The existence of amino acid metabolic reprogramming in tumor cells is well established. However, the potential correlation between blood amino acids and the risk of colon adenocarcinoma remains largely unexplored.We utilized Mendelian randomization (MR) analysis to examine the association between 20 amino acids in the blood and the risk of colon adenocarcinoma. Additionally, reverse MR analysis was employed to identify the presence of reverse causality. A two-step MR analysis was conducted to ascertain the potential mediating effect. Lastly, the alanine detection data from colon adenocarcinoma patients in our hospital were utilized to investigate the differences in alanine levels among healthy individuals and patients with colon cancer, as well as among patients with different stages and locations of colon cancer. Furthermore, a Kaplan–Meier curve was employed to examine the correlation between alanine and overall survival, followed by the implementation of COX univariate analysis.The results of our study indicate that there is an inverse correlation between alanine and the risk of colon adenocarcinoma. Additionally, we found no significant evidence to support a causal relationship between colon adenocarcinoma and alanine. Furthermore, our analysis revealed that alanine aminotransferase (ALT) and blood glucose do not act as mediators in this causal pathway. Moreover, individuals diagnosed with colon adenocarcinoma exhibited a significant decrease in alanine levels, particularly in cases of stage IV colon adenocarcinoma with distant metastasis. Additionally, elevated alanine levels were associated with improved overall survival rates among colon adenocarcinoma patients.The results of this study indicate that alanine exhibits protective characteristics against the onset of colon adenocarcinoma and may play a role in promoting a more favorable disease prognosis. Consequently, dietary interventions aimed at increasing alanine intake may serve as a potential strategy for the prevention and treatment of colon adenocarcinoma.The online version contains supplementary material available at 10.1186/s12885-023-11514-w. Colon cancer is a malignancy with a high incidence rate that poses a significant threat to human health . It is iPrevious research has demonstrated that the amino acid composition in the blood of individuals with gastric , 7 and bThe genetic epidemiological approach known as Mendelian randomization (MR) employs single nucleotide polymorphisms (SNPs) that exhibit strong associations with the exposure as instrumental variables (IVs) to estimate the potential causal relationship between the exposure and the outcome . Since gColon cancer encompasses a diverse range of pathological subtypes, including adenocarcinoma, mucinous adenocarcinoma, signet ring cell carcinoma, squamous cell carcinoma, adenosquamous carcinoma, and medullary carcinoma, among others. Adenocarcinoma represents the predominant pathological subtype . The preInitially, we employed a two sample Mendelian randomization approach to investigate the correlation between 20 amino acids and the risk of colon adenocarcinoma. Our findings revealed that alanine exhibited a significant association with the risk of colon adenocarcinoma. Subsequently, we conducted a reanalysis of the relationship between alanine and the risk of colon adenocarcinoma by utilizing three sets of alanine data while imposing the condition of linkage disequilibrium (LD). In order to examine the potential for reverse causality and mediating effects, we conducted a reverse analysis of the impact of colonic adenocarcinoma on alanine. Additionally, we investigated the possibility of ALT and gluconic serving as mediating factors in influencing the outcome. Finally, we utilized hospital data to observe the levels of alanine in the blood of patients diagnosed with colon adenocarcinoma and to explore the correlation between alanine levels and the stage and prognosis of the disease. A schematic of the study design is shown in Fig. https://gwas.mrcieu.ac.uk/), which were limited to the European population. Blood amino acid data, along with relevant clinical pathological and prognostic information, were collected from 83 healthy individuals and 236 patients with colon adenocarcinoma at the First Affiliated Hospital of Jinzhou Medical University. After a minimum of 12 h of fasting, blood samples were collected from all participants. Our previously published article provides a comprehensive method for detecting amino acids [The genome-wide association study (GWAS) datasets for 20 amino acids, colon adenocarcinoma, Alanine aminotransferase, and Fasting blood glucose were obtained from the IEU GWAS database  and demonstrated no linkage disequilibrium (LD) with other SNPs  were employed as instruments for these blood amino acid. However, due to insufficient SNP availability for certain amino acids under the aforementioned conditions, the p value for arginine, proline, glutamic acid, and lysine was adjusted to 5e-7, while the p value for cysteine, threonine, and aspartic acid was set to 5e-6.Upon conducting a screening, it was discovered that alanine exhibited an association with the risk of colon adenocarcinoma. To ensure accuracy, we utilized three sets of alanine exposure data from the IEU GWAS database and identified SNPs that demonstrated a significant association with blood alanine at the genome-wide level  and were not in linkage disequilibrium (LD) with other SNPs  as instrumental variables for alanine. Due to a limited number of SNPs available for instrumental variable analysis in met-a-469, the p-value was adjusted to 5e-7.Furthermore, a reverse Mendelian randomization analysis was conducted utilizing colon adenocarcinoma as the exposure and alanine as the outcome. SNPs as an instrumental variable associated with colon adenocarcinoma were established at the genome-wide significance level  and were required to exhibit no linkage disequilibrium (LD) with other SNPs .The Inverse Variance Weighted (IVW) method was utilized as the primary approach for our MR analysis to investigate the causal impact of 20 blood amino acid levels on the risk of colon adenocarcinoma. Additionally, we employed other methods such as Weighted Median and Weighted Mode. Subsequently, a series of sensitivity analyses were conducted, including Heterogeneity (Cochran's Q statistics), Horizontal Pleiotropy , and Leave-One-Out analysis. We also performed an MR-PRESSO analysis and utilized the MR-PRESSO outlier test method to remove outlier SNPs.The present study conducted MR analysis, difference analysis of alanine level in blood among normal individuals and those diagnosed with colon adenocarcinoma, difference analysis of alanine level across various stages, Kaplan–Meier method was used to draw the survival curve, and the Log-rank test was used for comparison, with P < 0.05 as statistically significant. and univariate Cox analysis to examine the relationship between age, gender, stage, differentiation, and prognosis. All of the aforementioned analyses were deemed statistically significant at a p value of less than 0.05. Kaplan–Meier method was used to draw the survival curve, and the Log-rank test was used for comparison, with P < 0.05 as statistically significant.Utilizing the IVW method, an MR analysis was conducted to investigate the correlation between 20 blood amino acids and the risk of colon adenocarcinoma. The results revealed a causal association between alanine and colonic adenocarcinoma, with a significance level of p < 0.05. Conversely, no significant relationship was observed between other amino acids and the risk of colon adenocarcinoma, with a p value exceeding 0.05. The detailed results are in Table To ascertain the precise association between alanine and the risk of colon adenocarcinoma, we employed three MR techniques to scrutinize the correlation between three distinct alanine exposure datasets and the risk of colon adenocarcinoma. Our analysis of alanine with an ID of met-d-Ala and the risk of colon adenocarcinoma revealed that the IVW method yielded a p value of less than 0.05, the Weighted median method yielded a p value close to 0.05, and the OR value was less than 1 Fig. A. FurtheTo investigate the potential reverse causal association between alanine and colon adenocarcinoma, a Mendelian randomization (MR) analysis was conducted with colon adenocarcinoma as the exposure variable and alanine as the outcome variable. The results of the analysis revealed a nonsignificant relationship between the two variables, with a p value greater than 0.05 Fig. A. There No significant causal relationship was observed between alanine and ALT, Fasting blood glucose (FBG), as well as between ALT, Fasting blood glucose, and colon adenocarcinoma, as indicated by P values greater than 0.05 Table .Table 3TThrough our data analysis, it was determined that the blood alanine levels of individuals diagnosed with colon adenocarcinoma were significantly lower in comparison to those of healthy individuals Fig. A. This dAmino acids serve as substrates for protein synthesis and are integral to the proliferation and progression of tumors. Moreover, amino acids comprise a vast and intricate metabolic network that is closely interconnected with other metabolic pathways . It is nMendelian randomization is a new epidemiological analysis method, which can reduce the bias of conventional epidemiological analysis methods and the influence of confounding factors . Given tSubsequently, in order to accurately determine the relationship between alanine and the risk of colon adenocarcinoma, we conducted an analysis of the relationship between alanine and colon adenocarcinoma risk across three alanine groups. The resulting p values of IVW were all less than 0.05. Sensitivity analysis revealed that the MR-Egger Intercept p value and the Cochran Q test P value were both greater than 0.05. Leave-one-out analysis also found that the results were not affected by a single SNP. All of these suggest that alanine is negatively associated with the risk of colon adenocarcinoma and that the results are reliable.Our previous study also found that the content of alanine in the blood of colon cancer patients was significantly lower than that of colon polyps, and the difference was statistically significant . FurtherAlanine is a crucial nonessential amino acid that serves a significant function in the maintenance of blood glucose stability , cellulaConsequently, we conducted an analysis to determine if glucose and ALT acted as mediating factors in the progression of colon adenocarcinoma via alanine. The findings indicated that the impact of alanine on glucose and ALT did not demonstrate statistical significance.So, alanine may serve as a protective factor against colon adenocarcinoma by inhibiting its occurrence. Our research findings indicate a significant decrease in blood alanine levels among colon adenocarcinoma patients compared to healthy individuals. Additionally, studies have demonstrated that the reduction of alanine can intensify the nonadherent growth of colon cancer HCT116 cells, which is a characteristic feature of aggressive tumors . FurtherSimultaneously, our investigation revealed a notable decrease in alanine levels among patients diagnosed with stage IV colon adenocarcinoma with metastasis in comparison to those without metastasis. Our prognostic assessment demonstrated that patients exhibiting elevated alanine levels exhibited a more favorable prognosis, indicating that alanine elevation serves as a promising prognostic indicator for colon adenocarcinoma. The underlying mechanism may be attributed to its impact on invasion and metastasis.It is widely acknowledged that tumors exhibit aberrant amino acid metabolism, resulting in abnormal amino acid metabolites in the bloodstream of cancer patients. However, the specific amino acids in plasma that serve as risk or protective factors for cancer have yet to be definitively identified. The findings of this study demonstrate an inverse relationship between alanine and the risk of colon adenocarcinoma, as well as a correlation between alanine levels and the prognosis of this malignancy, indicating that alanine may serve as a protective factor against colon adenocarcinoma. The discovery holds immense potential significance as elevating alanine levels may be a viable strategy for the prevention and treatment of colon cancer in the future.Additional file 1. The following supporting information can be downloaded at: www.mdpi.com/xxx/s1, supporting materials met-d-Ala; supporting materials met-a-469; supporting materials met-c-840; supporting materials reverse MR. Patient clinical pathological information, alanine data, and survival information can be downloaded from supplementary materials


