Association between methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphisms and essential hypertension: A systematic review and meta-analysis

ObjectiveMany studies have investigated the role of 5,10-methylenetetrahydrofolate reductase gene (MTHFR) C677T/A1298C polymorphisms in essential hypertension (EH), but results are inconclusive. The purpose of this meta-analysis was to clarify the effects of MTHFR C677T/A1298C polymorphisms on the risk of EH.MethodsElectronic databases were searched to identify relevant studies published until January 2014. Data were extracted by two independent authors. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association between MTHFR C677T/A1298C polymorphisms and the risk of EH using random effect models or fixed effect models. Finally, 30 studies with 5207 cases and 5383 controls were included for C677T polymorphism and 6 studies with 1009 cases and 994 controls were included for A1298C polymorphism.ResultsMeta-analysis results indicated that MTHFR C677T polymorphism contributed to an increased risk of EH (for T vs. C: OR = 1.30, 95%CI = 1.18–1.43; for TT + CT vs. CC: OR = 1.34, 95%CI = 1.24–1.46; for TT vs. CC: OR = 1.62, 95%CI = 1.32–1.99; for TT vs. CT + CC: OR = 1.41, 95%CI = 1.26–1.59). However, no significant association was detected between MTHFR A1298C polymorphism and the risk of EH.ConclusionThis meta-analysis supports that MTHFR C677T polymorphism plays a role in developing EH. MTHFR A1298C polymorphism may not be associated with an increased risk of EH. Further large and well-designed studies are warranted to confirm these findings.     

Association between Toll-like receptor gene polymorphisms and risk of Helicobacter pylori infection: A protocol for systematic review and meta-analysis

Background:There were many case-control studies performed the association between TLRs gene polymorphisms and the correlation of Helicobactor pylori infection, these results were inconformity. Therefore, a comprehensive meta-analysis was performed to evaluate the TLRs gene polymorphism and susceptibility to H. pylori infection.Methods:Eligible studies were searched from PubMed, EMBASE, Web of science, Cochrane library, CNKI, CBM, Wan Fang Database and VIP Database, all the databases were searched from inception to December 2020. OR with the corresponding 95% CI were presented as associations between certain TLR gene polymorphism and the risk of H. pylori infection, all the included data will be analyzed with the software of Review Manager 5.2 and STATA 14.2.Results:This study will provide a high-quality evidence to find the TLR gene polymorphisms with H. pylori infection susceptibility.Conclusion:This study will explore which TLR genotype increase the risk of H. pylori infection.     

Association of the MTHFR C677T and A1298C polymorphisms with methotrexate toxicity in rheumatoid arthritis: a meta-analysis

The aim of this study was to explore whether the C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase (MTHFR) play a role in methotrexate (MTX) toxicity in rheumatoid arthritis (RA). MEDLINE and EMBASE database searches and subsequent manual searches were utilized to identify articles in which C677T and A1298C MTHFR polymorphisms were evaluated in RA patients taking MTX. A meta-analysis was conducted to identify associations between MTHFR polymorphisms and MTX toxicity. Twelve studies comprising a total of 2,288 RA patients were included in our meta-analysis. Meta-analysis revealed an association between the overall toxicity of MTX and the MTHFR 677TT genotype (odds ratio [OR]?=?1.615, 95 % confidence interval [CI]?=?1.185–2.200, p?=?0.002). Stratification by ethnicity indicated an association between the MTHFR 677TT genotype and the overall toxicity of MTX in East Asians (OR?=?1.583, 95 % CI?=?1.075–2.331, p?=?0.020). The toxicity of MTX also was found to be associated with the TT genotype in patients taking folate (OR?=?1.893, 95 % CI?=?1.283–2.793, p?=?0.001). Stratification by toxicity type indicated an association between the MTHFR 677TT genotype and any adverse effects (OR?=?1.716, 95 % CI?=?1.127–2.612, p?=?0.012). Meta-analysis stratified by toxicity type indicated an association between the MTHFR 1298CC genotype and any adverse effects (OR?=?0.501, 95 % CI?=?0.284–0.886, p?=?0.017). The results of our meta-analysis suggest that the MTHFR C677T and A1298C polymorphisms are associated with MTX toxicity in RA patients.     

