metabolism and RSA risk were included, among which 20 studies were related to MTHFR C677T, 11 to MTHFR A1298C and 6 to MTRR A66G. The studies suggested that MTHFR C677T polymorphism was closely connected with RSA risk under all models (P < .05). Furthermore according to the subgroup analysis of ethnicity, the correlation between C677T polymorphism and RSA was stronger in north of China when compared with south of China and other Asian countries (P > . 05). For MTHFR A1298C, it was closely related to RSA risk in all gene models except for (AC vs AA) (P < .05). However, when it comes to MTRR A66G, there was no significant correlation between gene A66G polymorphism and RSA risk except for the additive gene model (G vs A) (P < .05).The present evidence shows that the correlation between gene polymorphisms and RSA risk can be found in MTHFR C677T, A1298C (except for heterozygote model) and MTRR A66G (only in additive genotypes), and the detection of the correlated gene polymorphisms mentioned above is of certain guiding significance for preventing RSA and screening high-risk groups.
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Methylenetetrahydrofolate reductase C677T polymorphism and diabetic retinopathy risk: a meta-analysis of the Chinese population.
Xu, WH, Zhuang, Y, Han, X, Yuan, ZL
The Journal of international medical research. 2020;(1):300060518816834
Abstract
OBJECTIVES This study evaluated associations between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms and diabetic retinopathy (DR) susceptibility within the Chinese population. METHODS Five databases (PubMed, EMBASE, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure) were used for literature searches of open access articles from inception through April 2017. RESULTS Eight publications were identified involving 600 DR cases, 363 healthy controls, and 646 nondiabetic retinopathy (NDR) controls. There was a positive association between MTHFR C677T polymorphisms and DR risk within the Chinese population (DR with NDR controls: T vs. C, odds ratio (OR): 2.14, 95% confidence interval (CI): 1.55–2.97; TT vs. CC, OR: 4.19, 95% CI: 2.09–8.41; TT + CT vs. CC, OR: 2.83, 95% CI: 1.86–4.40; TT vs. CC + CT, OR: 2.48, 95% CI: 1.52–4.05. DR with healthy controls: T vs. C, OR: 2.48, 95% CI: 1.99–3.09; TT vs. CC, OR: 4.92, 95% CI: 3.18–7.62; TT + CT vs. CC, OR: 3.22, 95% CI: 2.32–4.48; TT vs. CC + CT, OR: 3.11, 95% CI: 1.83–5.28). The association was similar in South China and North China, when stratifying by geographic areas. CONCLUSION MTHFR C677T polymorphisms increase DR risk within the Chinese population.
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Association of MTHFR gene polymorphisms with pancreatic cancer: meta-analysis of 17 case-control studies.
Nie, F, Yu, M, Zhang, K, Yang, L, Zhang, Q, Liu, S, Liu, M, Shang, M, Zeng, F, Liu, W
International journal of clinical oncology. 2020;(2):312-321
Abstract
BACKGROUND Pancreatic cancer (PC) is a seriously malignant tumor with a low 5-year survival rate. The relationship between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and PC has been reported by several studies. However, the results were controversial. Thus, we conducted a meta-analysis to summarize available data on MTHFR gene and PC. METHODS We searched PubMed, Embase, Web of Science, Wanfang, CNKI databases prior to July 2019. Data were analyzed by RevMan 5.3 and STATA 12.0 software. Odds ratio (OR) and 95% confidence interval (CI) were used to evaluate the strength of the association. Subgroup analysis, sensitivity analysis and assessment of publication bias were performed in this study. RESULTS Ten articles with 17 reports (10 for C677T, 7 for A1298C) were eligible for inclusion in the meta-analysis (1864 cases and 3165 controls for C677T, and 1488 cases and 1946 controls for A1298C). Our meta-analysis detected that C677T was associated with PC for three genetic models (allele model: OR = 1.24, 95% CI: 1.00-1.53, P = 0.047; recessive model: OR = 1.39, 95% CI: 1.04-1.86, P = 0.027; homozygous model: OR = 1.60, 95% CI: 1.04-2.45, P = 0.034). In the stratified analyses according to ethnicity, source of controls and genotyping method, significant association was observed in genotyping method subgroup. For the A1298C polymorphism, no significant association was observed either in overall analysis or in subgroup analysis under all genetic models. CONCLUSIONS MTHFR gene C677T rather than A1298C polymorphism may be associated with PC. Larger sample size studies should be performed to find the association between MTHFR gene and PC.
