P = .003, odds ratio [OR] = 1.21), rs55705857 . In particular, both homozygous GG  and heterozygous GT  genotypes of rs4295627 were associated with glioma risk. Further studies are needed to explore the role of the 8q24 variants involved in the etiology of glioma.With the advances in sequencing technologies and genome-wide association studies (GWAS), several inherited variants that increase glioma risk have been identified. Ten studies including 8818 cases and 17,551 controls were collected to conduct a meta-analysis to evaluate the associations between 6 variants in 8q24 and glioma risk. Of the 6 variants located in 8q24, 2 have strong significant associations with the risk of glioma, including rs4295627 ( Since then, new risk variants have been identified.–9 In 2011, Jenkins et al reported that the glioma risk loci in 8q24 were associated with the development of glioma. These findings were then replicated in different ethnic populations: Safaeian et al followed up on these reports to evaluate the GWAS-identified SNPs on glioma risk in European ancestry, and found that rs4295627 in 8q24 was statistically significantly associated with increased risk of glioma; Wei et al evaluated these glioma risk variants in a Chinese Han population, and found that both the rs891835 and the rs6470745 in 8q24 are associated with increased glioma risk. However, another study did not show any significant associations between 8q24 variants and glioma risk.Gliomas account for over 80% of primary malignant brain tumors, however, <50% of glioma patients live longer than 5 years after diagnosis.Several meta-analysis have been done to evaluate the contribution of variants in the 8q24 region to risk of glioma, findings from these studies were generally inconsistent and the mechanisms of these associations remain unclear. Here we performed a comprehensive meta-analysis, involving a total of 8818 cases and 17,551 controls, to evaluate all genetic studies that investigated associations between 6 variants in 8q24 and risk of glioma.22.1We conducted this study in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. We systematically searched PubMed and Embase to identify genetic association studies published in print or online before April 1st, 2018 in English language using key terms “8q24” and “polymorphism or variant or variation or genotype” and “glioma or brain tumor.” Two investigators (YT and JL) independently assessed the eligibility of each study. All studies included in this meta-analysis must meet all the following inclusion criteria: evaluating the associations of the 8q24 variants with glioma risk; providing sufficient data or multivariate-adjusted risk estimates  or standard errors [SEs]) to calculate these estimates. The exclusion criteria were as follows: insufficient data; they were published as letters to editors or conference abstracts; they were studies about cancer mortality.2.2Guidelines recommended were used to report meta-analyses of observational studies by investigators (YT and JL) to extract data. Extracted data from each eligible study included name of first author, study design, publication data, source population, ethnicity, sample size, variants, alleles, and genotype counts, Hardy–Weinberg equilibrium (HWE) among controls. Ethnicity was classified as Caucasian, African, Asian, or others . In this meta-analysis, 10 eligible publications are available with sufficient data. All analyses were based on previous published studies, thus no ethical approval and patient consent are required.2.3 was used to estimate the genetic effects and mode of inheritance. Cochran Q test and calculated І2 statistic were performed to evaluate heterogeneity between studies. І2 values <25% represent no or little heterogeneity, values 25% to 50% represent moderate heterogeneity, and values >50% represent large heterogeneity. Sensitivity analyses were conducted to examine if exclusion of first published report or studies deviated from HWE in controls influence the significant association. Harbord test was performed to evaluate publication bias. Small study bias was calculated by Egger test. All analyses were conducted using Stata, version 14.0 , with the metan, metabias commands.For each study, the OR was used as the metric of choice. Pooled ORs were computed by the fixed effects model and the random effects model based on heterogeneity estimates. Once an overall gene effect was confirmed, the genetic model-free approach suggested by Minelli et al33.1Our initial database search identified 36 potentially relevant studies. Based on a review of titles and abstracts, 22 publications were retained. The full text of these 22 publications was reviewed in detail, and 10 studies were eligible for inclusion in the meta-analysis. The specific process for identifying eligible studies and inclusion and exclusion criteria are summarized in Fig. 3.2Of the 6 variants located in 8q24, 2 have strong significant associations with risk of glioma, including rs55705857, rs4295627, and rs6470745 has a weak significant association. No significant associations were found between rs10464870, rs891835 and rs16904140, and glioma (data not shown).3.3P = .003, random effect OR = 1.21, 95% CI: 1.07, 1.37; Q = 66.78, P = .000, I2 = 85.0%, Fig. P = .022, random effect OR = 1.22, 95% CI: 1.03, 1.46; Q = 46.1, P = .000, I2 = 87.0%). No publication bias was found in the eligible studies  and heterozygous GT genotype .Only 3 studies reported the genotype information of rs4295627 T>G. The genotype effects for GG versus TT (OR1) and GT versus TT (OR2) were calculated for each study. A multivariate meta-analysis was conducted to estimate the pooled risk , rs55705857  have strong significant associations with the risk of glioma. In particular, both homozygous GG  and heterozygous GT  genotypes of rs4295627 were associated with glioma risk. Based on several gene-association studies and several thousand participants, our findings were robust in terms of study design and sensitivity analyses. No evidence of publication bias or small study bias was found.Of the 6 variants located in 8q24, 2 have strong significant association with risk of glioma, 1 has a weak significant association with risk of glioma. Our primary analysis shows that, the rs4295627  in the 8q24 region and risk of glioma.CCDC26. Genetic association studies, especially GWAS, indicated that the rs4295627 SNP may contribute to the increased risk of glioma. The rs55705857 G-allele can also increase tumorigenic potential of tumor initiating cells in oligodendrogliomas and astrocytomas. The differential activity of Ras/MAPK pathways and the RTK activation are involved in this process. Some research has indicated that the expression of CCDC26 upregulated in glioma tissues and cell lines, and CCDC26-siRNA inhibited glioma growth and metastasis. Further studies are needed to clarify the physiological function of CCDC26 and the functional consequence of these variants in vivo.Both the rs4295627 and the rs55705857 are mapped to the There are several limitations of the study should be mentioned. First, it is likely that some publications were overlooked although we conducted an exhaustive literature search, some relevant published studies or unpublished studies with null results were not identified. Second, data about the types of glioma was absent from most of the 22 studies included in this meta-analysis. Third, due to insufficient data, we were unable to evaluate publication bias for associations between several variants in 8q24 region and glioma. Therefore, future studies with larger sample size are warranted to confirm these associations.In summary, we have identified 3 variants in the 8q24 region that showed strong evidence of an association with glioma risk in this large-scale research synopsis and meta-analysis. Further functional studies are needed to explore the exact mechanisms of 8q24 variants involved in parthenogenesis of glioma.Data curation: Yu Tong.Formal analysis: Yu Tong.Investigation: Fengyan Zhao.Project administration: Dezhi Mu.Software: Lv Ye, Shiping Li, Junjie Ying.Supervision: Yi Qu, Jinhui Li.Writing – original draft: Yu Tong.Writing – review & editing: Dezhi Mu.Dezhi Mu orcid: 0000-0002-2599-7041.