类风湿关节炎患者MTHFR基因A1298C、C677T多态性与甲氨蝶呤疗效及不良反应的关系

目的探讨类风湿关节炎（RA）患者亚甲基四氢叶酸还原酶（MTHFR）基因A1298C（rs1801131）、C677T（rs1801133）单核苷酸多态性（SNPs）与甲氨蝶呤（MTX）疗效和不良反应的相关性。方法收集初治活动期RA患者78例,均口服MTX10—15mg／周。观察治疗0周、4周、8周、12周、24周临床症状及实验室指标变化,评价疗效及不良反应。采用实时荧光定量PCR方法检测基因型,分析各等位基因频率与MTX疗效及不良反应的相关性。结果MTHFRA1298C位点的C等位基因频率在治疗有效组明显高于治疗无效组（30．8％VS9．6％,P〈0．05）。C677T位点的T等位基因频率在有不良反应组与无不良反应组间差异有统计学意义（57．8％vs31．8％,P〈0．05）。结论MTHFR基因A1298C多态性与MTX的疗效相关,C677T多态性与MTX不良反应具有相关性。     

Sacubitril/Valsartan for heart failure: A protocol for systematic review and meta-analysis

Background:Sacubitril–valsartan has been shown to have superior effects over angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients with heart failure (HF). However, the effects of sacubitril–valsartan have never been systematically evaluated. Therefore, we performed a protocol for systematic review and meta-analysis to evaluate the efficacy and safety of sacubitril–valsartan in patients with HF.Methods:We selected 8 databases, including PubMed, the Web of Science, Embase, Cochrane Library, the Chinese National Knowledge Infrastructure, the Chinese Science Journal Database, Wanfang Data, and the Chinese Biomedical Literature Database. The search time was from database establishment to March 2022. Two reviewers will screen the records and include quality studies according to inclusion criteria independently. Two reviewers will assess the risk of bias of the included studies by the “Risk of Bias Assessment Tool” of the Cochrane Handbook for randomized controlled trials. Statistical analysis will be performed with Review Manager software 5.3.Results:A synthesis of current evidence of sacubitril–valsartan for treating HF will be provided in this protocol.Conclusion:The results of this study will provide a theoretical basis for the clinical use of sacubitril–valsartan to treat HF.     

Association between RGS4 gene polymorphisms and schizophrenia: A protocol for systematic review and meta-analysis

Background:Schizophrenia is a complex brain disorder, the pathogenesis of which remains unclear. Regulator of G-protein signaling 4 is regarded as a candidate gene for schizophrenia risk. The association between the regulator of G-protein signaling 4 gene and the risk of schizophrenia is complicated and controversial, thus, an updated meta-analysis is needed.Methods:A search strategy using Medical Subject Headings was developed in English (PubMed, SZGene) and Chinese (CNKI, Wanfang, and Weipu) databases. Inclusion and exclusion criteria were used to screen for eligible studies. Parameters, such as P value of Hardy–Weinberg equilibrium, odds ratios, 95% confidence intervals, P values of association, heterogeneity (P_h), and publication bias, were analyzed by the Stata software using a random effects model. Subgroup analyses were performed to detect heterogeneity.Results:There were 15 articles regarding rs10917670 (8046 cases and 8837 controls), 16 regarding rs951436 (8990 cases and 10,568 controls), 15 regarding rs951439 (7995 cases and 8646 controls), 15 regarding rs2661319 (8320 cases and 9440 controls), and 4 regarding rs10759 (2752 cases and 2866 controls). The frequencies of rs10917670 and rs951439 were not significantly different between the case and control groups (P > .05). As shown by the East Asian and hospital-based subgroup analyses, the genotype TT of rs951436 might be related to the risk of schizophrenia. The genotypes CC + CT of rs2661319 and CC + CA of rs10759 were statistically different between the 2 groups, and the East Asian population contributed to these differences.Conclusion:The genotypes CC + CT of rs2661319 and CC + CA of rs10759 might be associated with the risk of schizophrenia.     

Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and male infertility risk: An updated meta-analysis

Background:18 previous meta-analyses have been published on the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms with male infertility risk. However, results of the previous meta-analyses were still inconsistent. Moreover, their meta-analyses did not assess false-positive report probabilities except one study. Furthermore, many new studies have been published, and therefore an updated meta-analysis and re-analysis of systematic previous meta-analyses were performed to further explore these issues.Objectives:To determine the association between MTHFR C677T and A1298C polymorphisms and male infertility risk.Methods:Crude odds ratios and their 95% confidence intervals were used to assess the association between MTHFR C677T and A1298C polymorphisms and male infertility risk. We used the Bayesian false discovery probability (BFDP) to assess the credibility of statistically significant associations.Results:Fifty-nine studies were included concerning the MTHFR C677T and 28 studies were found on the MTHFR A1298C with male infertility risk. Overall, the MTHFR C677T was associated with increased male infertility risk in overall populations, Africans, East Asians, West Asians, South Asians, azoospermia, and Oligoasthenoteratozoospermia (OAT). In further sensitivity analysis and BFDP test, the positive results were only considered as “noteworthy” in the overall population (TT vs CC: BFDP = 0.294, CT + TT vs CC: BFDP = 0.300, T vs C: BFDP = 0.336), East Asians (TT vs CC: BFDP = 0.089, TT vs CT + CC: BFDP = 0.020, T vs C: BFDP < 0.001), West Asians (TT vs CC: BFDP = 0.584), hospital-based studies (TT vs CC: BFDP = 0.726, TT vs CT + CC: BFDP = 0.126), and OAT (TT vs CT + CC: BFDP = 0.494) for MTHFR C677T. In addition, a significantly increased male infertility risk was found in East Asians and population-based studies for MTHFR A1298C. However, we did not find that the positive results were considered as “noteworthy” in the overall and all subgroup analyses for MTHFR A1298C.Conclusions:In summary, this study indicates that the MTHFR C677T is associated with increased male infertility risk in East Asians, West Asians, and OAT. No significant association was observed on the MTHFR A1298C with male infertility risk.     

Association between TGF-β gene polymorphism and myopia: A systematic review and meta-analysis

Introduction:The present study was conducted to determine the association of transforming growth factor-beta (TGF-β) gene polymorphism and myopia.Method:Four hundred twelve articles were identified, of which 11 articles with 5213 participants in 4 countries were included in the final analysis. Review Manager software (RevMan, version 5.4) was used for data analysis.Result:Odds ratio (OR) value of TGF-β1 rs1800469 is 1.33 (95% confidence interval [CI] = 1.15–1.54) in the allelic model; in the dominant model is 1.76 (95% CI = 1.16–2.67); in homozygous model is 5.98 (95% CI = 4.31–8.06). OR value of TGF-β1 rs4803455 is 0.62 (95% CI = 0.43–0.88) in recessive model. TGF-β2 is not associated with myopia. Relevant study on TGF-β3 is scarce.Conclusion:Our systematic review and meta-analysis found that TGF-β1 rs4803455 and rs1800469 were correlated with myopia.     

Associations and interaction effects of maternal smoking and genetic polymorphisms of cytochrome P450 genes with risk of congenital heart disease in offspring: A case–control study

To assess associations and interactions of maternal smoking and cytochrome P450 (CYP450) genetic variants with the developments of congenital heart disease (CHD) and specific subtypes.A case–control study of 654 cases and 666 controls was conducted from November 2017 to March 2020. The exposures of interest were maternal active and passive smoking before/in the early pregnancy and CYP450 genetic polymorphisms. Data were analyzed using the Chi-square test and logistic regression analysis.After adjusting for the potential confounding factors, our study showed maternal active (OR_adj = 2.34, 95%CI: 1.19–4.60) or passive (OR_adj = 1.76, 95%CI: 1.34–2.31) smoking before pregnancy, passive smoking in the early pregnancy (OR_adj = 3.05, 95%CI: 2.26–4.12), as well as polymorphisms of CYP450 at rs1065852 (G/A vs G/G: OR_adj = 1.46, 95%CI: 1.07–1.99; A/A vs G/G: OR_adj = 1.63, 95%CI: 1.15–2.33) and rs16947 (A/A vs G/G: OR_adj = 3.61, 95%CI: 2.09–6.23), were significantly associated with risk of total CHD in offspring. Similar results were also found for some subtypes of CHD. Additionally, significant interactions between maternal smoking and CYP450 genes on the risk of CHD were observed.Maternal smoking and CYP450 genetic variants were associated with increased risk of CHD and specific subtypes in offspring. And the effects of CYP450 genes on CHD may be modified by maternal smoking.     