All subgroups also maintained significant differences stratified by continents , analysis technique , and sample source . Conclusion: Cord blood leptin levels were significantly higher in GDM compared to controls. Further research is needed to clarify its role as a predictive biomarker of subsequent metabolic diseases in mothers with GDM and offspring.Background: The literature provides limited evidence of cord blood leptin levels in gestational diabetes mellitus (GDM), with contradictory and inconsistent results with respect to their possible implications for maternal, perinatal, and future complications. Methods: MEDLINE/PubMed, Embase, Scopus, and Web of Science databases were searched in order to investigate the state of evidence on the association of leptin profile in cord blood during perinatal complications in GDM. We critically assessed the risk of bias using the Newcastle-Ottawa scale. Meta-analyses were performed, and heterogeneity and publication bias were analyzed. Results: sixteen primary-level studies were included, recruiting 573 GDM and 1118 control pregnant women. Cord blood leptin levels were significantly higher in GDM participants compared to controls  = 0.37 to 0.80,  It is known that many biological parameters are modified by gestational diabetes mellitus (GDM) and could potentially be used as predictors. About 1–14% of all pregnancies are complicated with GDM, which, classically, is defined as an intolerance to carbohydrates that begins, or is first recognized, during pregnancy and resolves after delivery . GDM is Fetal growth is the result of complex interactions between the placental, fetal, and maternal environments, and is controlled by genetic, hormonal, and nutritional factors. Nevertheless, the hormonal mechanisms involved in fetal growth are not fully understood. Both GDM as well as obesity/overweight during pregnancy are risk factors for hormonal neonatal and harmful anthropometric outcomes ,7. PreviWhile the role of maternal leptin profile in the development of GDM and its maternal-fetal complications has been extensively evaluated by primary studies and higher-level of evidence-based research, such as a recent meta-analysis published by our group , currentThis systematic review and meta-analysis strictly complied with the pertinent PRISMA reporting checklist and with the MOOSE statement, specifically designed for meta-analyses of observational studies ,18, and www.crd.york.ac.uk/PROSPERO (accessed and registered on 26 July 2020), CRD42020194274 code) [A methodological study protocol was a priori designed with the aim of potentially reducing the risk of bias, improving transparency, precision, and, in summary, the integrity of the present study. It was also registered in the PROSPERO international prospective register of systematic reviews (74 code) .MEDLINE (through PubMed), Embase, Web of Science, and Scopus databases were searched for studies published before March 2022 (upper limit), with no lower date limits. The search strategy was driven by combining pertinent thesaurus terms  with free terms, and built to maximize sensitivity. The following syntax was implemented in MEDLINE and adapted for the rest of databases : (“DiabeInclusion criteria: (1) Primary-level studies without publication date or language restrictions, or without follow-up, geographical areas, or patients’ age limits; (2) GDM patients were compared to controls (non-GDM pregnant women); (3) Cord plasma or serum leptin profile levels assessment; (4) Observational studies, regardless of their prospective/retrospective nature or their cross-sectional/longitudinal design.in vitro); (3) Studies that do not investigate the disease of interest , do not study cord leptin profile, or without a control group; (4) Insufficient essential data to analyze means ± standard deviations (SD); (5) Data from overlapping populations.Exclusion criteria: (1) Withdrawal papers, interventional studies, meta-analyses, reviews, letters, editorials, meeting abstracts, personal comments, book chapters, and case reports; (2) Preclinical studies . Discrepancies among both researchers were resolved by consensus with a third author (P.R.-G.). Articles were selected in two stages: first, piloting the titles with abstracts of the retrieved registers; and second, full-text reading the potential sample, excluding those that did not really meet the review eligibility criteria.Two authors (M.d.M.R.-R. and C.L.-T.) separately extracted the datasets of interest from the chosen articles by using Excel software . Data were gathered on the study authors, year of publication, geographical area, publication language, sample size, study design, source of sample (serum/plasma), cord leptin profile determination  in GDM and controls, diagnostic criteria for GDM, criteria for control sampling, personal and family risk of diabetes, gestational age, control of risk factors during pregnancy , glycosylated hemoglobin (A1cHb), fetal and maternal outcomes, follow-up period, and assessment of patient drop-out rate.The Newcastle-Ottawa quality assessment scale (NOS) was used in order to assess the risk of bias (RoB) . RoB crip < 0.05). Statistical heterogeneity was assessed using the Cochran’s Q test  and quantified through the I2 statistic , which estimates what proportion of the variance in observed effects reflects variation in true effects rather than sampling error [p < 0.10 considered significant) and funnel plot construction [Mean ± SD cord blood leptin profile levels were managed from the study sample in order to contrast the GDM group vs. controls. Standardized mean differences (SMDs)—estimated by Cohen’s d method—with 95% confidence intervals (CI) were computed and adopted as effect size metrics based on the expected methodological heterogeneity, mainly due to variations in leptin determination methods and heterogeneous laboratory protocols. If only medians with an interquartile range and/or maximum-minimum ranges were available, means ± SDs were estimated following Luo et al.  and Wan ng error . Preplanng error . Weightetruction ,29. Stattruction .The flow diagram in n = 16 primary-level studies) are summarized in The characteristics of our study sample , moderate (37.5%), and high (25%) overall RoB. The most frequent potential biases were an inadequate description of fetal or maternal outcomes and the failure to report follow-up period information. In this regard, the RoB with respect to the follow-up and drop-out rates was elevated in 81.3% of the studies. It is worth highlighting the relevance of declaring the lost to the follow-up, which is essential data to evaluate any differences in obstetric and perinatal outcomes and on the subsequent follow-up and development of complications in both the child and the mother.p < 0.001), showing significant heterogeneity , by analysis technique , by sample source . Finally, the primary-level studies showing a low risk of bias also maintained this significant difference and harbored a large effect size .Analysis of subgroups. All subgroups maintained the precedent significant differences after subgroup meta-analyses were carried out , stratifUnivariable meta-regression analyses. The effect of the remaining study covariates on cord blood leptin levels among patients with GDM compared to controls showed no significant differences .Sensitivity analysis. The precedent overall results did not substantially vary after the sequential repetition of meta-analyses, omitting one study each time . This suEgger = 0.02) revealed the presence of small-study effects, thus publication bias could not be potentially ruled out.Small-study effects analysis. The visual inspection analysis of the asymmetry of the funnel plot constructed  and the p < 0.001). This finding is consistent with previous studies in this regard [This systematic review with meta-analysis has included 16 primary-level studies and 1691 patients. It is shown that cord leptin profile levels were significantly higher in women with GDM than in the control group . It means that these higher-quality primary-level studies identified the highest differences in cord blood leptin levels between pregnant women with GDM and controls. This fact increases the quality of the evidence of the results reported in our meta-analysis, which could even be underestimated in the studies reporting a small effect size and harboring a higher risk of bias. Therefore, future studies focused on this topic should consider the potential biases and recommendations reported in this systematic review and meta-analysis to improve and standardize future research.According to our risk of bias (RoB) analysis, which was carried out using the Newcastle-Ottawa Quality Assessment Scale (NOS tool), all the studies included in our systematic review were not methodologically designed with the same rigor. A meta-analysis stratified by overall risk of bias revealed that the subgroup of studies designed with better methodological quality  achieved better meta-analytic performance. (SMD = 0.93, 95%CI = 0.57 to 1.30, a priori planned and performed for all meta-analyses. In addition, more homogeneous subgroups were observed after stratified meta-analyses, with some subgroups yielding consistent non-heterogeneous results. Another possible limitation is the suspicion of publication bias, which could not be ruled out in this meta-analysis. The current tendency to publish positive results as a priority is an inherent obstacle to the editorial process that is difficult to overcome in biomedicine. Regardless, the SMD reported in our meta-analysis for cord leptin levels was considerably higher in GDM versus controls, and the sensitivity analyses performed without relevant variation in the magnitude of the effect support, in summary, the stability and robustness of our results.To the best of our knowledge, this is the first systematic review and meta-analysis about cord leptin levels in GDM. A potential limitation of our meta-analysis is the existence of a moderate degree of statistical heterogeneity. It should be noted that clinical and methodological heterogeneity was expected, so random-effects models were Our meta-analysis evidences higher cord blood leptin levels in women with GDM compared to controls. However, given the few papers reporting clinical-metabolic variables, a more comprehensive analysis of the possible involvement of cord blood leptin in the pathophysiology of GDM and maternal-fetal outcomes in these patients has not been possible. Thus, it is not yet known the possible importance of higher levels of cord leptin in maternal-fetal outcomes. The limitations of the current methods of fetal anthropometric assessment or prevention strategy for GDM demonstrate the need to discover early predictors of GDM to establish intervention and prevention strategies in high-risk women. Further studies are needed to evaluate the role of cord leptin and other biomolecule levels in the future development of T2DM and other metabolic diseases in GDM mothers and offspring.