Overall, antibiotic use was an independent risk factor for cancer occurrence . The risk was especially increased for lung cancer , lymphomas , pancreatic cancer , renal cell carcinoma , and multiple myeloma . There is moderate evidence that excessive or prolonged use of antibiotics during a person’s life is associated with slight increased risk of various cancers. The message is potentially important for public health policies because minimizing improper antibiotic use within a program of antibiotic stewardship could also reduce cancer incidence.The association between antibiotic use and risk of cancer development is unclear, and clinical trials are lacking. We performed a systematic review and meta-analysis of observational studies to assess the association between antibiotic use and risk of cancer. PubMed, the Cochrane Library and EMBASE were searched from inception to 24 February 2019 for studies reporting antibiotic use and subsequent risk of cancer. We included observational studies of adult subjects with previous exposure to antibiotics and available information on incident cancer diagnoses. For each of the eligible studies, data were collected by three reviewers. Risk of cancer was pooled to provide an adjusted odds ratio (OR) with a 95% confidence interval (CI). The primary outcome was the risk of developing cancer in ever versus non-antibiotic users. Cancer risk’s association with antibiotic intake was evaluated among 7,947,270 participants ( Antibiotics are antimicrobial substances that are active against bacteria and represent the most important armamentarium for fighting bacterial infections. In general, management of patients with suspected bacterial infections consists of initiation of empiric therapy , followed by adjustment once microbiology information becomes available. In particular, isolation of bacteria from clinical samples yields information that can be used to guide the selection of appropriate regimens based on prior knowledge of bacterial susceptibility to certain antibiotics. Recent advances in knowledge have provided information that antibiotics can influence an individual’s health status via the concomitant damage of bacteria that usually live in healthy humans, the microbiota. These organisms and their genes, metabolites, and interactions with one another, as well as with their host collectively, represent our microbiome . DespiteFusobacterium spp. and colorectal cancer [Fusobacterium spp. may contribute to tumorigenesis by an inflammatory-mediated mechanism, but the precise role of Fusobacteria in colorectal carcinoma pathogenesis requires further investigation. All these findings suggest that alterations in CRC microbiota may contribute to the etiology of colorectal cancer [Neoplastic conditions could be affected or driven by disturbances in gut microbiota. For example, structural fecal bacterial distinction between colorectal cancer (CRC) patients and healthy volunteers have been demonstrated . Genomicl cancer . Indeed,l cancer . Antibiol cancer ,6. This Given the enormous interest and implications for the community, we aimed to evaluate whether antibiotic use represents an independent risk factor for the development of solid tumors and lymphomas in adult humans through a systematic review and meta-analysis of epidemiological studies.We followed the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines . We perfFor each of the eligible studies, the following data were collected: Author name, year of publication, country, number of patients (including cases and controls for case–control studies), type of study, type of analysis, exposure (cumulative time on treatment and/or number of prescribed doses), type of antibiotics, type of incident cancer evaluated and covariates for odds ratios (ORs) adjustment. In the case of studies with potentially overlapping populations, the largest or most up-to-date study was included. Risk of bias in individual studies was assessed independently by four local reviewers  and by an external reviewer (JCH) with the Newcastle-Ottawa Scale for retrospective studies . We rateThree alternative analyses were designed: (i) Ever-use versus never-use meta-analysis; (ii) latency period analysis—that is, the time elapsed between last antibiotic use and incident cancer diagnosis ; and (iii) a dose–response analysis with comparison of a higher number of prescriptions versus none and longer duration of antibiotic exposure versus no antibiotics for each trial. The effect estimates (ORs) were extracted from each publication. Results were displayed in a standard forest plot. Concerning the main analyses, only the adjusted ORs were extracted from each study  to minimize the effects of confounding variables. The fixed-effects model (Mantel–Haenszel method) and the random effects (DerSimonian–Laird) model were used to calculate the pooled OR . HeterogThe analysis was performed with Review Manager (RevMan) version 5.3  and Comprehensive Meta-Analysis software version 3.3.070 (20 November 2014).n = 7,947,270 patients) met eligibility criteria and were included in the meta-analysis . A total of 17 incident neoplastic conditions and eight antibiotic classes  were associated with cancer incidence in at least three papers. The number of patients in each study ranged from 260 to 3,112,624 . The observation intervals ranged from 4.7 to 20 years. All studies except one included subjects from Western countries. Fourteen trials (56%) were of moderate to high quality according to the NOS scale.p < 0.001). There was evidence of high heterogeneity, therefore, a random effect model was used ; after recalculating the ORs of these publications without these patients, the result was similar.All studies were used to evaluate the pooled OR for risk of cancer in ever versus non antibiotic users. The exposure to antibiotics increased the risk of cancer by 18% .Eight trials evaluated the relationship between time elapsed since last antibiotic use and new incident cancer diagnoses . There was no association between a longer latency period and risk of cancer .Number of prescriptions (the highest number versus none or the lowest number) and duration on antibiotic therapy were most strongly associated with cancer risk , lymphomas , pancreatic cancer , renal cell carcinoma , prostate cancer , and multiple myeloma . The antibiotic classes with the strongest association were beta lactams adjusted , cephalosporines , macrolides  and quinolones . Results were similar for cohort and case-control studies.p = 0.48; p = 0.03). According to the trim and fill method, which looks for missing studies based on a random-effects model, no studies are potentially missing.There was no evidence of publication bias with Begg’s test (n = 21 and n = 6 studies with 47% and 50% associated with high risk of bias). There is moderate evidence that antibiotic use slightly increases the risk of hematological (multiple myeloma and lymphoma), gastrointestinal , lung and genitourinary cancers . There is very weak evidence that the risk is increased for breast and other cancers such as gynecological cancers and melanoma. Finally, there is moderate evidence that this risk is associated with specific classes of antibiotics  but low or insufficient evidence of associations with the other analyzed classes.There is moderate evidence that previous use of antibiotics during a person’s life is associated with a slightly increased risk of some cancers (excluding leukemia). The analysis is derived from 25 case-control or cohort studies with mainly low-moderate risk of bias in 56% of studies. There is moderate to low evidence that this risk is associated with the number of antibiotic prescriptions and duration of antibiotic exposure respectively (p < 0.001) but the causality of this association remained elusive [In this analysis based on 7,947,270 individual participants from 25 observational studies, antibiotic use was associated with an 18% increased risk of cancer. The highest risk was found in individuals with a long duration of antibiotic exposure or in those receiving higher doses. There was a 30% increased incidence of lung, hematological, pancreatic and genitourinary cancers compared to controls due to increased antibiotic exposure. Conversely, our study found no association between esophageal or cervical cancer and antibiotic use and a small increase in risk for CRC, gastric cancer and melanoma. To our knowledge, this is the most up to date and extensive meta-analysis that assessed the association of different doses/timing of antibiotic exposure with various incident cancer diagnoses. In a published meta-analysis of five case-control studies, antibiotic use was associated with an increase in breast cancer risk  [Antibiotics may influence cancer risk through several mechanisms. First, as mentioned above, the gut microbiota is not a simple intestinal layer but is a key regulator of digestion along the gastrointestinal tract. Commensal bacteria also play a pivotal role in the extraction, synthesis, and absorption of many nutrients and metabolites, including bile acids, lipids, amino acids, vitamins, and short-chain fatty acids. The gut microbiota has a crucial immune function against pathogenic bacterial colonization, inhibiting their growth, consuming available nutrients and/or producing bacteriocins. Gut microbiota also prevent bacterial invasion by maintaining integrity of the intestinal epithelium. All these functions can be altered when antibiotics are consumed, and consequently, systemic inflammation can arise and latent cancer cells can grow . Several Guerin) . Antibio Guerin) . Similar Guerin) ,39. In sFusobacterium nucleatum is associated with intestinal tumorigenesis, modulates the tumor-immune microenvironment and can respond to the antibiotic metronidazole by reducing cell proliferation [E. coli infection may promote chronic inflammation which leads to cell proliferation and tumor formation. The role of H. pylori in the pathogenesis of gastric cancer is well described. It could therefore be postulated that eradication of H. pylori and Fusobacterium or E. coli with prior use of antibiotics may reduce the risk of gastric and CRC respectively. However, despite these hypotheses, other risk factors probably related to a dysregulated gut or gastric microbiota can augment gastric cancer and CRC incidence in adults. In the present analysis, a protective effect is somewhat observed with cervical cancer, where risk is reduced by 25% by previous antibiotic use. Even if Human Papillomavirus (HPV) is the main factor involved in the pathogenesis of cervical cancer, Chlamydia trachomatis infection represents an independent risk factor, in particular when associated with HPV [For some cancers, a specific association with local microbiota is described ,41,42,43feration . There iwith HPV . It is lE. coli–related ciprofloxacin resistance [E. coli resistance is a facilitating factor associated with CRC [According to the antibiotic classes implicated in putative risk of cancer, higher risk is associated with beta-lactams, cephalosporins and fluoroquinolones. Although the risk is quite similar, with no class associated with an excessive risk above the general pooled weighted ratio, these three classes are the most frequently investigated and used in the community, with insufficient data found for aminoglycosides and lincosamides. A broad range of antibiotics has been shown to transiently or permanently alter the composition of healthy adult microbiotas, usually via depletion of one or several species . Amoxicisistance . It is pwith CRC . AntibioOur study has significant strengths. First, to our knowledge, this is the largest meta-analysis of adult subjects exposed or not during their lifetimes to antibiotics for various conditions and evaluated for incidence of cancer (solid tumors and lymphomas). In this meta-analysis which included approximately 8 million subjects, we found an 18% increase in the risk of various cancers. This risk is notably increased (30%) in those exposed several times or for more extended periods during previous years. Second, we used multivariate-based ORs adjusted for other comorbidities, age, gender, sex, body mass index, concomitant drugs or other medical variables. We therefore defined antibiotic use as an independent risk factor for cancer.However, our study has some limitations. First, this is not an individual patient data meta-analysis. An individual participant data analysis is not subject to the potential bias that arises in a study-level meta-analysis and would be the optimal approach to combine evidence across multiple studies and perform time-to-event analyses. Second, personal health conditions are partially unknown at the time of cancer diagnosis, and other risk factors such as diet, lifestyle, pollution or other chronic conditions that can increase baseline risk or influence the normal microbiome cannot be excluded. Third, seven studies did not report risk according to antibiotic class. Fourth, the data refer to cancer incidence only, so stage and/or pathology report and outcome are not available. Fifth, only one study included patients of Asian origin, so generalization to the worldwide population is not possible. Finally, in 12 studies, the median observation period (follow-up) was not reported.https://www.who.int/antimicrobial-resistance/global-action-plan/en/). In a similar position paper, the European Surveillance of Antimicrobial Consumption Network joined the European Union in providing guidelines on the prudent use of antimicrobials in humans . The term “antimicrobial stewardship” refers to policies, education strategies and interventions aimed at optimizing antimicrobial use. In this way, inappropriate prescriptions can be reduced with more guidelines on the use of antibiotics in both ambulatory [Many antibiotics prescribed in hospitals are unnecessary or inappropriate. Some scientific societies have provided authoritative statements or guidelines to guide clinicians toward better antibiotic use. The World Health Organization defined a global action plan to ensure optimal treatment and prevention of infectious diseases with adequate and safe medicines that are quality-assured, used responsibly and accessible to all who need them . These data derive from a large number of patients included in observational studies. Despite being associated with obvious bias, this information should encourage clinicians to adopt appropriate use of these drugs to treat infections according to published guidelines.