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Methylenetrahydrofolate Reductase Gene C677T Polymorphism and Diabetic Retinopathy: a Meta-Analysis.
Shen, C, Zhao, M, Li, YY, Liu, NP
Chinese medical sciences journal = Chung-kuo i hsueh k'o hsueh tsa chih. 2020;(1):71-84
Abstract
Objective To investigate the association between the methylenetetrahydrofolate reductase gene C677T (MTHFR C677T) polymorphism and diabetic retinopathy (DR). Methods A total of 6971 subjects including 2707 DR patients and 4264 controls from 23 studies were enrolled in the study. A random-effects model was applied to estimate the overall effects and the stratified effects of the MTHFR C677T polymorphism on the risk of DR, and study quality was also assessed. Results Strong associations were observed between the MTHFR C677T polymorphism and DR. The carries of MTHFR C677T were more likely to be found in the DR group in relative to the healthy control group with odds ratio 1.68, 2.55, and 2.31 respectively in allele contrast model (T vs. C, 95%CI: 1.29-2.18, P<0.001, I 2=78.4%), homozygous model (TT vs. CC, 95%CI: 1.70-3.83, P=0.008, I 2=54.4%) and dominant model (TT+CT vs. CC, 95%CI: 1.62-3.29, P<0.001, I 2=74.7%). This association can also be found in contrast to the Ncd (non-complicated diabetic mellitus) group (allele contrast, OR=1.50, 95%CI: 1.07-2.11, P=0.032, I 2=62.1%; homozygous, OR=2.39, 95%CI: 1.06-5.38, P=0.017, I 2=66.7%; dominant, OR=1.59, 95%CI: 0.97-2.62, P=0.056, I 2=56.5%). For the heterozygous model (CT vs. CC), the association was significant in contrast to the healthy control group (OR=1.46, 95%CI: 1.64-3.69, P=0, I 2=77.3%), while in contrast to the Ncd control group the association was not statistically meaningful (OR=1.38, 95%CI: 0.87-2.18, P=0.131, I 2=43.7%). For the recessive model, 1.92-fold increased risk was found only in contrast to the Ncd control group (95%CI: 1.07-3.43, P=0.064, I 2=55.0%). There was no significant association found in the models in contrast to the DM control group. Conclusion In this meta-analysis, we found an association between the MTHFR C677T polymorphism and DR, especially in contrast to the Ncd control group. Further studies are required to establish more definite relationship.
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Association of Methylenetetrahydrofolate Reductase, Vitamin D Receptor, and Interleukin-16 Gene Polymorphisms With Renal Cell Carcinoma Risk.
Zhou, T, Li, H, Xie, WJ, Zhong, Z, Zhong, H, Lin, ZJ
Technology in cancer research & treatment. 2019;:1533033819859413
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Abstract
In this meta-analysis, we investigated the association of methylenetetrahydrofolate reductase, vitamin D receptor, and interleukin-16 gene polymorphisms with the risk of renal cell carcinoma. We searched the PubMed and Cochrane Library databases up to July 1, 2017, and included 12 eligible case-control studies in our analysis. The vitamin D receptor ApaI A allele, ApaI AA and aa genotypes, BsmI B allele, and Fok1 FF genotype were all associated with the risk of renal cell carcinoma in Asian populations. However, methylenetetrahydrofolate reductase (rs1801133 and rs1801131), vitamin D receptor (TaqI and Fok1), and interleukin-16 (rs4778889 and rs11556218) gene polymorphisms were not associated with the risk of renal cell carcinoma. Our study indicates that the vitamin D receptor ApaI A allele, ApaI AA and aa genotypes, BsmI B allele, and Fok1 FF genotype are associated with renal cell carcinoma risk.
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Association between MTHFR 677C>T polymorphism and vascular complications in sickle cell disease: A meta-analysis.