The PECO strategy was used to identify prospective or retrospective observational studies assessing root caries in patients with periodontal disease without language or year publication restrictions. Two reviewers extracted data and evaluated the individual risk of bias in the eligible studies. Random effects meta-analyses were performed to calculate the Odds Ratio (OR). The risk of bias was assessed by the NIH tool, and the certainty of evidence was classified according to the GRADE tool. There were 1,725 studies retrieved, of which four met the eligibility criteria. All of them were evaluated for the control statements for possible confounders, bias consideration, and confounding factors because they had multivariate analysis. Adults with periodontal disease had a greater chance of presenting root caries than adults without, with OR 1.38 . The certainty of evidence was classified as very low. Within the limits presented in this review, there was an association between periodontal disease and root caries, highlighted in the qualitative synthesis and the meta-analysis results.Some periodontal diseases can be associated with cariogenic bacterial growth due to various oral health imbalances. This fact may be linked to a greater development of root caries. Thus, this systematic review analyzed the evidence on the association between periodontal disease and root caries. An electronic search was performed in five databases (Cochrane Library, LILACS, MedLine  Periodontal health is the absence of histological signs of periodontal inflammation and the absence of signs of periodontium anatomical change , 2. PeriAny carious lesion that develops on the tooth’s root surface is called root caries . It is dRoot caries has a bidirectional effect on periodontal tissues and tooth surfaces, which worsens the impact of both illnesses on a patient’s oral health . UsuallyMetabolically specialized microorganisms cause caries and periodontal disease. Positive feedback loops are involved in the progression of these diseases, but they are triggered by different stressors. In caries, continued exposure to sugars and organic acid fermentation can result in a positive feedback loop, increasing the amount of acidogenic and aciduric microorganisms and raising the pH of the medium. Plaque accumulation causes inflammation in gingivitis, and a positive feedback cycle increases inflammatory factors, which can dysregulate the host immune response and destroy periodontal tissues , 14.Moreover, root caries is challenging to identify, especially in the early stages of demineralization . HoweverTherefore, since there is some evidence regarding the relationship between periodontal disease and root caries, this systematic review aims to summarize the findings on whether there is an association between periodontal disease and root caries in adult patients.https://doi.org/10.17605/OSF.IO/R97HY. This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)  p<0.001, I2 = 0% .The outcome analyzed by both studies included in the meta-analysis showed low certainty of evidence. The assessment of the certainty of evidence summary is presented in This systematic review assessed the association between periodontal disease and root caries. The presence of association is demonstrated by the qualitative synthesis and the meta-analysis, which found that those with periodontal disease had a 38% more chance of presenting root caries. Furthermore, the certainty of the evidence analysis indicates a low level of evidence, which is expected for observational studies. Although the studies used correlation analysis, the results did not include covariates or indicate which teeth groups were most affected.The relevance of investigating the association between periodontal disease and root caries is because some periodontal diseases, such as periodontitis, can lead to the occurrence of gingival recession and exposure of root surfaces to the aerobic microbiota of the mouth, which may favor cariogenic bacterial growth . BecausePeriodontal disease and root caries have been shown in the literature to have a positive relationship with age , 44. ThuThese observations are in accordance with the results of AlQobaly and Sabbah (2020) , which fAnother modifying factor of root caries and periodontal disease is oral hygiene habits, which, if maintained, would reduce the occurrence of both diseases. Yu et al. (2021)  used oraIt is important to note that all articles included in the systematic review cannot address causality because they are cross-sectional studies. However, it is well known that poor oral hygiene is one of the multifactorial causes of both periodontal disease and root caries , 43. GivAlthough all studies assessed the association between periodontal disease and root caries by correlation or regression, only two used confounding variables to adjust the results , 38. IntThe most recent periodontitis classification is based on severity levels defined by clinical interdental loss, radiographic bone loss and tooth loss, complexity, extent, and distribution . RegardiThere was a high proportion of adjustment variables (41/56), indicating a very good statistical control of identified confounders. The multivariate analysis considers multiple known confounders that can statistically reinforce the results’ validity of observational studies . HoweverRegarding the methodology quality, the only fair quality study  had riskAs for the most explored confounding domains, some eligible studies have shown interesting positive results for participants who were men , 38, 40 Detailing the least explored domains, Saotome et al., 2006  uncovereThe level of evidence remained low because there was no representativeness of participants in the included studies and, therefore, a low weight. Still, it is recommended that more attention be provided to individuals who present both root caries and periodontal disease, especially elderly patients. It is suggested that more preventive activities be carried out in the middle-aged to the older population and also that clinical trials be conducted to see if early treatment of root caries prevents the onset of periodontal disease; or whether periodontal therapy would minimize the appearance of root caries since both are associated, with no causative factor involved.Therefore, some strengths of this study should be highlighted. This systematic review is a pioneer in approaching this theme. In addition, it followed strict criteria, always in accordance with the most current specific guidelines, and carried out a comprehensive individual critical analysis of eligible studies.Nevertheless, some relevant limitations were found in the eligible studies. Due to their observational study design, they do not allow causality inference , not perIn conclusion, our study provides evidence of an association between root caries and periodontal disease. However, we acknowledge that this topic is complex and multifaceted, and there are varying perspectives and among researchers and clinicians regarding the relationship between these two conditions. Some may argue that the observed association is confounded by common risk factors, such as age, diet, and oral hygiene, or that the studies included in our analysis were subject to biases and limitations. Others may suggest alternative explanations or mechanisms for the observed association, such as microbial interactions or host immune response. We therefore encourage readers to consider these different perspectives and draw their own conclusions based on the available evidence. Further research is needed to elucidate the underlying mechanisms and establish a temporal relationship between the events of this association, as well as to explore potential preventive and therapeutic strategies for these prevalent oral diseases.Within limits presented in this review, it is concluded that there was a positive association between periodontal disease and root caries, which was highlighted in the qualitative synthesis and in the result of the meta-analysis.S1 Checklist(DOCX)Click here for additional data file.S1 File(DOCX)Click here for additional data file.


ACE-DD variant , ESR1-PvuII  significantly increases the risk of migraine in Indian population. Also, a protective role of the LRP1-rs11172113variant was observed for both migraine and its clinical subtype i.e., MA  respectively. Overall, the results of this meta-analysis indicated that the ACE-DD variant and the ESR1-PvuII were associated with an increased risk of migraine in the Indian community, while the LRP1-rs11172113 variant was associated with protection from migraine in this population.Migraine is a complex disorder with multigenic inheritance and is characterized by the cardinal symptom of unilateral headache. Many genes are responsible for increasing the susceptibility of disease within different populations. Therefore, our primary aim in this review was to catalog the many genes that have been studied in India and after collecting the necessary information, we calculated a more precise risk relationship between an identified variation and migraine. The gene and its associated risk variant were discovered in the Indian population using a PRISMA-based systematic literature review guideline from online databases such as PubMed & Google Scholar. We constructed pooled odds ratios with 95% confidence intervals using multiple genetic models. Also, we looked for heterogeneity using Cochran's Q Test and the I2 statistic. Publication bias was analyzed using Begg's and Egger's tests. A p-value less than 0.05 was judged to be statistically significant for all tests. After a critical analysis, a total of 24 studies explored about 21 genes with 31 variants out of which only nine genes have been studied more than two times in the Indian population and thus were found eligible for the meta-analysis. It has been found, that the  International Classification of Headache Disorder 3rd edition (ICHD-3) has classified the disorder into two main clinical subtypes i.e., Migraine with Aura (MA) and Migraine Without Aura (MWA) based on the criteria of presence and absence of aura feature (ICHD-3.org/1-migraine/). Various factors, such as cortical spreading depression (CSD), activation and desensitization of the Trigeminal-vascular system, neurogenic-neuroinflammation, etc., which are collectively responsible for the etiology of migraines, have previously been explored6. Factors that are responsible for increasing the risk of migraine are crucial and are broadly categorized into environmental and genetic factors. Former which is responsible for hindering the susceptibility threshold of pain which is set by the latter factor i.e., genetic risk factors1.Migraine is a complex and polygenic disorder, featuring different characteristics such as nausea, vomiting, phonophobia, photophobia, and interestingly the cardinal feature i.e., unilateral headache7. Other than the advanced GWAS, numerous independent studies have been carried out in various populations and have identified various genes that are responsible for disease risk attribution. Using India as an example of a population, which is part of the Asian ethnic group where migraine disorder is very common12, many genes have been studied  or Single Nucleotide Variation (SNV) which are responsible for altering the function of the same. The most recent and updated meta-analysis of the Genome-Wide Association Study (GWAS) data has shown that many genes with modest effects are involved in disease riskAs a result, in the current review study, we first sought to identify the different genes explored in the Indian population before pooling the risk of similar genes to determine the precise association in the same population. The current study is unique in that it is the first of its kind to include all of the risk genes and variants from the Indian population to determine the precise risk.The presented review aimed to find out the critical genes that increase the risk of migraine and its clinical subtype in the population of India which belongs to the Asian ethnic group. To achieve the aim, we used the approach of a “systematic way of literature survey” which was done from the online database and search engines such as PubMed-NCBI  (Pubmed.NCBI.nlm.nih.gov), and Google Scholar (Scholar.google.com.tw) respectively. We bypassed exploring other databases and utilized PubMed because of its comprehensive collection of references, which includes MEDLINE , life science journals, and electronic books.OR Gene variant with migraine in India AND migraine genes in India OR migraine polymorphism in India”. Only articles published in the English language were evaluated using the linguistic filters as a factor for publication selection. We also tried to exclude study data if unpublished (Research Square/ Researchsquare.com), incomplete, or only partially available. Because partial and missing data are not included in the study, there is no such detrimental effect and we did our utmost to eliminate any undesirable characteristics. The search was completed and studies were included following the PRISMA  guidelines (www.prisma-statement.org)  or ICHD-3″ International Classification of Headache Disorders-3, the authors must have looked at the genetic polymorphisms/variants and must have provided the detailed description about the variant under study with proper reference ID (rsID) or change of nucleotide”, “the genotype frequencies of the investigated variants must be stated unambiguously among migraineurs and controls”, “Hardy–Weinberg