P = 0.033). After adjusting for the risk factors, a significant difference was still observed between the responsive and resistant groups . Moreover, the recessive model was associated with a decreased drug resistance  after correcting the risk factors. Meta-analysis of nine studies revealed similar results. In conclusion, our results proved that the rs3812718 TT genotype was associated with a high risk of developing drug resistance, and the recessive model could decrease the risk of VPA resistance.Resistance to valproic acid (VPA), a first-line antiepileptic drug (AED), is occurring at an alarming rate, particularly in children. Signal nucleotide polymorphisms are considered crucial in this process. Therefore, we investigated whether the SCN1A polymorphism rs3812718 could be associated with VPA resistance. A total of 231 children with epilepsy who were solely administered VPA were enrolled. DNA was extracted from the peripheral blood samples and was genotyped by the Mass Array method. Furthermore, a meta-analysis was conducted between the drug responsive and resistant patients who were exposed to voltage-gated sodium channels. Results revealed that the TT genotype was associated with a higher risk of developing drug resistance (OR = 2.636, 95% CI 1.08–6.433,  Resistance to antiepileptic drugs (AEDs) is crucial in epilepsy treatment. About 50–60% patients can be effectively treated by a single AED, the remaining being resistant to the treatment . Genetic+) channels [+ channel neuronal type I alpha subunit (SCN1A), which encodes the α-subunit of the Nav1.1 Na+ channel, is presumed to be associated with AED resistance. An SCN1A functional polymorphism (IVS5-91 rs3812718 C > T) located in the 5′ splice donor site was reported to generate alternative splicing products, resulting in altered proportions of exon 5′ transcripts in the neonate and adult brain tissue [Single nucleotide polymorphisms (SNPs) are reported to be associated with AED resistance, in particular, by blocking the voltage-gated sodium  and coadministered valproic acid (VPA) resistance epilepsy in a cross-sectional study of Japanese patients . Tate etng drugs ,8.+ channels; therefore, we speculated that the SCN1A genotype polymorphism may also be associated with a reduced therapeutic effect of VPA by altering the response of the Na+ channel [VPA, a fatty acid with an anticonvulsant property for treating several epilepsies and seizures, is prescribed worldwide as an effective and economic first-line AED . Neverth channel . The prePatients were consecutively enrolled between February and October 2017 from the outpatient and inpatient department of Fuzhou Neuropsychiatry Hospital. The inclusion criteria were: (1) patients aged 2–18 years with epilepsy ; (2) thoOn enrollment, the patients provided their clinical history including the demographic data, dosage regimens, and seizure type and frequency (before drug intake and after 1-year of treatment). A 1-year follow-up was done to evaluate the therapeutic effect of VPA. Steady-state venous blood samples were collected after the regular intake of sustained-release VPA tablets twice a day for at least 30 days. VPA-resistant epilepsy was defined as a reduced percentage of seizure frequency  and reduced seizure frequency (more than 50% was regarded as responsive epilepsy) . The seiBlood samples of all participants were collected and stored at −80°C until use. Genomic DNA was extracted from the whole blood using a commercial kit  according to the manufacturer’s protocol. Patients’ DNA was purified by Qiagen DNA purification kit . Genotyping was identified by MassArray method .Studies published by 20 May, 2018 were identified by a systematic literature search in PubMed, Embase, Web of Knowledge, China National Knowledge Infrastructure (CNKI) and WanFang Data. MeSH and title/abstract were used for all eligible studies that mainly focus on the genotype of rs3812718 polymorphism either in VPA responsive or resistant patients. The search strategy was as follows: (‘seizure’ or ‘epilepsy’) AND  AND (‘resistan*’ or ‘respons*’).Eligible studies must met the following criteria: (1) the study evaluated the association between rs3812718 polymorphism and AED resistant, (2) the report focused on detailed genotype frequencies among human beings, and (3) the investigation was a case–control study. Accordingly, the exclusion criteria were as follows: (1) studies without detailed genotype data; and (2) reports with overlapping data. The ‘Search strategy’ was shown in Supplement Materials.2 test and a P value <0.05 was considered significant disequilibrium. Differences in genotypic frequencies between groups were calculated by the Pearson’s chi-square test or Mann–Whitney U test. Odds ratios (ORs) with 95% CI were calculated. Logistic regression analysis was used to evaluate the contribution of genetic and non-genetic factors to the VPA resistant under dominant and recessive model. Patients’s age, body weight and seizure frequency were treated as risk factors to be adjusted in the analysis.All statistical analyses were performed by SPSS . Hardy–Weinberg equilibrium (HWE) was assessed by using a χQ statistic and I2 statistic. Once, Q-test >0.10 or I2 < 50%, the fixed effect model (Mantel–Haenszelmethod) was used to calculate the pooled ORs, otherwise, the random-effect model (DerSimonian–Laird method) was used. The significance of the pooled ORs was assessed by Z-test, where P < 0.05 indicated statistically significant. Begg’s and Egger’s linear regression tests were applied to assess the potential publication bias. The statistical analyses were performed by using the STATA version 12.0  [For meta-analysis, the OR and 95% confidence interval (95% CI) were calculated to assess the relationship of rs3812718 polymorphism between AEDs responsive and resistant. Pooled ORs were obtained from combination of single study under recessive model (TT vs. CT+CC) and dominant model (TT + CT vs. CC). Heterogeneity was evaluated by n = 185) and VPA resistant (n = 46). The demographics characteristics are listed in A total of 231  patients with a mean age of 9.80 ± 5.1 years and body weight 33.48 ± 16.2 kg were enrolled in the study. All patients were Chinese with confirmed epileptic diagnosis. Of these, 142 patients were classified as general type, 62 as focal type, and 27 as unable to be classified. The seizure frequency was less than once per day in 143 patients, between one and five times per day in 72 patients, and over five times per day in 16 patients. All participants were divided into two groups, VPA responsive (P > 0.05). The genotype distribution is listed in The genotypes of CC, CT, and TT were present in 25%, 48%, and 27% patients, respectively. The MAF  of rs3812718 polymorphism was 0.4879. Deviation from the Hardy–Weinberg equilibrium was not observed (P = 0.033). Significant differences were still observed between the responsive and resistant groups  even after adjusting the age, body weight, and seizure frequency (P = 0.051). However, after adjusting the age, body weight, and seizure frequency, a significant difference was observed between the two groups . Meanwhile, the TT genotype with any clinical parameters was also analyzed, and no significant differences were observed between the patients carrying the TT genotype and those carrying the other two genotypes.P > 0.05). A sensitivity analysis was conducted to assess the influence of each individual study on the pooled OR. The results revealed that no single study influenced the quality of the pooled ORs in the sensitivity analyses.The study characteristics included in this meta-analysis are listed in + channel AEDS and its effect on epilepsy. Our results revealed that the recessive model can significantly decrease the risk of drug resistance  by using a fixed model. Subgroup analysis indicated the significant association of the rs3812718 polymorphism with drug resistance in the Asian population , but not in the Caucasian population , we found a significant correlation between the maximum doses of AEDs and carriers of the C allele (C/T or C/C genotype). Our results were partially consistent with the findings of Kazuko Nakagawa et al. [Drugs affecting the voltage-gated Naa et al. , which wVPA emerges with a broad-spectrum efficacy range, which considerably varies among patients consuming the same dose of VPA. Although VPA therapy is relatively safe, epilepsy control with VPA can be a difficult and lengthy process owing to the drug’s narrow therapeutic index . In addi+ channel transcripts in human epilepsy have been discovered in the brain tissue. Genetic variants from ion channels and functionally related genes may affect the response to first-line AEDs; thus, identifying genetic markers in the treatment response has been an urgent need in epilepsy therapeutics [Mutations in Naapeutics ,27. SCN1apeutics . Neverthapeutics .+ channels fails to efficiently explain the drug resistance of VPA. Second, as the sample size was small, few indices in our research were nearly at the edge of the significance. Third, as fewer studies were available on the relationship between rs3812718 polymorphism and VPA resistance, we had to consider all the published articles that evaluated the effects of AEDs on the Na+ channel, eventually leading to diverse analyses.This is the first study to report the significant association of SCN1A polymorphism (IVS5-91 rs3812718 C > T) with VPA resistance among children. Although our results are promising and may help in identifying patients with VPA resistance, these should be considered as preliminary results and further research is necessary. Moreover, the present study has certain limitations. First, the considerably complex mechanism of VPA and our focus solely on the NaIn conclusion, our study had for the first time showed an association between the resistant and responsive of VPA and rs3812718 polymorphism. However, these data need to be replicated in a larger cohort of patients, and functional studies will be necessary to investigate whether and how rs3812718 polymorphism might influence key pathways involved in the pathogenesis of epilepsy and seizure.