Lakkakula, BVKS
Transfusion clinique et biologique : journal de la Societe francaise de transfusion sanguine. 2019;(4):284-288
Abstract
Sickle cell disease (SCD) is considered as a vascular disease due to its chronic vascular manifestations such as leg ulcers, priapism, acute chest syndrome (ACS), stroke, retinopathy, renal insufficiency, pulmonary hypertension, avascular necrosis of the femoral head (AVNF) and splenic infarction. Emerging evidence has shown that the MTHFR 677C>T variant allele is associated with vascular complications (VC) in patients with SCD; however, results from individual studies are inconclusive. The aim of this meta-analysis is to evaluate the association between the MTHFR 677C>T polymorphism and the susceptibility for VC in SCD patients. Articles published in English were collected from Medline, PubMed, Embase, and Web of Science databases. As a result, 11 studies in different populations including 614 SCD patients with VC, and 559 patients without VC were selected. Meta-analysis in fixed effect model showed that mutant genotypes (CT+TT vs. CC) of the MTHFR 677C>T polymorphism is associated with increased risk of vascular complication (OR=1.81, 95% CI=1.37-2.40, P<0.001). This study did not demonstrate publication bias or between-study heterogeneity. Our meta-analysis establishes that the MTHFR 677C>T polymorphism as a high-penetrant risk factor for VC in SCD patients. Further research is needed to support the clinical utility of MTHFR genetic testing for predicting VC in patients with sickle cell disease.
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The relevance of MTHFR C677T, A1298C, and MTRR A66G polymorphisms with response to male infertility in Asians: A meta-analysis.
Shi, TL, Wu, Y, Li, Y, Chen, ZF, Ma, YN, Zhang, ZT, Zhang, YH, Zhang, L
Medicine. 2019;(8):e14283
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Abstract
Although published studies have reported the association between MTHFR C677T (rs 1801133), A1298C (rs 1801131), and MTRR A66G (rs1801394) polymorphisms and male infertility in Asian populations, the results are conflicting. In order to accurately evaluate the relevance, a meta-analysis was performed.We searched for potential studies in 4 databases, containing PubMed, ScienceDirect, China National Knowledge Infrastructure (CNKI), and Wanfang database until May 31, 2018. The summarized odds ratio (OR) with 95% confidence intervals (95% CI) were calculated to evaluate the relevance in 5 genetic models. The heterogeneity test, sensitivity analysis, and publication bias test was performed by Review Manager 5.3 software.Overall, 22 case-control studies with 5049 cases and 4157 controls were included in this meta-analysis, which contained 20 studies of MTHFR C677T polymorphism, 12 studies of MTHFR A1298C polymorphism and 4 studies of MTRR A66G polymorphism. The results indicated that MTHFR C677T, A1298C, and MTRR A66G polymorphisms were significantly associated with male infertility in Asian populations (Dominant model: MTHFR CC + CT vs TT: OR = 0.60, 95% CI (0.53, 0.67), P <.00001; MTHFR AA + AC vs CC: OR = 0.62, 95% CI (0.49, 0.79), P = .0001; MTRR AA + AG vs GG: OR = 0.60, 95% CI (0.45, 0.81), P = .001. Recessive model: MTHFR CC vs CT + TT: OR = 0.67, 95% CI (0.61, 0.74), P <.00001; MTHFR AA vs AC + CC: OR = 0.79, 95% CI (0.70, 0.88), P <.0001; MTRR AA vs AG + GG: OR = 0.70, 95% CI (0.56, 0.88), P = .002. Heterozygote model: MTHFR CC vs CT: OR = 0.74, 95% CI (0.67, 0.82), P <.00001; MTHFR AA vs AC: OR = 0.83, 95% CI (0.73, 0.93), P = .002; MTRR AA vs AG: OR = 0.76, 95% CI (0.60, 0.92), P = .02. Homozygote model: MTHFR CC vs TT: OR = 0.48, 95% CI (0.41, 0.56), P <.00001; MTHFR AA vs CC: OR = 0.61, 95% CI (0.39, 0.93), P = .02; MTRR AA vs GG: OR = 0.51, 95% CI (0.36, 0.72), P = .0001. Allele model: MTHFR C vs T: OR = 0.70, 95% CI (0.66, 0.75), P <.00001; MTHFR A vsC: OR = 0.82, 95% CI (0.71, 0.95), P = .01; MTRR A vs G: OR = 0.76, 95% CI (0.66, 0.88), P = .00003). Stratified analyses by geographical location and source of controls showed the same results. Sensitivity analyses indicated that the final consequences of this meta-analysis were stable, and the publication biases test had not found obvious asymmetry.This meta-analysis indicates that MTHFR C677T, A1298C, and MTRR A66G polymorphisms are the risk factors with susceptibility to male infertility in Asians.