Equilibrium (HWE) conditions are required for all experiments”, “studies should provide clear data to calculate the odds ratios (ORs) and the corresponding 95% confidence intervals (CI)”.When necessary information was missing from an article, it was sourced from another publication.The demographic characteristics of each study were extracted, including the state in which the research was conducted, the number of patients and healthy individuals, any cohort data, the genotypic frequency from both cases and controls, the first authors, the years of publication, and the technique used to determine the genotype? Also features such as gene coding protein, chromosomal location, the function of a protein, and polymorphism ID/SNP-ID/rsID were extracted from the online data where required. If any statistical/numerical data were found missing, previous research/references were analyzed. All the data/features extraction was first done by our two authors  and then the quality was assessed by the other two authors .The quality of research articles is an important factor to consider when performing a meta-analysis, which entails pooling independent research studies to determine the precise result. In light of this, the present research assessed the quality of all previously published studies by utilizing the criteria established by the Newcastle–Ottawa scale (NOS) such as (1): selection of cases and controls that include cases and control definition, and their selection(2): comparability (comparability of cases and controls) and (3): ascertainment of exposures . Each section with the correct method is assigned one star (1 point) with an exception in Comparability” section which is with two stars (2 points). Therefore, a study will be disqualified if it receives fewer than 5 stars (< 5) (or 5 points), which is considered to be a good study and can only receive a maximum of 9 stars  (Supplementary File: S2(I2 > 75: Random model). I2 is an estimate to define the proportion of inter-study variability attributed to chance rather than heterogeneity.Genotypic and allelic frequency was first calculated for all studies included in the meta-analysis and then the Chi-square test was used to analyze whether the population is in HWE (p > 0.05 for the population in HWE) or not (p < 0.05). To find out the strength of the association between the variant of interest, and the risk of migraine, the logistic regression utilizing OR (Odds Ratio) model with 95% CI  was used. Here odds ratio is defined as the OR > 1 is defined as the odds of exposure among cases being greater than the odds of exposure among controls & OR < 1: the odds of exposure among cases are lower than the odds of exposure among controls. Different genetic models such as allelic , dominant (dominant vs. heterozygote + pure recessive), recessive (recessive vs. dominant + heterozygote), and over-dominant (heterozygote vs. pure dominant + recessive) were used to observe the strength of association (OR) using random: Dersimonian and Laird method or fixed model (Inverse variance method) based on I2) tests respectively. Also, we performed the sensitivity analysis to observe the influence of individual studies on the pooled ORs and 95% CIs by the criteria of “exclusion of each study”.All tests were two-sided, and a value < 0.05 was considered statistically significant. The current meta-analysis process, from the choice of statistical tests to the analysis of the findings, was conducted following the Cochrane guidelines (Training.cochrane.org/handbook/current). All the statistical analysis was done with Meta-Genyo online Statistical Analysis System software .The publication bias including reporting bias and heterogeneity of the research studies were assessed using Begg's and Egger's tests and χ2 based on Cochran’s Q Test with I-square , which checks to see if the included trials have sufficient numbers of participants. Based on an overall risk of 5% and a relative risk reduction of 20% (with 80% power), the TSA tool  was used to compute the necessary information size for evaluating the validity of a meta-analysis. (TSA—ctu.dk). With specific settings “Set Effect Measure and model” , “Set Zero Event Handling (SZEH)” , “Set Confidence Interval (SCI)” . There are, however, two basic possibilities: (1) no further research is needed if the cumulative Z value/curve exceeds the RIS (Required Information Size); (2) additional studies are needed if the Z curve does not surpass the RIS threshold.39. Therefore, to analyze the most connected gene/node among the studied genes in the respective population, the String v11 (String-db.Org/), a potential protein–protein interaction tool that collects data from several online databases was used. After PPI (Protein–Protein Interaction), the network was built, edited, and analyzed using the Cytoscape tool version 3.9.1, a free and publicly available bioinformatics tool for analyzing and interpreting gene expression profiles, and molecular interaction networks (Cytoscape.org/).It is critical to identify the most important wiring connection/most connected node/dot in the gene/protein interaction network used to understand disease progression because any change in the peripheral gene will eventually affect the regulation of the core gene/ most connected node23, three studies for ACE (I/D polymorphism)24, LRP1- rs1117211328, PRDM16- rs265189926, TRPM8- rs10166942 and rs1050486126, ESR1 PvuII and XbaI37, DAO- rs10156191, rs205212935 and TNF-α G308A30.Using the strategy of systematic way of literature survey Fig. , a totalMTHFRand rs10166942 of TRPM8 were excluded due to not being found in HWE  , dominant model , and overdominant model . Subgrouping based on the criteria of the ”study conducted in which region of India i.e., such as South India (SI) and North India (NI)”, no significant association was observed  and the risk of migraine in the Indian population after utilizing different genetic models and these include the allelic model , was used to examine publication bias across all studies included in the meta-analysis . By placing the most accurate research on top and the least precise studies at the bottom of a scatter plot, we were able to create a "funnel plot" that displays the distribution of accuracy across all investigations. All genetic models resulted in symmetrical funnel plots, indicating that no publication bias existed. Fig. .Figure 424 (Supplementary Table There are 3 studies2 = 0%) and  respectively in contrast to dominant and over-dominant model  and  respectively. After subgroup based on the clinical subtype i.e., MA and MWA, the variant showed a significant association after utilizing different genetic modes such as allele , recessive  in contrast to dominant  and over-dominant model  in MA group in compare to MWA where allele and recessive model showed significant association  in comparison to dominant and overdominant model  respectively. In addition, subgrouping based on the criteria of the ”study conducted in which region of India i.e., such as South India (SI) and North India (NI)”, was not done due to all studies were from north India.The present meta-analysis found a significant association between the selected variant and risk of overall migraine after utilizing the allele Fig. A and recThere was no evidence of publication bias because all funnel plots for genetic models were symmetrical  Fig. B Supple S1. The ESR1 studies in the Indian population by three different research groups37 (Supplementary Tables 2 = 0%), dominant , and recessive model  significantly increase the risk of migraine. After subgrouping based on clinical type criteria, a significant association was also found in both MA , and MWA , and recessive model: OR: 1.94 [1.30–2.89], I2 = 0%).In the present study, we found two variants such as PvuII and XbaI of 37 discussing the impact of XbaI polymorphism on the susceptibility of migraine and its type. The pooled OR of both studies did not show any significant association with the risk of migraine or with the migraine sub-type , dominant , recessive , and over-dominant model   and control (n = 868) groups, the association value was not statistically significant for any genetic model under study such as allelic (OR: 1.12 [0.84–1.51] I26 (Supplementary Table 2 = 44%), dominant , in contrast to recessive and over-dominant  and  respectively where the non-significant association was observed.In the present review, we found two studies2 = 52%), dominant , and over-dominant  significantly showed protective role in MA. But, in the case of MWA, only dominant  and over-dominant model  showed a protective role in contrast to allele  and recessive  where a non-significant association was observed. There was no evidence of publication bias because all genetic models produced symmetrical funnel plots and recessive model  showed non-significant association with the risk of migraine in contrast to dominant  and over-dominant model  which significantly increase the risk of migraine in Indian population. All genetic models yielded symmetrical funnel plots, eliminating publication bias. A sensitive study on all genetic models carefully removing individual studies proved the meta-analysis's stability.The present meta-analysis provides pieces of evidence that allele  further studies are required , with active interaction sources which include test mining, experiments, databases, co-expression, neighborhood, gene fusion, and co-occurrence were utilized. We found that there were 32 connections/ edges between the processed 16 nodes/protein with an average node degree of four and six expected number of edges, 0.683 of average local clustering coefficient, and a significant PPI enrichment p-value (1.57e-14). It was observed that the highest degree (Degree: 8) was found with TNF-α followed by APOE and SLC6A4 (Degree: 7) Table .Table 3P7. Other than the advanced GWAS, multiple studies have been conducted in different populations and found different genes. Specifying with the example of population, many genes have also been explored in the Indian population belonging to Asian ethnic groups constituted of different states  45.Concerning the The prime strength of the present pairwise meta-analysis is the strategy utilized for the literature survey, then the inclusion of searched studies based on the criteria discussed (Section ”Inclusion and exclusion features”), and secondly the use of statistical analysis for finding the risk association between the different risk variants and diseases under consideration. Thirdly, the presentation of pooled summary estimates is considerably simpler to understand. Fourth, we have also found the risk attribution between the selected variants and migraine subtypes (MA and MWA). Fifth, we also presented the protein–protein interaction in an attempt to find out the most connected node in the network of nodes selected from the population under study. Sixth, a precise risk attribution toward the risk of migraine within a specific population i.e., the Indian population has been established. Apart from the strength, the first limitation is that migraine is an extremely heterogeneous condition, as all studies have diagnosed the suspected individual using criteria of ICHD-3 / HIS, but still, there could be misclassification. Second, the present analysis is only limited to clinical subgrouping and no subgroup was done based on gender. Also, there was an incredible disparity in sample size between the studies. Also, the risk of non-significantly associated variants can be modified by different modifier genes which were not explored in the present study. Additionally, the risk of disease can be attributed to the interaction between the markers of the same gene. In addition, concerning with the included studies in the meta-analysis were not enough, therefore for a precise estimate, more studies are required.ACE-I/D, and ESR1-PvuII showed a significant association with the risk of migraine in contrast to LRP1-rs11172113 and MTHFR-C677T, PRDM16-rs2651899, DAO-rs10156191which showed protective and non-significant association in respect to Indian population respectively. We also noticed that there was much disparity in the sample size between studies, specifically the patient’s group was even not found in HWE. Also, the ratio between case and control was not even equal in the different studies, and for a fixed sample size, the chi-square test for independence is most powerful if the number of cases is equal to the number of controls 46. Additionally, we can increase or recruit more controls to boost the study's statistical power if we are unable to find enough cases, but only up to 4 controls for every one case. Given the expense of recruiting them, adding more controls (more than four) might limit the increase in statistical power beyond this ratio47. There have only been a few, sometimes just two, studies exploring specific variants, which makes it necessary for more research to be done to support the risk attribution hypothesis.In the present study, we aimed to find out the critical gene or genes that are responsible for the significant risk attribution toward disease susceptibility within a specific population (India) using a high statistical meta-analytical research approach. Different genes such as ESR1-PvuII showed a significant risk of migraine in the Indian population in contrast to LRP1- rs11172113 which showed a protective role in the respective population.In conclusion, this present meta-analysis showed that the ACE-DD variant and Supplementary Information.