Several studies have reported the Cyclooxygenase 2 (COX-2) rs689466 polymorphism as a susceptibility locus of colorectal cancer (CRC), but their findings are inconsistent. Thus, this meta-analysis was performed to more accurately identify the effects of this polymorphism on CRC risk.Potential case-control studies on EMBASE, Google Scholar, Web of Science, Cochrane Library, and PubMed were searched. The strength of association was quantified by pooled odds ratio and 95% confidence interval. Totally 16 articles involving 8998 cases and 11,917 controls were included.None of the five tested genetic models revealed an association between rs689466 polymorphism and CRC risk. Stratified analysis by ethnicity uncovered a positive association between this polymorphism and higher CRC risk in Caucasians, but not in Asians. In addition, we found that high expression of COX-2 was associated with better overall survival for all CRC patients.To sum up, the COX-2 rs689466 polymorphism may be related with susceptibility to CRC in Caucasians. This finding should be verified by larger-size studies with different ethnic groups. Colorectal cancer (CRC), the second largest cause of cancer-induced death in the world , was estCyclooxygenases (COXs), including two isoforms of COX-1 and COX-2 identified so far, are critical in transforming arachidonic acid to the precursor of prostaglandins—prostaglandin H2 . COX-2 oCOX-2 containing 10 exon counts is located in the chromosome 1q31.1. Rs689466 polymorphism is in the promoter zone of COX-2 gene. The association between rs689466 polymorphism and CRC risk has been explored extensively . HoweverTwo reviewers systematically and independently searched EMBASE, Google Scholar, Web of Science, Cochrane Library, and PubMed to find potential studies without any restriction. The key words included “polymorphism”, “single nucleotide polymorphism” or “SNP”, “colorectal cancer”, “colorectal tumor” or “CRC”, and “Cyclooxygenase-2” or “COX-2”. References of identified studies were manually screened to search any omitted article.The inclusion criteria were (1) case-control studies, (2) enough data for computation of pooled odds ratio (OR) with 95% confidence interval (CI), (3) evaluation of association between COX-2 rs689466 polymorphism and CRC risk, and (4) target at humans.http://www.oncolnc.org/) website was used to evaluate prognostic value of the mRNA expression  of COX-2 gene. We analyzed the overall survival (OS) of CRC patients by calculating Log rank p value and hazard ratio (HR) with 95% confidence intervals.OncoLnc  to predict potential associations between the SNPs and gene expression levels.We also performed the expression quantitative trait loci (eQTL) analysis using GTEx portal web site , cancer type, name of first author, publication year, and country of origin. If data were unavailable in an article, we contacted the authors for relevant data. If more than one ethnicity were involved in one article, we collected genotype data separately.The quality of each included study was assessed using the Newcastle-Ottawa Scale (NOS) . Generalp < 0.10 and I2 > 50%. A random-effect model was used in case of significant heterogeneity; otherwise, a fixed-effect model was used [χ2 test. The positive findings were evaluated by calculating false-positive report probability (FPRP). An FPRP threshold of 0.2 and a prior probability of 0.1 were set to detect an OR for a correlation with the tested genotype. FPRP < 0.2 implied a possible relationship. Publication bias was tested by visually inspecting the symmetry of Begg’s funnel plot and assessing Egger’s test [α, the type I error probability for a two-sided test; P0, the probability of exposure in controls; N is the number of case patients; m, the ratio of control to experimental subjects; Ψ, odd ratio of exposure in cases relative to controls. Statistical significance was set at p < 0.05.Statistical analyses were carried out using Stata 11.0 . Stratified analyses of ethnicity, source of control (SOC), Hardy–Weinberg equilibrium (HWE), and genotyping methods were also conducted. Regarding potential heterogeneity among studies, we defined significant heterogeneity at the levels was used . The effr’s test . The PowThe initial search returned 161 articles. Then, 43 duplicated articles were excluded, and 75 articles were omitted after title and abstract examination. Of the remaining 43 articles, full-text review denied 27 articles. Finally, 16 studies with 8998 cases and 11917 controls were included –25. The p = 0.0357, Fig. We evaluated the association between COX-2 gene expression and CRC prognosis using the OncoLnc website. Our data showed that high expression of COX-2 was associated with better OS for all CRC patients , p = 0.627; GG vs. AA 1.10 (0.84–1.44), p = 0.478; GA vs. AA 1.07 (0.95–1.21), p = 0.453; Table p < 0.05, Fig. p = 0.068, Table We also conducted a meta-analysis between an important single nucleotide polymorphism (SNP) of COX-2 gene and CRC risk, and found that the COX-2 rs689466 polymorphism is not associated with CRC risk (G vs. A: OR = 1.06 (95% CI 0.94–1.19), Sensitivity analysis shows no single study largely influenced the pooled data, indicating that our results are statistically robust. Neither Begg’s funnel plot  in this meta-analysis. Although our results suggested that COX-2 rs689466 polymorphism was not associated with a higher CRC risk in the overall population, subgroup analysis of ethnicity showed that COX-2 rs689466 polymorphism was associated with increased CRC risk in Caucasians, but not in Asians, suggesting different racial inheritance for Caucasians and Asians. The ethnic difference may be explained by the different allele frequency of this polymorphism. Asians have higher A allele frequency than Caucasians (European) (0.494 vs. 0.194). Another reason may be the differences among ethnic groups in sample sizes. In this meta-analysis, the sample sizes of Caucasians and Asians were different. Furthermore, varied living environments and diets may be important factors. In addition, clinical heterogeneity may also contribute to contradictory findings. As reported, G allele of rs689466 polymorphism could transcriptionally activate COX-2 . We suppThis meta-analysis has several limitations. Firstly, subgroup analyses of age, sex, smoking, drinking status, or tumor size were not conducted due to data shortage. Secondly, estimates of confounding factors were unadjusted, which might affect the final results. Thirdly, possible gene-gene and gene-environment interactions were ignored because of data insufficiency. Fourthly, only Asians and Caucasians were included, and the findings may be inapplicable to other racial groups. Fifthly, we did not explore the association between rs689466 polymorphism and COX-2 protein. Lastly, only four Asian studies were included in this meta-analysis.In conclusion, this meta-analysis confirms an association between COX-2 gene rs689466 polymorphism and increased CRC risk among Caucasians. Nevertheless, this finding should be validated by further studies in other ethnicities.Additional file 1: Figure S1. The association between rs689466 polymorphism and the expression of COX-2 gene.