Association between shift work and risk of metabolic syndrome: A systematic review and meta-analysis

AimsA comprehensive assessment of the association of shift work with risk of metabolic syndrome (MetS) through a systematic review and meta-analysis has not been reported. We aimed to evaluate the relationship from observational studies.Data synthesisWe searched PubMed, Embase, and Web of Science databases from inception to December 16, 2020. Articles were chosen according to established inclusion criteria. Studies with data on men and women and different types of shift work were treated as independent studies. Relative risks (RRs) and 95% confidence intervals (CIs) were pooled by using random-effects models with heterogeneity (I²) > 50%; otherwise, a fixed-effects model was used. A total of 7192 articles was searched from PubMed, Embase and Web of science. Finally, we included 23 articles (38 studies) in this meta-analysis. The pooled RRs and 95% CI of MetS risk with shift work, 1-shift work, 2-shift work, and 3-shift work versus non-shift work were 1.30 (95% CI 1.19–1.41), 0.95 (95% CI 0.82–1.11), 1.19 (95% CI 0.91–1.56) and 1.17 (95% CI 1.00–1.37), respectively. The results from subgroup analyses stratified by sex, age, and region supported our overall findings that shift work is a risk factor for MetS.ConclusionsThis meta-analysis suggests that shift work increases risk of MetS. Higher risk of MetS was found in the shift workers who were 2-shift or 3-shift or women or Asian workers.     

Association of folate metabolism-related genetic polymorphisms with susceptibility to breast cancer: A protocol for a systematic review and meta-analysis

Background:Breast cancer has recently become one of the most common causes of cancer-related deaths, and several studies have suggested that genetic polymorphisms in the folate metabolism pathway may be associated with susceptibility to breast cancer, although their results have been inconsistent or inconclusive. Therefore, the aim of this meta-analysis was to obtain accurate, consistent conclusions regarding the potential associations of genetic polymorphisms in the folate metabolism pathway with the risk of breast cancer, based on case-controlled studies.Methods:From the beginning of database establishment through May 2021, we indexed and searched domestic and foreign databases, including the Chinese National Knowledge Infrastructure, Web of Science, VIP and BioMedical Database of China, PubMed, EMBASE, Wanfang database, and the Cochrane Library. To determine the effects of folate metabolism-related genetic polymorphisms on breast cancer risk, we used Stata version 16.0 to analyze all data and calculated variable odds ratios and 95% confidence intervals.Results:The findings of the current meta-analysis are going to be presented to peer-reviewed journals for publication when the analysis is completed.Conclusion:The meta-analysis will summarize the association of genetic polymorphisms in the folate metabolism pathway with breast cancer.Registration number:May 26, 2021.osf.io/25r48. (https://osf.io/25r48/).     

The relationship between CHRNA5/A3/B4 gene cluster polymorphisms and lung cancer risk: An updated meta-analysis and systematic review

Background:Genetic polymorphisms in the 15q25 region have been associated with the risk of lung cancer (LC). However, studies have yielded conflicting results.Methods:Searches were conducted in databases, including PubMed, EMbase, Web of Science, CNKI, and Wanfang, for case-control studies up to August 1, 2019. After retrieving eligible studies and data extraction, we calculated pooled odds ratios with 95% confidence intervals. In the meta-analysis, we included 32 publications with a total of 52,795 patients with LC and 97,493 control cases to evaluate the polymorphisms in the CHRNA5/A3/B4 gene cluster in the 15q25 region.Results:Data of the meta-analysis showed a significantly increased risk of LC in the presence of genetic polymorphisms (rs1051730, rs16969968, rs8034191). In the smoking subgroup, the CHRNA3 rs1051730 polymorphism was found to contribute to LC risk using following 5 models: the allelic model, the homozygous model, the heterozygous model, the dominant model, and the recessive model. Thus, the rs1051730 polymorphism may modify LC susceptibility under the condition of smoking. Stratification studies for CHRNA5-rs8034191 showed that Caucasian groups with the wild-type genotype (C/C) may be susceptible to LC in all 5 models. No significant relationship between CHRNA3 rs6495309 or rs3743073 and LC susceptibility was found. However, Asians with the rs3743037 B-allele showed an obviously higher risk of LC susceptibility than the Caucasian population, observed via allelic, heterozygous, and dominant models.Conclusions:The 3 polymorphisms of rs1051730, rs16969968 and rs8034191 in the CHRNA5/A3/B4 gene cluster in the 15q25 region were associated with LC risk, which might be influenced by ethnicity and smoking status.     