Diet is emerging as a modifiable component of lifestyle for influencing the incidence of liver cancer.To investigate and quantify the potential relationship between food groups and liver cancer.PubMed and Web of Science were searched for eligible observational studies until 31st March, 2023.The meta-analysis was conducted by pooling relative risk (RR), odds ratio (OR) or hazards ratio (HR) with 95% confidence intervals (CIs). Potential sources of heterogeneity were detected by subgroup analysis. Sensitivity analysis and publication bias test were also carried out.I2 = 25.3%) and 0.86 , respectively. However, there were null associations of nuts, poultry, egg and sweetened beverages consumption with liver cancer and the association between refined grains and liver cancer was inconclusive. In dose-response meta-analysis, the pooled estimates of liver cancer were 0.77 (95% CI: 0.65–0.91) for every 50 g/day increment in whole grains intake. Non-linear dose-response relationship (P = 0.031) was observed in the association between the intake of legumes and liver cancer, and the protective effect occurred with the dose ranging from 8 g/day to 40 g/day.Through stepwise screening, a total of 27 studies were included. The pooled estimates of liver cancer for whole grains and legumes intake were 0.66 (95% CI: 0.54–0.82; This meta-analysis shows that whole grains and legumes were inversely associated with liver cancer, whereas intake of nuts, poultry, egg and sweetened beverages may not be associated with liver cancer. Further quantitative research needs to be undertaken within a range of populations to investigate the relationship between food groups and liver cancer.PROSPERO registration no. CRD42021246142The online version contains supplementary material available at 10.1186/s12937-023-00858-5. Liver cancer is the sixth most frequently diagnosed cancer and the third leading cause of cancer-related death worldwide in 2020 . The gloEating patterns assessed by hypothesis-driven approaches such as the Mediterranean diet score and the healthy eating index were reported to be associated with the risk of liver cancer –6. HowevIn the present study, we conducted a systematic review and meta-analysis of the association of specific food groups including grains (whole grains and refined grains), legumes, nuts, poultry, eggs and sweetened beverages with liver cancer to provide a better dietary instruction for the lay public.The current meta-analysis was conducted according to the standards and recommendations set by the preferred reporting items for systematic reviews and meta-analyses (PRISMA) , and wasPubMed and Web of Science databases were systematically searched from the inception to 31st, March 2023. The search terms listed in supplementary table Studies meeting the following criteria were included: (1) study type was an observational study; (2) information about the association for at least one of the following 6 food groups: grains (whole grains and refined grains), legumes, nuts, poultry, egg and sugar sweetened beverages on liver cancer; (3) directly reported odds ratio (OR) or hazards ratio (HR) or relative risk (RR) with 95% confidence interval (CI), or indirectly provided relevant data for calculation; (4) if study populations overlapped, the one with larger sample size was included. The exclusion criteria were as follows: (1) food groups included in published meta-analyses related to liver cancer in recent three years  –12; (2) Data was extracted cross-checked by two researchers (Liu K and Xu L) independently from eligible studies. The extracted information included name of first author, publication year, data collection year, type of study design, country or region, sample size, dietary assessment method, type of food groups, type of liver cancer and variables adjusted or matched.The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of included studies with scores ranging from 0 to 9 points . This scThe multivariate-adjusted estimates were selected if they were reported in the original article; otherwise, the unadjusted estimates were calculated using the original data. In the categorical meta-analysis, ever intake of food groups was compared with non/occasional intake of food groups, which was defined by study-specific reference ranges. If the group of ever intake of food groups was set up into multiple categories, we combined the effect estimates into a single value in each study. For the food groups with less than 3 studies, no quantitative analysis was carried out.I2) value [The heterogeneity was evaluated by Q-statistic test and I-squared (2) value , 15. The2) value . Subgrou2) value  test and2) value  test werFor the significant association between specific food groups and liver cancer, we also pooled estimates comparing highest with lowest intake of food groups among the studies with equal or more than three different categories of intake of food groups. Furthermore, we conducted a two-stage dose-response meta-analysis . BrieflyP < 0.05 was regarded as statistically significant.All statistical analyses were performed using STATA version 11.0 and The flowchart of the literature search is presented in Fig. I2 = 25.3%; Fig. For whole grains, a total of 2 prospective studies , 48 and P = 0.734) or Egger’s test (P = 0.721)  per 50 g/day increase in whole grains intake. However, no evidence of a non-linear association was observed (P = 0.102 for non-linearity).The inverse association between whole grains intake and liver cancer remained significant for highest versus lowest whole grains intake  showed that decreased liver cancer was observed when legumes intake ranged from 8 g/day to 40 g/day, and the most protective effect  was observed at the dose of 36 g/day legumes consumption, as depicted in Fig. The association between legumes consumption and liver cancer was insignificant when comparing highest versus lowest legumes consumption , subgroup analysis suggested that the protective effect of whole grains on liver cancer were consistently found in high-quality and large-scaled studies. Increased intake of whole grains and their component bran has been reported to have beneficial effects on diseases related to liver disease and liver cancer, including glycemia, insulin sensitivity, metabolic regulation, and reduced inflammation, etc –55. TherInterestingly, we found that a reverse association of legumes and liver cancer with a low heterogeneity. Furthermore, the dose-response relationship meta-analysis suggested that there was a statistically significant association between legumes consumption and liver cancer at a certain dose range of 8-40 g/day. However, given the lack of robustness of the result and the fact that most studies focused on Asian populations, further evidence is needed in larger cross-population cohort studies in future. Regarding the potential mechanism, legumes contain a variety of phytochemicals, such as phytoestrogens, mostly isoflavone (genistein and daidzein) and lignans as well as saponins and phytosterols . AnticanFor nuts, most of tree nuts contain multiple hydrophilia compounds  as well as lipophilic components , which have been shown to exert indirect anticancer activities via their anti-inflammatory and antioxidant actions . A recenThe present study also has several limitations. First, it is worth noting that residual components may influence the association of these food groups with liver cancer. For example, fermented beans than unfermented beans, sugar sweetened beverages than artificially sweetened beverages. Similarly, limited studies have provided information on the histopathological type of liver cancer, and therefore, we could not perform subgroup analyses or conduct the analysis separately according to these factors since preliminary studies reported limited or unclear results for food composition and liver cancer type. Secondly, meta-analysis across ethnic populations often leads to heterogeneity of findings because they have different dietary backgrounds, and statistically significant heterogeneity among studies was observed. However, the use of random-effects model was allowed to take the heterogeneity among studies into account. Thirdly, relatively few studies on some food groups are available and insufficient for further quantitative analysis, and there is no detailed data for dose-response analysis of the association between poultry consumption and liver cancer. Fourthly, the included studies are at risk of selection bias for cases and controls and the potential misclassification introduced by the lack of specificity in exposure definition. Moreover, insufficient adjustment for potential confounders  is also an important consideration on account of the nature of observational studies. Finally, the cutoff value of distinguishing between high and low consumption of food groups were diversiform in the included studies, which might contribute to the heterogeneity among the studies.In summary, our results demonstrated that whole grains, and legumes were inversely related with liver cancer. A null association was noted between nuts, poultry, egg and sweetened beverages consumption and liver cancer. Therefore, further well-designed cohort or clinical studies are needed to confirm the association.Below is the link to the electronic supplementary material.Supplementary Material 1