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.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.The results of this meta-analysis will be submitted to a peer-reviewed journal for publication.This meta-analysis will summarize the association between CYP2A13 polymorphisms and the risk of lung cancer.INPLASY202090102 This phenomenon indicates that the occurrence of lung cancer is also related to individual susceptibility.In recent years, with changes in the environment, the incidence and mortality of lung cancer have been increasing rapidly.,11 In lung tissue, CYP2A13 is mainly located in bronchial epithelial cells. Studies have shown that smoking is an important risk factor for lung cancer. Cigarette smoke containing a lot of chemicals is inhaled through the respiratory system, CYP2A13 metabolizes the nicotine in cigarette smoke and the pro-carcinogen N-nitroso (4-(methyl-nitrosamine)-1-(3-pyridyl)-1-butanone, NNK), which forms the active metabolites can cause damage to the respiratory system.–18 CYP2A13 can efficiently metabolize and activate aflatoxin B1, generate a variety of metabolites including epoxide, and then combine with DNA, RNA, protein, and other biological macromolecules in the body to form DNA, RNA, and protein adducts to cause cytotoxicity, Inflammation, DNA damage, and other toxic effects, which may cause cell malignant transformation and cause body tumors.–25 At present, there is no consistent conclusion on the genetic polymorphism of CYP2A13 and lung cancer susceptibility. Therefore, in this study, the meta-analysis method was used to systematically evaluate the relationship between CYP2A13 gene polymorphism and lung cancer susceptibility, in order to provide a basis for exploring clinical drug targets and cancer prevention.CYP2A13 is mainly expressed in the respiratory system, with the highest expression in the olfactory mucosa, followed by lungs and trachea.22.1We will search the PubMed, Cochrane Library, Web of Science, CNKI databases, and the time period for the reference searches was from the first available article to September 2020. The following key words were used for the searches: “Cytochrome P450 2A13,” “CYP2A13,” “lung cancer,” “lung carcinoma,” “lung tumor,” “polymorphism,” “polymorphisms,” “variant,” “variants.”2.2(1)Using case-control study method to assess the relationship of CYP2A13 polymorphisms with lung cancer risk.(2)The size of the sample, odds ratios (ORs), and their 95% confidence intervals (CIs) were provided.(3)In the case of multiple publications from the same study group, the most complete and recent results will be used.2.3(1)Multiple publications reporting the same finding.(2)Abstracts, reviews, comments, and animal studies.(3)Lack of sufficient data.2.4Data will be carefully extracted from all selected articles by 2 of the authors, independently. When discrepancies appear, another investigator will be recruited to assess the data. The information extract from the studies included the first author's name, the year of publication, the country of the study, the ethnicity of the subjects, the diagnostic method, the number of cases in the lung cancer group and the control group, and the numbers of each genotype identified.2.5 The evaluation project consisted of 8 parts, and except for the fifth evaluation criterion of 2 points, the scores of the other items are all 1 point. The total scores of the NOS range from 0 points to 9 points. If the total score of the 8 items is ≥7 points, the quality of studies is considered reliable.The quality of the included studies will be independently assessed by the Newcastle-Ottawa Quality Assessment Scale (NOS).2.6 will be applied to estimate the strength of associations between the CBS gene polymorphisms and lung cancer risk. The heterogeneity between the included studies will be judged on the basis of P and I2 values. Values of P > .10 and I2 < 50% indicate that the fixed effect model could be used in this meta-analysis. However, values of P < .10 and I2 > 50% indicate the existence of significant heterogeneity. We will identify the source of heterogeneity and perform further analysis, and the random effects model will be used after excluding the effects of significant clinical heterogeneity.The statistical analysis will be performed by using Review Manager 5.3. Pooled odds ratios and 95% confidence intervals2.7To further study the effect of sample size, diagnosis methods and ethnicity on heterogeneity, subgroup analysis will be performed.2.8The funnel plot and Egger test will be conducted to detect publication bias if the number of studies >10.2.9We will perform a sensitivity analysis to verify the robustness of the study results. This will be achieved by assessing the impact of the sample size, high risk of bias, missing data, and selected models. Following the analyses, if the quality of a study is judged to be low, it will be removed to ensure the robustness of the results.2.10Ethical approvals patient consent are not required because this is a meta-analysis based on published trials. The finding of this project will provide a general review and evidence of the association between CYP2A13 polymorphisms and the risk of lung cancer. The results will be submitted to a peer-reviewed journal for publication. We hope that finding will help clinicians can carry out early screening, early diagnosis, and early treatment of lung cancer patients.3This systematic review will be the first to assess the association between CYP2A13 polymorphisms and the risk of lung cancer. The review contains 5 sections: search strategy, study inclusion and exclusion, data extraction, statistical analysis, subgroup analysis. The results will be submitted to a peer-reviewed journal for publication. We hope that finding will help clinicians can carry out early screening, early diagnosis, and early treatment of lung cancer patients.Conceptualization: Long Ma, Gang Jin, Yi Yang, Zijiang Zhu.Data curation: Long Ma, Gang Jin, Yi Yang, Yao Pang, Wenhao Wang, Hongyi Zhang, Jiawei Liu, Peng Wu, Zequan Wang, Kui Wang, Ruitong Chang, Jialong Li.Formal analysis: Long Ma, Gang Jin, Yi Yang, Yao Pang, Wenhao Wang, Hongyi Zhang, Jiawei Liu, Peng Wu, Zequan Wang, Kui Wang, Ruitong Chang, Jialong Li.Funding acquisition: Long Ma, Gang Jin, Yi Yang, Yao Pang, Wenhao Wang, Zijiang Zhu.Investigation: Long Ma, Gang Jin, Yi Yang, Yao Pang, Wenhao Wang, Hongyi Zhang, Jiawei Liu, Peng Wu, Zequan Wang, Kui Wang, Ruitong Chang, Jialong Li.Methodology: Long Ma, Gang Jin, Yi Yang, Hongyi Zhang, Jiawei Liu, Peng Wu, Zequan Wang, Kui Wang, Ruitong Chang, Jialong Li, Zijiang Zhu.Project administration: Long Ma, Gang Jin, Yi Yang, Yao Pang, Wenhao Wang, Hongyi Zhang, Jiawei Liu, Peng Wu, Zequan Wang, Kui Wang, Ruitong Chang, Jialong Li.Resources: Long Ma, Gang Jin, Yi Yang, Yao Pang, Wenhao Wang, Hongyi Zhang, Jiawei Liu, Peng Wu, Zequan Wang, Kui Wang, Ruitong Chang, Jialong Li.Software: Long Ma, Gang Jin, Yi Yang, Wenhao Wang, Jiawei Liu, Zequan Wang, Zijiang Zhu.Supervision: Long Ma, Gang Jin, Yi Yang, Zijiang Zhu.Validation: Long Ma, Gang Jin, Yi Yang, Yao Pang, Wenhao Wang, Hongyi Zhang, Jiawei Liu, Peng Wu, Zequan Wang, Kui Wang, Ruitong Chang, Jialong Li.Visualization: Long Ma, Gang Jin, Yi Yang, Yao Pang, Wenhao Wang, Hongyi Zhang, Jiawei Liu, Peng Wu, Zequan Wang, Kui Wang, Ruitong Chang, Jialong Li.Writing – original draft: Long Ma, Gang Jin, Yi Yang, Zijiang Zhu.Writing – review & editing: Long Ma, Gang Jin, Yi Yang, Zijiang Zhu.


Periodontitis is a kind of chronic infectious disease, affecting the health of billions of people. In recent years, a number of studies have shown that multiple immune gene polymorphisms are associated with the susceptibility to periodontitis, among which TLR-2 plays a critical role in periodontitis. But most of the studies reported TLR-2 gene polymorphism and susceptibility to periodontitis are not consistent. Therefore, we included all eligible studies in our study for further meta-analysis.  We used electronic databases, including CNKI, PubMed, EMBASE, and Web of Science databases, and relevant research published through June, 2020. Selecting studies involved case-control trials. For all eligibility studies, odds ratios (ORs) and 95% confidence intervals (95% CI) are provided or can be calculated from the study data. The size of the combined effect was calculated using STATA 15.0. p = 0.014, OR = 1.208, 95% CI: 1.039-1.406), recessive model , and codominant model . In subgroup analysis, TLR-2 rs5743708 polymorphism was associated with periodontitis risk in Asians under an allelic model , dominant model , and codominant model .  Our meta-analysis included 14 articles representing 18 case-control studies with a total of 3873 cases and 3438 control subjects. Significant association was found between periodontitis and TLR-2 rs1898830 polymorphism under the allelic model (A allele vs. G allele:  The TLR-2 rs1898830, rs5743708 polymorphism may be associated with susceptibility to periodontitis. In the future, genome-wide approaches and large-scale, multiethnic case-control trials are still needed. Periodontitis is a chronic infectious disease caused by the accumulation of bacteria such as P.g  and A.a (Aggregatibacter actinomycetemcomitans), which leads to the destruction of the surrounding periodontal tissue, including deep pockets, loss of attachment, and loss of the alveolar bone , 2. Moreβ [Toll-like receptors (TLRs) are kinds of pattern recognition receptors (PRRs), which can be specific to identify pathogenic microorganisms that are conservative antigen molecules in evolution, such as lipopolysaccharide (LPS), which are the main components of the outside membrane of gram-negative bacteria, lipoproteins, or other parts of bacterial or fungal cell wall components, causing the host production of inflammatory cytokines and chemokines such as IL-18 and IL-1β . Thus, Pβ . The rolβ . In addiβ . In Scheβ .Interestingly, although numerous studies have demonstrated a link between TLR-2 and periodontitis susceptibility, focusing on certain SNPs like rs5743708 and rs1898830, they showed no positive conclusion from their findings. This could be due to a small sample size and incomplete capture of genetic variation, or previous studies focused only one or several SNPs. Genetic association studies designed to examine the relationship between genetic variation and complex results must be treated with caution, even if the results are negative, as many factors may affect the results . The metThe meta-analysis and systematic review reported here are in accordance with the Preferred Reporting Items for the Systematic Review and Meta-Analyses (PRISMA) statement . The litData were collected from the CNKI , PubMed (PubMed is an interface for the Medline database), Embase, and Web of Science databases up to June, 2020 . The search terms comprised