Association between CYP2A13 polymorphisms and lung cancer: A protocol for systematic review and meta-analysis

Background:Recently, lung cancer has become the most common cause of cancer-related death, several studies indicate that the cytochrome P450 2A13 (CYP2A13) polymorphisms may be correlated with lung cancer susceptibility, but the results have been inconsistent and inconclusive. Therefore, the aim of this meta-analysis is to provide a precise conclusion on the potential association between CYP2A13 polymorphisms and the risk of lung cancer based on case-control studies.Methods:The PubMed, Embase, Cochrane Library, Web of Science, and China National Knowledge Infrastructure (CNKI) databases will be searched for case-control studies published up to September 2020. Odds ratio (OR) and 95% confidence interval (95% CI) were used to determine the effects of the CYP2A13 polymorphism on lung cancer risk, respectively.Results:The results of this meta-analysis will be submitted to a peer-reviewed journal for publication.Conclusion:This meta-analysis will summarize the association between CYP2A13 polymorphisms and the risk of lung cancer.INPLASY registration number:INPLASY202090102     

Association of cytochrome P450 2C19 polymorphisms with coronary heart disease risk: A protocol for systematic review and meta analysis

Background:Polymorphisms in the cytochrome P450 2C19 (CYP2C19) gene have been reported to be associated with coronary heart disease (CHD), but the results were not consistently analyzed among different patient groups. To derive a more precise estimation of these associations, we will conduct a meta-analysis to investigate the polymorphisms of CYP2C19 in all published studies.Methods:Electronic databases (Google Scholar, ISI Web of Science, Pubmed, Embase, China National Knowledge Infrastructure, Wanfang, and China Biological Medicine) will be used to search clinical case-control or cohort studies about CYP2C19 polymorphism and CHD published until November 2020. Two reviewers will independently select the study, extract the data, and evaluate the quality of the study. Odds ratios with 95% confidence interval will be used to evaluate the strength of the association between the CYP2C19 polymorphism and CHD susceptibility under 4 genetic models. Subgroup analysis will be conducted by different ethnicity and genotyping method. Sensitivity analysis will be performed via sequentially omitting each of the included studies 1 at a time. Begg funnel plots and Egger test will be used to examine the potential publication bias. All the statistical analyses will be performed using Review Manager 5.3 and Stata 12.0.Results:This study will provide a better understanding of the association between CYP2C19 polymorphisms and coronary heart disease risk.Conclusion:The publication of this protocol will minimize the possibility of bias due to post hoc changes to the analysis protocol, thus helping to obtain reliable evidence.OSF registration number:DOI 10.17605/OSF.IO/R7U93     

Gwakhyangjeonggi-san for irritable bowel syndrome: A protocol for systematic review and meta-analysis

Background:Irritable bowel syndrome (IBS) is a chronic functional bowel disorder characterized by abdominal pain or discomfort, stool irregularities, and bloating. Owing to its atypical symptoms and various mechanisms, there is no standard treatment for IBS. Gwakhyangjeonggi-san (GJS), a traditional Korean herbal medicine, has been used to treat lower intestinal abnormalities in Asia. We will systematically review randomized controlled trials (RCTs) to evaluate the efficacy and safety of GJS as a complementary treatment for IBS.Methods and analysis:Four English databases, namely, Medline (via PubMed), EMBASE, the Cochrane Central Register of Controlled Trials, and the Allied and Complementary Medicine Database, will be searched for entries up to May, 2021. Additional databases will include 5 Korean databases, 1 Chinese database, and 1 Japanese database. RCTs and quasi-RCTs will be searched for to assess the effectiveness and safety of GJS. The primary outcome measure will be the overall efficacy rate, and the secondary outcome will include data such as global symptom scores, IBS Quality of Life measurements, and adverse events. Data analysis will be performed using Review Manager Version 5.3, and the risk of bias will be assessed using the Cochrane Collaboration''s risk-of-bias tool. The quality of the results will be evaluated using the Grading of Recommendations Assessment, Development, and Evaluation approach.Conclusion:This systematic review will provide evidence for the efficacy and safety of GJS for IBS.OSF registration number:DOI 10.17605/OSF.IO/V93JN (https://osf.io/v93jn).