The relationship between inflammatory bowel disease (IBD) and the risk of Parkinson’s Disease (PD) has been investigated in several epidemiological studies. However, the results of these studies were inconclusive and inconsistent. We evaluated the potential relationship between IBD and PD risk by a meta-analysis.Search the electronic databases PubMed, Embase and Cochrane databases from inception to November 30, 2022, to identify relevant studies that assess the risk of PD in patients with IBD. The cohort, cross-sectional, mendelian randomization and case-control studies that reported risk estimates of PD and IBD were included in our analysis. The random-effect model and fixed-effects model were used to calculate the summary relative risks (RRs) with 95% confidence intervals (CIs).P = 0.019). Omit of any single study from this analysis had little effect on the combined risk estimate. No evidence of publication bias was found. In the subgroup analysis, the combined RR was 1.04  for Crohn’s disease (CD), and 1.18  for ulcerative colitis (UC). In addition, a significant association was identified in patients with IBD aged ≥ 60 years , but not in age < 60 years . Meanwhile, the meta-analysis results suggested a protective role for IBD medication use against PD development, with the RR was 0.88 .In total, 14 studies  involving more than 13.4 million individuals were analyzed in our analysis. Our results suggested that the risk of PD in IBD patients is moderately increased, with the pooled RR was 1.17 (95% CI: 1.03–1.33, Our results indicated that patients with IBD had a moderately higher risk of PD compared to non-IBD individuals. Patients with IBD should be aware of the potential risks for PD, especially who were ≥ 60 years old. Parkinson’s disease (PD), a multifactorial movement disorder disease, which is the second most common neurodegenerative disorder. The primary cause of this disease is the loss of dopaminergic neurons in the substantia nigra and the abnormal accumulation of intracellular α-synuclein, which usually develops between 65 and 70 years old, and accounts for up to 1% of people over 60 years old . The cauInflammatory bowel disease (IBD) is chronic systemic inflammatory disorders, which including Ulcerative colitis (UC) and Crohn’s disease (CD). It has been reported that more than 1.8 million adults are affected by IBD in the United States .P < 0.001). In recent years, several clinical studies with large samples have been conducted to investigate the association between IBD and PD, again, with conflicting results . The research strategy was as following: “ and .” Additionally, we also checked the reference list of related articles and reviewed them to identify other potential studies.A study was considered eligible in this meta-analysis if it met the following criteria: (1) case-control, cohort, or cross-sectional study that explored the association of IBD and PD risk; (2) the publication was written in English; (3) IBD, UC or CD was the exposure, and PD was the outcome of interest; (4) the RR, odds ratio (OR), hazard ratio (HR), standardized incidence ratios (SIR), or incidence rate ratio (IRR), and their 95% confidence interval (CI) were reported, or could be calculated from the original data. If the same study (or the same data source) has more than one publication, only the study with the largest number of samples is included. Studies were excluded if they were cases report, commentaries, reviews, comments, editorials, or experimental studies.For each study, the following data were extracted: first author’s name, year of publication, study location/period, data source, study design, sample size, follow-up duration, age, variables adjustment, risk estimates, and their corresponding 95% CIs. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of cohort study , and theAll data were collected and processed by two independent researchers (CZ and XXP), and any disagreements were resolved through discussion and consensus with the third investigator (QZ).2 statistic (I2 ≤ 25%), moderate heterogeneity (I2 = 25–50%), or high heterogeneity (I2 > 50%). RR was calculated using a random-effects model (DerSimonian and Laird), which was considered as a conservative method of estimating cumulative effects. To explore the impact of a single study on the overall risk estimates of IBD and PD risk, we conducted a sensitivity analysis by omitting each study in each turn , disease subtype (CD vs. UC), gender , age (<60 vs. <65 vs. ≥60 years) and IBD treatment .n = 319), Embase (n = 445) and Cochrane databases (n = 21) were initial screening identified. After reading the title or abstract, 765 articles were excluded, and the full-texts of the 20 potentially relevant publications were then scrutinized. When manually searching the references of all relevant studies, one article was included . Although significant heterogeneity was found among these 12 studies , the result suggested that patients with IBD had a 17% higher risk of PD risk compared with non-IBD.Twelve studies , 22, 26 P = 0.311), for UC was 1.18 . Meanwhile, the significant heterogeneity was detected in the analysis, with  and  respectively. The forest plot of the PD risk in patients with IBD, CD, and UC are shown in The risk estimates for CD and UC were reported in 11 studies , 26, 27,Further subgroup analyses were performed to expose the potential heterogeneity, and the results are shown in P = 0.000). Two cross-sectional studies (P = 0.499) and 1.00 , respectively. These results showed that IBD patients do not increase the risk of PD compared with non-IBD patients. For the remaining one case-control study  with low heterogeneity , and the RR for female was 1.54  with high heterogeneity .In the stratified analysis by gender, five studies were included , 15, 19.P = 0.639). However, eight studies evaluated the association in age ≥ 60, with the summary RR was 1.22 . We observed a 22% increased risk of PD in patients aged ≥ 60 years.In the stratified analysis by age, a total of eight studies providing sufficient data in our analysis , 19, 20.P = 0.126).In the stratified analysis by IBD medication use, six studies , 16, 19 P = 0.013).In the stratified analysis by IBD-related bowel surgery, two studies , 16 provP = 0.622) and Egger’s (P = 0.404)  to 1.04  . The Beg= 0.404) .To our knowledge, this is the most comprehensive meta-analysis and systematic review investigating the association between IBD and PD risk up to date. In this meta-analysis, although only 14 studies, the study involving more than 13.4 million subjects. Our study demonstrated that the risk of PD in IBD patients was an increase of 17% in a comparison of patients with non-IBD. Meanwhile, subgroup analysis also found that IBD patients had an increased risk of developing PD regardless of stratification factors, except for CD group and age < 60 years. Furthermore, the study also hinted early IBD medication use in patients with IBD may reduce the risk of PD.P = 0.007), but not in age < 60 years old . Weimers et al. . It should not be surprising that a meta-analysis exhibits high heterogeneity. These 14 studies were included in our analysis were all derived from different research designs, geographic regions, demographic characteristics, and adjustments for confounding factors, which may be the sources of heterogeneity. Although we conducted a subgroup analysis of the study design, people from different geographical regions have different living habits, work styles, health care visit, and genetic backgrounds, which may lead to a high level of heterogeneity. Therefore, we used the random-effects model in these analyses with high heterogeneity, which was considered as a conservative method of estimating cumulative effects.In a meta-analysis, heterogeneity should be concerned. Moderate and high heterogeneity was observed in our study. Low heterogeneity was observed from a subgroup analysis of male, with heterogeneity (The exact mechanism of the association between IBD and PD risk is still unknown. On the one hand, more and more evidences support that gastrointestinal tract inflammatory plays a crucial role in the initiation and progression of PD , 41, 43.On the other hand, growing research shows that PD and IBD have common key genetic factors. Bialecka et al.  publisheSeveral strengths should be mentioned in our study. Firstly, our study included 14 studies involving a large number of participants, which improved the ability to find significant associations and provided more reliable estimates. Compare with the former meta-analysis in 2022 by Zhu et al.  and SzanSome potential limitations in the current study should be considered. First, although a large number of participants were involving, only 14 studies were included in the study. Second, only English publications were included, so that other language studies may be ignored. Third, moderate to high heterogeneity was observed in our study, although several subgroups were conducted, it may be inevitable, because the confounding factors from original studies were unavoidable.In conclusion, this meta-analysis provides evidence that IBD was associated with an increased risk of PD. IBD patients should be paid more attention to the potential risk of PD, especially those over 60 years old. In addition, early IBD medication use in patients with IBD might reduce the risk of PD development. Further prospective larger well-designed epidemiological studies are warranted to validate this finding from our meta-analysis.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.H-XL and QZ conceived and designed the work. H-XL, X-XP, and CZ contributed to the systematic literature search, selected the studies for inclusion, and extracted the data. KZ, X-XP, and CZ analyzed and interpreted the data and made the figures. Y-ZL, KZ, and QZ wrote, reviewed, and critiqued the manuscript. All the authors revised the important sections in the manuscript and approved the final draft.