the following 3 items and were combined using the Boolean operator AND: gene name . genetic polymorphisms , and disease  to identify studies describing associations of genetic polymorphisms with periodontitis susceptibility. Relevant publications were also identified via searches supplemented by a literature review. Published articles in Chinese and English were retrieved. Moreover, hand searches for references cited in the published original and review articles were also performed.Two authors identified studies eligible for further review by performing an initial screen of identified titles or abstracts. Articles considered for inclusion in the meta-analysis had to meet the following inclusion criteria: (a) studies used validated genotyping methods (such as PCR-RFLP or TaqMan) to measure the association of SNPs in TLR-2 genes with periodontitis risk; (b) a case-control cohort or nested case-control design; (c) the full text of the studies was available, and the data of the studies were not duplicated in another manuscript; (d) the case group of patients had a clinical diagnosis of periodontitis, including CP patients and aggressive periodontitis (AgP) patients, whereas the control group was the periodontal healthy population; and (e) when multiple document data were identical or overlapping, the most recently published paper was selected. Reviews, editorials, and case reports were excluded. Both reviewers fully agreed on the eligibility of the included articles in this first screening. Then, we performed a second screening based on full-text review. Studies such as cohort studies or nested case-control design analyses are included. According to the objective of this analysis, studies were excluded if they did not provide enough information on genotype frequency or did not report sufficient genotype distribution for the calculation of odds ratios (ORs) and its variance. Besides, studies were also excluded if the genotype distributions of control subjects were varied from Hardy-Weinberg equilibrium (HWE). Moreover, the case groups which suffered not only from periodontitis but also from other diseases were also excluded.http://www.oege.org/software/hwe-mr-calc.shtml). p value less than 0.05 of HWE was considered to be significant. Data extracted was performed independently by two investigators, and discrepancies were reviewed by a third reviewer. The quality of the observational studies was assessed using the Newcastle-Ottawa scale, and they were examined independently by two researchers . Briefly, a quality score (0-9) was generated according to a maximum of 1 star for each item on selection. And the quality of each study was assessed by using the following methodological components: (1) subject selection and (2) comparability of subject.We extracted detailed data on the first author's name, year of publication, region of the study, disease type, genotype, and smoking status. Furthermore, the evidence of HWE in controls was verified through the application of an online software (I2 statistic and the Cochrane Q (χ2) statistic, with a p value of 0.10 set for significance of the test of heterogeneity. I2, directly calculated from the Q statistic, indicates the percentage of variability in effect estimates because of true heterogeneity, rather than sampling error. I2 ranges from 0% to 100%, with 0% indicating the absence of any heterogeneity. Although absolute numbers for I2 are not available, values < 50% are considered to have low heterogeneity, and the effect is thought to be fixed. Conversely, when I2 exceeds 50%, then heterogeneity is thought to exist and the effect is random.Between-study and between-subgroup heterogeneities were evaluated by calculating the I2 > 50% could suggest heterogeneity and suggest the random-effect model (DerSimonian-Laird) for the secondary endpoint. Otherwise, the fixed-effect model (Mantel-Haenszel) for the primary was used to calculate pooled ORs. Two-sided probability values of <0.05 were considered statistically significant. Potential publication bias of studies with different sample sizes was examined by visual inspection of funnel plots. This study is registered with PROSPERO, number CRD42020154093.We performed a detailed meta-analysis to evaluate the association between TLR-2 SNPs and periodontitis susceptibility. We used five models, including the allele model, codominant models, dominant model, and recessive model, and subgroup analyses were performed based on the case type and racial descent. All data were analyzed using Stata version 15.0. Odds ratios (OR) and 95% CIs were calculated as the parameter of efficacy. Our search identified a total of 381 potentially relevant studies . No prevp = 0.014, OR = 1.208, 95% CI: 1.039-1.406), recessive model , and codominant model . In the subgroup analysis, the association was found only in Asian populations under the allelic model  and codominant model  [I2 = 0) for the TLR-2 rs1898830 polymorphism in five gene models, indicating the robustness of the meta-analysis for chronic periodontitis. Although a limited number of studies (n = 2) have been included for the rs1898830 polymorphism, it suggested that rs1898830 (A>G) may be associated with periodontitis risk in Asians  , 25, 29 n Asians .p = 0.269, OR = 0.922, 95% CI: 0.797-1.065). No association was found between the ethnic subgroup analysis and the disease type subgroup analysis. Subgroup analysis by disease type found that the marginal significance was in the codominant model of TC VS. TT ; statistical heterogeneity varied from absent to moderate especially among Asians and AgP subgroup analysis . Moreover, the genotype distributions of all the included studies were in accordance with HWE except for the study of Ding et al.  either in Caucasian or disease study   .p = 0.633, OR = 0.949, 95% CI: 0.765-1.177). Ethnic subgroup analyses showed that rs5743708 was associated with periodontitis risk in Asians under the allelic model , dominant model , and codominant model . Stratification by disease type indicated no association between the TLR-2 rs5743708 polymorphism and periodontitis in CP and AgP. The overall genotyping distribution in all studies was in HWE equilibrium [Thirteen studies with a total of 2361 cases and 2722 controls found no association between rs5743708 and periodontitis risk under the five gene models   .p = 0.038) in Asians. In Fukusaki et al.'s study, they reported three point mutations in the 5′-untranslated region and one synonymous mutation in the coding region of TLR2 that were identified at base-pair positions -183, -148, -146, and +2343 (corresponding to rs5743709), rs1816702, rs11938228, rs3804099 [One SNP, namely, rs12191786, has been reported in two studies, but both of them deviated from the HWE equilibrium; therefore, we excluded the SNPs from our meta-analysis , 30 was at a decreased risk of chronic periodontitis in Asians under the allelic model (A VS. G) and codominant model (GG VS. AA). Four papers studying rs1898830 showed that the polymorphism of this gene was not significantly correlated with the periodontitis susceptibility , 25, 29,There are more than 20 single nucleotide polymorphism (SNP) sites for the TLR2 gene included in the Hapmap database. Exon 3 is the largest exon in TLR2 and contains several synonymous and nonsynonymous SNPS, as shown in the NCBI (NCBI build GRCh37).We identified four known SNPs: two common variants ) and two rare variants , a missense mutation in the third exon of the TLR2 gene, which has been the most internationally reported to be associated with periodontitis. In total, ten publications have examined the role of TLR-2 rs5743708 genetic variation in periodontitis, suggesting that rs5743708 may not be related to the periodontal disease, which is consistent in previous papers , 35. WhiNo significant association was observed for other sites mentioned in the papers between genetic TLR-2 polymorphisms of rs13150331 (A>G), rs12191786 (C>T), rs1816702 (C>T), rs11938228 (C>A), rs3804099 (T>C), rs7656411 (T>G), and base-pair positions -183 (A>G), -148 (C>T), -146 (T>G), and +2343 (G>A) (corresponding to rs5743709), except for one study, which reported decreased risk of rs7696323 polymorphism (C>T) in aggressive periodontitis in Asians . As for In recent years, increasingly more studies on TLR single nucleotide polymorphisms (SNPs) have been reported. The main consideration factor is that TLR SNPs may reduce the response efficiency of TLR ligands, thus affecting the susceptibility to infectious diseases , 37. AggSo far, a number of studies have evaluated the association between PRRs, SNPs, and periodontitis, including CD14, TLR2, TLR4, and MBL2. However, most of the studies on gene polymorphism of TLR-2 have considered that there is no obvious correlation between TLR-2 polymorphism and periodontitis. Therefore, the meta-analysis on the relationship between TLR-2 gene polymorphism and periodontitis susceptibility has not been reported alone, while the meta-analysis on TLR-4 and CD14 has been published; the conclusions are still inconsistent , 39, 40.Our study has some limitations. First, the included studies varied in several ways, including age, gender, and smoking status. Only six articles cited smoking habits as a confounding factor. And we did not provide subgroup analysis for smoke status. Periodontitis is a multifactorial disease, and due to the lack of appropriate proportions of eligible studies, it is not possible to make detailed assessments of potential interactions, as gene-gene, gene-environment, or even different polymorphism loci of the same gene may regulate the risk of periodontitis. Second, due to the extremely low allele frequency of some SNPs such as rs5743704 (C>A), rs5743708 (G>A), and rs12191786(C>T), there is often no homozygous mutation or even no heterozygosity. For these SNPs, the calculation of some gene models (dominant model and a recessive model) cannot be carried out, which probably will affect our analysis results. In our meta-analysis, many individual studies seem to be underpowered. A sample size of 500-2000 case-control pairs is required to detect moderate genetic effect size . And a lIn summary, this meta-analysis of published data shows that a protect correlation between the rs1898830 (A>G) and rs5743708 (G>A) was associated with periodontitis risk in Asians. Limited by the number of included samples and SNP sites in the current association study, the above conclusions need to be further confirmed by the large sample, multiethnics, and multi-SNP-sites studies in future. We consider that the genetic information of TLR2 site has a certain reference value for the diagnosis, prevention, and treatment of chronic periodontitis. If this genetic information is available, it may provide preventive strategies and therapeutic interventions for patients with high susceptibility.