Microalbuminuria has been elevated as an outcome predictor in cardiovascular medicine. However, due to the small number of studies investigating the association of microalbuminuria and mortality in the coronary heart disease (CHD) population, the prognosis value of microalbuminuria in CHD remains under debate. The objective of this meta-analysis was to investigate the relationship between microalbuminuria and mortality in individuals with CHD.A comprehensive literature search was performed using Pubmed, EuroPMC, Science Direct, and Google Scholar from 2000 to September 2022. Only prospective studies investigating microalbuminuria and mortality in CHD patients were selected. The pooled effect estimate was reported as risk ratio (RR).rR = 2.07 (95% CI = 1.70–2.44); p = 0.0003; I2 = 0.0%] as well as cardiovascular mortality (CVM) . Subgroup analysis based on follow-up duration and a subset of CHD patients were similarly associated with an increased risk of ACM.5176 patients from eight prospective observational studies were included in this meta-analysis. Individuals with CHD have a greater overall risk of all-cause mortality (ACM) [This meta-analysis indicates that microalbuminuria is associated with a higher risk of mortality in individuals with CHD. Microalbuminuria can serve as a predictor of poor outcomes in CHD patients. As a result, the prognostic value of microalbuminuria in CHD remains under debate. Therefore, a meta-analysis was performed to better understand the effect of microalbuminuria on mortality in the CHD population.22.1A systematic literature search was conducted on Pubmed, EuroPMC, Science Direct, and Google scholar databases from 2000 to September 2022 b y two independent investigators (EG and DY) using MESH of the following keywords in combination: “coronary heart disease” AND “microalbuminuria” AND “mortality” OR “death” AND “follow-up”. Each search word was altered to adhere to the limitations of each database. In addition, hand-examined references from relevant papers and reviews were carefully evaluated. This meta-analysis was carried out according to the guideline of the Preferred Reporting Items for Systematic Reviews and Meta-analyses Statement (PRISMA).2.2The eligible prospective observational studies that meet the following criteria were included: (1) population: coronary heart disease without known renal disease adult patients; (2) exposure: microalbuminuria ; (3) comparison: without albuminuria; (4) description risk estimates for the association between microalbuminuria and ACM or CVM, providing at least age and/or gender-adjusted risk ratio (RR) with 95% confidence interval (CI) or providing events of outcome in observation. Any cause of death, regardless of etiology, was defined as ACM. CVM was characterized as mortality caused by myocardial ischemia and infarction, heart failure, cardiac arrest due to another or unknown cause, or cerebrovascular accident.Exclusion criteria were: (1) case–control, cross-sectional, retrospective cohort designs, review articles, editorials, commentaries, case reports/series, meta-analyses, and conference abstracts; (2) studies in languages other than English; (3) participants from the general population or other particular patients.2.3,The first author's last name, publication year, location, sample size, gender distribution, baseline age, study population, the definition of microalbuminuria, outcome evaluation, adjusted risk ratio (RR) with 95% confidence intervals (CIs), follow-up duration, and adjusted confounders were all taken from each study independently by two authors (EG and CP). The quality of the study and the risk of bias were assessed using a meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines.2.4p-value <0.05. A random effect Der-Simonian Laird model was used to calculate the pooled effect size despite their heterogeneity.All statistical analysis were performed using Software for Statistics and Data Science (STATA) version 16.1. The pooled effect size was calculated using multi-adjusted RR with 95% CIs of each study with statistical significance indicated by a Q test's P value of less than 0.10 and I2 value above 50% were used to determine statistical heterogeneity. To identify the source of bias and provide an ideal, more robust summary across the relevant studies, sub-group analysis was done depending on sample size, population, and follow-up time. A leave-one-out sensitivity analysis was conducted by removing any single study that would produce exaggerated effect sizes, which may distort the overall results. Publication bias was assessed by Begg's test and Egger's test quantitatively and qualitatively.The Cochran's 33.1,,There were 5176 patients from eight prospective observational studies included in our meta-analysis .26, 27, 283.2rR = 2.07 (95% CI = 1.70–2.44); p = 0.0003; I2 = 0.0%, p-heterogeneity = 0.79). Subsequently, regardless of the heterogeneity status, a subgroup analysis was performed based on follow-up duration which showed a considerable increase in those with short follow-up duration (rR = 3.72 (95% CI = 1.71–5.72); I2 = 0.0%, p-heterogeneity = 0.97). Nonetheless, this remained unchanged in a long follow-up duration . The statistical significance of pooled risk ratio of ACM was based on sample size subgroup analysis, which revealed that pooled RR were (rR = 2.05 (95% CI = 1.55–2.55); I2 = 0.0%, p-heterogeneity = 0.67) for smaller sample size, and (rR = 2.10 (95% CI = 1.55–2.66); I2 = 0.0%, p-heterogeneity = 0.54) for larger sample size. Due to large spectrum of CHD, further analysis was performed based on occurrence of myocardial infarction (MI), which showed pooled RRs of MI and other than MI were (rR = 2.08 (95% CI = 1.65–2.52); I2 = 0.0%, p-heterogeneity = 0.56) and (rR = 2.05 (95% CI = 1.34–2.75); I2 = 0.0%, p-heterogeneity = 0.92), respectively .Eight studies were included in the pooled RRs for all-cause mortality, as shown in ectively .Fig. 2Fo3.3,,rR = 3.23 (95% CI = 2.06–4.39), p < 0.0001; I2 = 0.0%, p-heterogeneity = 0.72]. Unfortunately, due to lack of studies, a subgroup analysis was not performed for cardiovascular mortality.Only three studies reported cardiovascular mortality as an outcome.3.4p = 0.386) and Egger's test (p = 0.144), as well as among studies that reported CVM [Begg's test (p > 1.00) and Egger's test (p = 0.934)].The sensitivity analysis of the leave-one-out study had no effect on the initial statistical significance (data is not shown). There was no evidence of publication bias among studies that reported ACM by Begg's test (4,Regardless of the small number of studies, this is the first meta-analysis to analyze the association between microalbuminuria and mortality in coronary heart disease. The meta-analysis indicates that microalbuminuria confers an increased risk of ACM and CVM. Previous meta-analyses have suggested a link between albuminuria and an increased risk of mortality and poor cardiovascular outcomes in various populations.The association between microalbuminuria and poor outcomes in CHD may not be surprising. The subgroup study based on the myocardial infarction population and other CHD populations revealed that the statistical significance remained the same in both categories. This demonstrates that microalbuminuria has the same amount of prognostic importance in both populations. Nonetheless, the mechanisms underlying the relationship between microalbuminuria and poor prognosis still need to be understood entirely.,,,,,The findings in this study might be explained by a number of different mechanisms. The initial clinical manifestation of glomerular vascular damage, which is a reflection of underlying macrovascular and microvascular disease, is microalbuminuria.,Several studies have provided clinical benefits of albuminuria measurements in predicting disease risk and outcome.In addition, this study offers some advantages. All of the included studies have prospective designs, diminishing recall risk and selection bias. Most of the studies in the meta-analysis reported multivariable-adjusted models that increased the study's pooled risk estimate value.Nonetheless, this meta-analysis has some limitations. First, it is crucial to emphasize that although this association was detected independent of renal function or the presence or absence of a diabetic or hypertensive history, and some of the studies have been adjusted with various covariates, the possibility of other uncontrolled confounding variables could not be ruled out. Individual patient characteristics may impact the pooled risk summary because this is a study-level meta-analysis. Second, the definition of microalbuminuria and cutoff values for UACR were not consistent among studies, thereby affecting their predictive values and the likelihood of misclassification. Third, a meta-regression could not be conducted to associate variables and outcomes of interest in this study, as well as subgroup analysis on the CVM due to the small number of studies. Fourth, the adjusted confounding factors of several included studies limited to only age and/or sex may have provided an overestimation of the risk estimate. Therefore, future prospective studies are needed to address the issues mentioned above.5According to this meta-analysis, microalbuminuria is associated with an elevated risk of all-cause and cardiovascular mortality in the coronary heart disease population. Thus, close monitoring for microalbuminuria may play an additional role in the prognostic stratification of coronary heart disease patients.EG, DY, FH: conception and design of study, data analysis, interpretation. EG, DY, FH CP: literature search, study selection, data extraction, drafting, and revision of the manuscript. EG, DY, FH, CP: read and approved the final version submitted for publication.This page contains no research involving human or animal subjects conducted by any of the authors.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Methodological quality was assessed by AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews 2). We retrieved 4478 articles, of which 43 met the inclusion criteria. The 43 eligible articles identified 31 potential environmental risk factors , 11 potential environmental protective factors , and 34 potential biomarkers  for meta-analyses. The credibility of evidence was convincing (class I) for tic disorders ; and highly suggestive (class II) for early-life antibiotic use , exposure to indoor dampness , acetaminophen exposure , childhood acid suppressant use , exposure to indoor mold , coronavirus disease 2019 , and prolonged breastfeeding . This study is registered in PROSPERO (CRD42022384320).Many potential environmental risk factors, protective factors, and biomarkers of AR have been published, but so far, the strength and consistency of their evidence are unclear. We conducted a comprehensive review of environmental risk, protective factors, and biomarkers for AR to establish the evidence hierarchy. We systematically searched Embase, PubMed, Cochrane Library, and Web of Science electronic database from inception to December 31, 2022. We calculated summary effect estimate (odds ratio (OR), relative risk (RR), hazard ratio (HR), and standardized mean difference (SMD)), 95% confidence interval, random effects The online version contains supplementary material available at 10.1007/s12016-023-08964-2. Allergic rhinitis (AR) is a chronic inflammatory disease of the nasal mucosa, which is caused by the release of immunoglobulin E (IgE)-mediated mediators (mainly histamine) after allergic individuals are exposed to allergens, and a variety of immune active cells and cell factors are involved , 2. In tGiven that AR is caused by the introduction of allergens in sensitized individuals, and the immune and inflammatory response induced by the excessive production of IgE in response to environmental allergens in atopic individuals , how to We followed the latest PRISMA   guidelinWe used computer to search Embase, PubMed, Cochrane Library, and Web of Science electronic database from inception to 31 December 2022, without any language restrictions. We used a combination of subject terms and free words for the search, with search terms including “allergic rhinitis”, “meta-analysis”, and “systematic review”. The search strategy was adapted to the different databases, and the full search strategy and search terms for each database are presented in the Appendix (p6). In addition, we manually traced the references of the included literature to supplement access to relevant studies.The types of articles we included were systematic reviews and meta-analyses, which mainly studied the association of environmental factors or biomarkers with AR. The types of design included in the original study were limited to Cohort studies  and case–control studies. Environmental factors (including risk and protective factors) and biomarkers (Appendix p7) are defined according to World Health Organization (WHO) , 23, andWe excluded articles that were not related to the research topic, which was not related to environmental factors, biomarkers and AR and their associations with each other. We excluded systematic reviews that did not perform a meta-analysis as well as meta-analyses that did not provide sufficient data. In addition, for systematic reviews and meta-analyses lacking sufficient data, we attempted to contact the corresponding authors to obtain the necessary data for re-analysis. We also excluded animal studies, duplicate publications, conference abstracts, protocols, posters, and letters. If two or more studies