Background: The association between Aldehyde dehydrogenase II (ALDH-2) rs671 polymorphism and essential hypertension (EH) risk or blood pressure (BP) levels remains unclear.Objective: To systematically review the influence of the aldehyde dehydrogenase II rs671 polymorphism on essential hypertension risk and blood pressure levels.Methods: The PubMed, EMbase, Web of Science, Cochrane Library, CNKI and CBM databases were electronically searched to identify case-control or cohort studies published prior to July 2019 that examined the association between the rs671 polymorphism and the risk of essential hypertension or blood pressure levels. A meta-analysis was conducted with Stata 15.1 software.Results: Twenty-two articles were included. Among these articles, 20 incorporated 30 individual studies evaluating the association between the rs671 polymorphism and EH , and 8 incorporated 12 individual studies evaluating the association between the rs671 polymorphism and BP . The results of the meta-analysis showed that the mutation of the rs671 polymorphism was associated with a significantly decreased risk of EH in all models: allelic model , homozygous model , heterozygous model , dominant model , and recessive model . In the stratified analyses, significant associations were found for males, drinkers and population-based studies. Simultaneously, the A carriers had lower SBP  and DBP  levels than individuals with the GG homozygote.Conclusion: The collective findings of this meta-analysis suggested that the ALDH-2 rs671 polymorphism represented an important genetic marker in the development of hypertension. Considering the overall quality of evidence and the relatively small pooled sample size, more well-conducted high-quality studies are required to verify the above conclusion.Systematic Review Registration Number: PROSPERO (CRD42019129746). Elevated blood pressure is the leading cause of death worldwide, and the burden of hypertension is expected to increase globally. In 2012, hypertension affected 270 million individuals in China and had a prevalence of 25.2% , the Cochrane Library, Chinese Biomedical Literature Database (CBM) and China National Knowledge Infrastructure (CNKI), for studies published prior to July 2019. The keywords included “hypertension,” “essential hypertension,” “EH,” “blood pressure,” “aldehyde dehydrogenase 2,” “ALDH 2,” “ALDH-2,” “rs671,” “genotype,” “alleles,” “polymorphism,” “mutation,” and “variation.” We used both MeSH terms and Title/Abstract search. Languages were not restricted during the searching process. Published articles listed in the references of the keyword index results were also screened carefully to avoid possible omissions.Studies were included if they fulfilled all of the following criteria: (i) case-control design or cohort study design; (ii) studies that examined the association between the ALDH-2 rs671 polymorphism and the risk of essential hypertension or blood pressure levels; (iii) diagnosis of hypertension defined as either systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg , or taking antihypertensive medication. The exclusive criteria were as follows: (i) repeated publication of literature or reported duplicate data; (ii) research that is not available in full text; and (iii) reports with incomplete data or no usable data.A data-extraction table was designed in Excel 2016 by all the researchers. The following information was included: name of the first author, year of publication, ethnicity of study population, study design, source of population, genotyping methodology, sample size, average age, gender, alcohol consumption, SBP and DBP. Two researchers independently extracted the necessary data, and all disagreements were resolved through discussion with a third researcher.Two researchers evaluated the quality of each included study using the Newcastle-Ottawa Scale (NOS) Stang,  independ2 test was used to assess whether the genotype distributions in the control group of each study were in Hardy-Weinberg Equilibrium (HWE). Heterogeneity among the same category was evaluated using the χ2 test and Cochran's Q statistic, and the I2 statistic was used to quantify the percentage variability of the heterogeneity . The detailed results of the WMDs and 95% CIs for different comparisons are shown in An integral analysis of 12 individual studies (Takagi et al., The sensitivity analysis was performed by sequentially dropping one inter-study at a time to detect the influence of each inter-study on the summary OR and WMD. The outcomes of our meta-analysis were not altered greatly when each individual study was omitted, suggesting that the overall results were stable and robust.p-values more than 0.05 was considered to have no evidence of publication bias (Publication bias of the included studies was assessed using Begg's test, Egger's test and the trim-and-fill method. First, we applied Begg's test and Egger's test to evaluate publication bias. All ion bias . The resion bias –15, whicPrevious studies exploring the association between the ALDH-2 rs671 polymorphism and hypertension risk and blood pressure levels have provided controversial results, and the sample sizes in most of these studies were relatively small; thus, it was difficult to obtain credible genetic effects. Meta-analyses have been considered as one of the most important tools to precisely define the association between selected genetic polymorphisms and the risk for a morbid state. Based on this situation, we performed this study.Our meta-analysis indicated that the ALDH-2 rs671 polymorphism is not only a major protective factor against the development of hypertension, particularly in males and drinkers, but it is also a critical factor in decreasing blood pressure. Based on the following aspects, we believe that our findings are more comprehensive and convincing. First, our meta-analysis incorporated more eligible studies, thus providing sufficient statistical power. Second, the association between the rs671 polymorphism and essential hypertension was investigated extensively with five genetic models. Third, we performed a series of more comprehensive subgroup analyses by factors addressed across different studies, which may influence the reliability. Fourth, the sensitivity analysis indicated that the results are stable and reliable. Finally, little evidence of publication bias was found in the overall analysis.For essential hypertension association studies, a statistically significant association between the rs671 polymorphism and EH risk was observed under all models. Li et al. did a case-control study and meta-analysis, and shown that ALDH2 rs671 polymorphism may not associate with EH (Li et al., For blood pressure association studies, a significant variation in blood pressure between A carriers and GG homozygote carriers was observed. This result was consistent with the results of the association between the rs671 polymorphism and EH risk. In the stratification analysis by gender, signification associations were found in the male subgroup for SBP and DBP levels, although no significant associations were found in females. In the stratification analysis by alcohol consumption, signification associations were found in both drinkers and non-drinkers' DBP levels, although no significant associations were found in SBP levels. Notably, there were relatively few studies based on gender differences and alcohol consumption differences; thus, it was difficult to obtain credible genetic effects.However, there were several limitations in our study. First, only articles published in English and Chinese were incorporated, which led to a potential selection bias. Second, because of the lack of uniform background data for studies in meta-analyses, the data were not further stratified by other factors that may affect blood pressure such as salt consumption and smoking. Third, The ALDH2 polymorphism is observed to be associated with increased risk for diseases such as coronary artery disease and diabetics. However, due to the limitation of included articles, further stratification of the subjects according to these accompanied diseases could not be implemented in this study. Forth, As medications could affect the BP levels. However, due to the limitation of included articles, we were unable to analyze the use of drugs. Fifth, significant heterogeneity was detected even we performed subgroup analyses. Finally, the meta-analysis was limited by the inadequate sample size, particularly in the alcohol consumption subgroup analysis.The collective findings of this meta-analysis demonstrated that the mutation of the ALDH-2 rs671 polymorphism was significantly associated not only with a decreased predisposition toward essential hypertension but also with lowering blood pressure, suggesting that the ALDH-2 rs671 polymorphism might represent an important genetic marker of hypertension. These findings potentially further our understanding of the contributing role of the ALDH-2 rs671 polymorphism in blood pressure regulation and in the pathogenesis of hypertension.All datasets generated for this study are included in the article/supplementary material.YZhe, CN, and ZF conceived and designed the experiments. YZhe, XZ, and YL performed the experiments. YZhe, XZ, and LQ analyzed the data. YZhe and YZha contributed materials and analytical tools. YZhe, XZ, and CN wrote the manuscript. YZhe, JL, and ZF revised the manuscript. All authors reviewed and approved the manuscript prior to submission.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


UGT1A1 plays a central role in the IRI metabolic pathway. A polymorphism UGT1A1*6 has been widely researched which may be related to response of IRI-based chemotherapy in CRC. All relevant studies were strictly searched from PubMed, Embase, Cochrane Library and Web of Science databases to explore the associations between UGT1A1*6 and response of IRI-based chemotherapy with CRC. Nine articles comprising 1652 patients were included in the final combination. Meta-analysis showed G allele or GG had a lower risk of severe late-onset diarrhea compared with A/AA in allele model and homozygote model , no significant association was observed in other models. In addition, a significant association between UGT1A1*6 and neutropenia was observed in all models , whereas, no relationship was found between UGT1A1*6 and clinical response among the different genotypes. UGT1A1*6 may be considered as a biomarker for IRI-based chemotherapy in CRC.Colorectal cancer (CRC) is a leading cause of cancer-related deaths across the world. Irinotecan (IRI) is commonly used to treat CRC, and IRI-based chemotherapy is linked with adverse reaction and the efficacy of the treatment regimen. The gene  Colorectal cancer (CRC) is the third most common cancer and the most common cause of deaths all over the world . Althoug71Arg) of the UGT1A1 gene (https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=4148323). Extensive studies have researched the response of IRI in CRC patients exposing different genotypes of UGT1A1*6 [A large number of studies found UDP-glucuronosyltransferase (UGT) enzymes involved in the metabolism of IRI, which take part in glucuronidation and transform the active metabolite IRI (SN38) into SN38 glucuronide (SN38G) . UGT enzUGT1A1*6 , but theUGT1A1*6 , and expEligible studies were obtained from PubMed, Embase, Cochrane Library (Cochrane Center Register of Controlled Trails) and Web of Science databases with the date up to 10 February 2020. The MeSH terms and full-text terms used are as follows: ‘irinotecan’, ‘UGT1A1’, ‘polymorphism’, ‘UGT1A1*6’, ‘rs4148323’, ‘Colorectal Neoplasms’, ‘chemotherapy.’ Furthermore, we perused relevant references to select additional relevant studies.All eligible studies were selected with the following inclusion criteria: (1) clinical trials and observational studies; (2) studies exploring the association between UGT1A1*6 polymorphism and response of IRI-based chemotherapy with CRC; (3) CRC diagnosis based on pathological examination or confirmed by proctoscope; (4) data were sufficient for tumor response (TR) (including complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD)), which used the WHO criteria  ; (5) theFollowing studies were excluded: (1) reviews, meta-analyses, case reports, letters, comments or duplicated data; (2) animal experiments; (3) studies with undefined genotypes; (4) studies with no effective data; (4) no criteria of diagnosis were described.Two reviewers (X.y.Z. and R.c.M.) independently extracted data using standardized criteria. If they could not form a settled consensus, all the authors must discuss the studies and reach a consensus. Information was carefully extracted as follows in each article: first author’s name, publication year, country, population ethnicity, gender, age, total number of patients, detection genotype methods of UGT1A1*6 polymorphism, the regimen of chemotherapy, IRI dose, response criteria, toxicity criteria and key elements of risk assessment of bias etc.The quality of included articles were assessed according to recommendation of Newcastle–Ottawa scale (NOS) . Eight i2I statistics were employed to evaluate the heterogeneity assumption. If significant heterogeneity existed , the random-effects model will be used to pool ORs. Otherwise, fixed-effects model will be chosen [The OR and 95% CI were used to assess UGT1A1*6 polymorphism and response of IRI-based chemotherapy with CRC in Asians. Cochran’s Q test and e chosen . We evalP<0.05 was considered as significant.Begg’s regression test and funnel plot used to calculate potential publication bias were tested. Sensitivity analysis was also performed to evaluate the stability of the meta-analysis when the significant heterogeneity existed. All the analyses were performed using the STATA 12.0 software. All statistics were two-tailed and As shown in Many previous researches analyzed the association between UGT1A1*6 polymorphism and IRI-based chemotherapy TR in different genotypes. According to RECIST medical efficacy appraisal standard, the response rate  and disease control rate  were used as end points to evaluate IRI-based chemotherapy TR.P=0.29); (2) homozygote model: ; (3) heterozygote model: ; (4) dominant model: ; (5) recessive model: . There was no significant heterogeneity among these models, 2I values were 38.1% (P=0.17), 2.8% (P=0.39), 0 (P=0.67), 0 (P=0.48), 0 (P=0.78) for allele model, homozygote model, heterozygote model, dominant model and recessive model, respectively. We also performed subgroup analysis by countries, and no associations were observed in different country ; (2) homozygote model: ; (3) heterozygote model: ; (4) dominant model: ; (5) recessive model: . Full details are shown in In addition, the DCR was used to evaluate the TR. We analyzed in five models and found no relationship with UGT1A1*6 polymorphism and IRI-based chemotherapy DCR : (1) allP=0.05); (2) homozygote model: ; (3) heterozygote model: ; (4) dominant model: ; (5) recessive model: . We found the heterogeneity in allele model and recessive model, 2I values were 73.9% (P=0.00), 70.5% (P=0.01) for allele model and recessive model respectively, the sensitive analysis was performed (P=0.00); (2) recessive model . Full details are shown in Five studies described the association between UGT1A1*6 polymorphism and severe late-onset diarrhea, respectively, and one study researched two different nations including Han and Xinjiang Uygur nationalities , therefoerformed ; we founerformed : (1) allP=0.00). Other gene models, the fixed-effects model was used to evaluate. Our results showed that UGT1A1*6 polymorphism was associated with IRI-induced severe neutropenia (P=0.00); (2) homozygote model: ; (3) heterozygote model: ; (4) dominant model: . We further performed sensitive analysis in recessive model (P=0.00) than previous result. Full details are shown in Seven studies described the association between UGT1A1*6 polymorphism and severe neutropenia, respectively, and one study researched two different nations including Han and Xinjiang Uygur nationalities , thus eitropenia : (1) allve model , and we ve model  (GG vs. P=0.00);  heterozyP=0.00); (2) homozygote model: ; (3) heterozygote model: ; (4) dominant model: ; (5) recessive model . In recessive model, we also found the significant heterogeneity, so we further performed sensitivity analysis. We found one study had obvious heterogeneity [P=0.00). Full details are shown in Moreover, we then performed the subgroup analyses by different countries. Whereas we only analyzed five models in China, the other countries cannot be analyzed for few studies. There was a statistically increased severe neutropenia in the comparison of five models in China. In different models present different results, we found the significant association in all genetic models between UGT1A1*6 polymorphism and IRI-induced neutropenia in China: (1) allele model: ;  heterozyWe performed the funnel plot and Begg’s test to assess the publication bias in all included literatures. Publication bias was not found among the studies by funnel plot. Begg’s regression test suggested that there were no obvious statistical publication bias. Details are shown in UGT1A1 gene, previous meta-analysis evaluated the impact of UGT1A1*28 polymorphisms with IRI-induced toxicity, and demonstrated UGT1A1*28 polymorphisms may be considered as a marker of IRI-induced toxicity in chemotherapy of cancer [UGT1A1 gene, the UGT1A1*6 (rs4148323) polymorphism is a missense polymorphism, which effects the translation of UGT1A1 protein (Gly71Arg) [Recent advances in chemotherapy for CRC, IRI-based chemotherapy treatment as an effective way for CRC patients and was considered to be the first-line treatment option. However, the obvious concern is efficacy and toxic side effects, especially the serious toxicity restricted its application, such as severe neutropenia and diarrhea. A large of studies found that variations of genes linked with efficacy and toxicity of IRI-based chemotherapy for CRC. UGT1A1 linked with activity of glucuronidation, and involves in the metabolism of IRI. Studies have indicated an association between UDP-glucuronosyltransferase-1A1 (UGT1A1) genetic polymorphisms and IRI-induced toxicity. UGT1A1 gene concludes many SNPs ,26, and f cancer . The othly71Arg) , the subly71Arg) . A largely71Arg) ,13,17. Xly71Arg)  studied Most studies reported that no association between UGT1A1*6 polymorphism and clinical response among the different genotypes. In this meta-analysis, no relationship was found between UGT1A1*6 polymorphism and clinical response, same results were analyzed in subgroup analysis. Our results are similar to previous studies.In the present study, we found that UGT1A1*6 polymorphism is a risk variant for severe drug toxicities in IRI-based chemotherapy with CRC patients. Our finding demonstrated that patients carrying base mutation increasingly likely to encounter severe neutropenia (grade III–IV) in all models. In subgroup analysis, UGT1A1*6 polymorphism still increases the risk of severe neutropenia. Similarly, UGT1A1*6 polymorphism increase risk of severe diarrhea (grade III–IV) in allele comparison and homozygote comparison, the results of subgroup analysis is same to overall analysis.Compared with previous meta-analysis, our study was the first report to estimate the relation between UGT1A1*6 polymorphism and clinical response and toxicity in CRC. The present study analyzed the association between UGT1A1*6 polymorphism and IRI-based chemotherapy TR and toxicity, and found the genotyping of UGT1A1*6 polymorphism may be useful for clinical application. Although we attempt to explore their clinical relevance, several limitations still exist in our research. First, many difference among primary studies, including chemotherapy regimens, research method and doses. Especially, different chemotherapy regimens were used in individual treatment, such as IRI + infusional 5FU+ LV (FOLFIRI), IRI and cisplatin, which would influence the efficacy and adverse reaction. Second, the variability in IRI doses maybe a source of heterogeneity, but no effective data were used to subgroup analyses by IRI doses. Third, the toxicity clinical responses were related to gender, as a study reported the incidence of serve neutropenia was higher in female than male, but no effective data were collected for analysis by gender. In addition, part of studies only included wild genotype and variant genotype, and other models were not analyzed except recessive model. Moreover, the interference of other factors, such as environmental and other genetic factors, as ABCB1 C3435T polymorphism. Finally, the sample size was limited. Thereby, more studies with a larger sample sizes and high quality clinical studies need to research, and enhance the reliability and stability of the meta-analysis.In conclusion, this meta-analysis suggested that the UGT1A1*6 polymorphism linked with IRI-induced adverse reaction with CRC, especially increase the incidence of serve late-onset diarrhea and neutropenia. No relationship was found between UGT1A1*6 polymorphism and clinical response.