were on the same topic or assessed the same exposure and outcome measures, we considered these studies on the same topic to have the possibility of overlap, which could lead to bias of publication. Therefore, first, we prioritize meta-analyses with adjusted study estimates over those with crude estimates; next, we select meta-analyses with higher AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews 2)  scores; Two researchers  independently screened the literature according to the inclusion and exclusion criteria, extracted data, and evaluated the evidence quality of the included studies. Firstly, the title and abstract of the articles were read to exclude obviously unqualified articles, and then, the full text of the articles after initial screening was further read to determine whether they were included. Standard data extraction tables were used to extract information.The extracted contents included (1) basic information, including the first author, the year of publication, the number of included studies, and the study design; (2) baseline information of included studies, including the number of cases, total sample size, environmental risk factors, protective factors or biomarkers; (3) the results of meta-analysis, including the heterogeneity evaluation index, the combined effect size and confidence interval of the primary outcome; (4) methodological quality assessment methods and tools for original studies or evaluation methods for the quality of reported evidence.https://www.metaumbrella.org/app) designed by Dr. Corentin J Gosling and Dr. Aleix Solanes et al., which automatically performs umbrella reviews , layering evidence according to various criteria, and generating visual representations of the results [We followed the previous umbrella review design and validated statistical methods in order to address the issues we encountered in our pooled summaries , 27. Fur results .p values [p value < 0.001 or < 0.000001 [Q test, a common test for heterogeneity in meta-analysis, and calculated the statistic I2 [p value < 0.1 for a small study effect was found). Selective analysis and reporting of selective results may lead to potential excess significance bias, which means that the number of statistically significant studies is suspicious to be too high. For this reason, Ioannidis’ test was used to evaluate whether there was a significant bias in the meta-analyses  [We conducted a comprehensive integrated analysis of the meta-analyses that met the inclusion criteria, and extracted basic data information and study estimates. We selected random-effect models to incorporate pooled effect estimates, 95% confidence intervals, and p values , 30. Thep values . To conf0.000001 , 33. Befistic I2 . Predictistic I2 . We asseistic I2 . We asse < 0.05) . We perfMethodological quality was assessed using AMSTAR 2 , and thep value, number of AR cases, p value of the largest study, heterogeneity (I2), small study effects, excess significance bias, 95% prediction interval, and 95% prediction interval of the largest study. However, since some of the variables in these criteria are continuous variables, there is an artificial demarcation of critical points. For example, a study involving 1001 patients with a highly significant p values < 0.000001 association between risk factors and outcomes may be classified as class I evidence according to the grading criteria of evidence, while another study with the same results in other aspects but only 1000 patients may be graded as class IV evidence. This may not be common, but researchers must be careful about the differences. Table According to previously published umbrella reviews and the metaumbrella application , 27, 38,We comprehensively searched four databases from inception to 31 December 2022 and retrieved a total of 4478 articles, 43 of which met the criteria by title, abstract, and full-text screening  had p values < 0.05, 16 (37%) had p values < 0.001, and 8 (19%) had p values < 0.000001. Only 15 of 43 meta-analyses showed less than 50% heterogeneity (I2 < 50%). The number of individual studies less than 3 could not conduct Egger’ s test, which resulted in our 4 of 43 meta-analyses not obtaining Egger’s test data. Among the 43 meta-analyses, only 8 (19%) meta-analyses did not include more than 1000 AR cases. Among the 43 meta-analyses (excluding not accessible data), the numbers of small study effects and excessive significance bias were 11 and 13, respectively. The 95% prediction interval and the 95% confidence interval of the largest study excluded null in 4 of 43 (9%) meta-analyses and 28 of 43 (65%) meta-analyses, respectively. Table The 43 meta-analyses of potential environmental factors were classified into 31 potential environmental risk factors  and 11 potential environmental protective factors , of which 1 potential factor had no effect on the occurrence of the disease . Of the 43 meta-analyses, the largest included 63 original studies and the smallest included 2 original studies, in which effect metrics included OR, RR, and HR. Among them, the study designs of 35 meta-analyses included cohort studies, 17 included case–control studies, and 22 included cross-sectional studies. Of the 43 random effects 2.5) from air pollution were graded as suggestive evidence (class III) as environmental risk factors, along with passive exposure to tobacco smoking, history of Kawasaki history, education level, and family history of allergies were also graded as recommended evidence. Farm milk consumption and early dietary introduction of fish as environmental protection factors were graded as suggestive evidence (class III). Ambient particulate matter (PM10), sulfur dioxide and ozone, as air pollution, were graded as weak evidence (class IV), and only vitamin D status as an environmental protective factor was rated as weak evidence (class IV). Figure Of all the environmental risk factors and protective factors, tic disorders  was the only one that was graded as convincing evidence (class I) that it was an environmental risk factor. Seven environmental risk factors and protective factors were graded as highly suggestive evidence (class II), of which early-life antibiotic use , exposure to indoor dampness , acetaminophen exposure , childhood acid suppressant use , and exposure to indoor mold  were environmental risk factors, and coronavirus disease 2019  and prolonged breastfeeding  were environmental protective factors. Nitrogen dioxide and ambient particulate matter , except for the studies that could not be used for subgroup analysis, most subsets retained the evidence level, and only 4 changed the original evidence level. Exposure to indoor dampness was upgraded from class II to class I evidence, exposure to indoor mold was upgraded from class III to class I evidence, active exposure to tobacco smoking was upgraded from not significant to class II evidence, and vitamin D status was downgraded from class IV to not significant.p value < 0.05), of which only 3 (8%) had p values < 0.001 and only 1 (3%) had p value < 0.000001. Seven (70%) of 10 associations statistically significant meta-analyses included more than 1000 AR cases, but only two of the eight meta-analyses showed less than 50% heterogeneity (I2 < 50%). Four of 10 (40%) statistically significant meta-analyses had small study effects, and 2 of 10 (20%) had excessive significance bias. The 95% prediction interval and the 95% confidence interval of the largest study excluded null in 3 of 10 (30%) statistically significant meta-analyses and 4 of 10 (40%) meta-analyses, respectively.The 34 meta-analyses of potential biomarkers were classified into 32 single nucleotide polymorphism biomarkers , one serum biomarker , and one biomarker of nasal inflammation , the largest of which included 30 original studies and the smallest of which included 3 original studies. These meta-analyses included only case–control studies, and the effect metrics were based on OR and SMD. In the random-effects model, only 10 of 34 (29%) associations were statistically significant (There were no biomarkers that were found with convincing evidence (class I). The only biomarker graded as highly suggestive evidence (class II) was nasal nitric oxide in AR patients, and the only biomarker graded as suggestive evidence (class III) was interleukin 13 (IL-13) rs20541 polymorphism in AR patients. The Appendix (p18–p22) provides detailed test data, levels of evidence, and supplementary data for potential biomarkers of AR.We conducted AMSTAR 2 quality assessments on all meta-analyses. Among potential environmental risk factors and protective factors, 1 of 43 (2%) meta-analyses was graded as high quality, 9 of 43 (21%) meta-analyses as moderate quality, 10 of 43 (23%) meta-analyses as low quality, and 23 of 43 (54%) meta-analyses as critically low quality. Of the potential biomarkers, none of the 34 meta-analyses were graded as high quality, one of the 34 (3%) meta-analyses was graded as moderate quality, 7 of the 34 (21%) meta-analyses were graded as low quality, and 26 of the 34 (76%) meta-analyses were graded as critically low quality. The methodological quality of most studies was flawed. No study provided complete search strategies, although by and large they appeared to be well developed. However, due to the lack of grey literature search, search registration, and consulting content experts in the field, it is difficult to give a very positive evaluation in the search strategy section.To date, this study is the first comprehensive review in the field of AR to summarize the evidence using state-of-the-art evidence strategies, which comprehensively and systematically collect and re-analyze meta-analyses data on environmental risk factors, protective factors and biomarkers of AR, and stratifying the level of evidence. Only eight factors were graded as high credibility, of which tic disorders (class I), early-life antibiotic use, exposure to indoor dampness, acetaminophen exposure, childhood acid suppressant use and exposure to indoor mold were environmental risk factors (class II), and coronavirus disease 2019 and prolonged breastfeeding (class II) were environmental protection factors.P < 0.0001) [Tic disorder (TD) is the only environmental risk factor that has been graded as convincing evidence in AR. TD is a neuropsychiatric disorder with a clear genetic predisposition that begins in childhood and adolescence . It incl 0.0001) . Althoug 0.0001) , 74–76.  0.0001) –79. Our Early-life antibiotic use is associated with AR and is an environmental risk factor for AR, which provides highly suggestive evidence. This association is noteworthy because antibiotics can prevent and cure many infections when the immune systems of infants and children are not fully developed, and because the cardiovascular and nervous systems of children are not fully developed, inappropriate antibiotic use may have an impact on future health outcomes , 81. RegChildhood acid suppressant use is associated with AR and is an environmental risk factor for AR, which provides highly suggestive evidence. Gastric acid inhibiting drugs are thought to be one of the causes of allergic diseases, and the mechanism may be that the drug reduces gastric acid secretion, which directly leads to intestinal ecological dysregulation and increases the risk of allergy . AlthougExposure to indoor mold and exposure to indoor dampness are associated with AR and are an environmental risk factor for AR, which provides highly suggestive evidence and upgrades to convincing evidence in the subgroup analysis of children. Indoor dampness and mold are important factors in residential indoor environment. On the one hand, it is related to high indoor water vapor content and insufficient ventilation; on the other hand, it is related to unreasonable construction and use of buildings that lead to excessive moisture or excessive water vapor accumulation in building materials, both of which create conditions for the breeding of moisture and mold . StudiesAcetaminophen exposure is associated with AR and is an environmental risk factor for AR, which provides highly suggestive evidence. Acetaminophen , one of the most widely used analgesics, is a classic dose-dependent liver injury drug and the most commonly used antipyretic analgesic drug in the world. Its antipyretic effect is slow and lasting, and it has the advantages of little irritation and few allergic reactions . A multiProlonged breastfeeding is associated with AR and is an environmental protective factor for AR, which provides highly suggestive evidence. Breast milk is considered the ideal food for healthy full-term infants and contains a variety of biologically active substances with nutritional, immune and disease-fighting and growth-promoting metabolic functions; breastfeeding has health benefits for infants, including short-term  and long-term  effects , 102. ThCoronavirus disease 2019 (COVID-19) is associated with AR and is an environmental protective factor for AR, which provides highly suggestive evidence. From the studies , we inclAlthough we have conducted standardized evidence hierarchy on the potential environmental risks, protective factors and biomarkers of AR, there are still some limitations. First, because the included studies were observational, the causality of these associations remains difficult to determine. Second, the diagnosis of AR in some children is based on questionnaires from parents and lacks objective clinical examination and professional diagnosis. Third, confounding factors present in observational studies are difficult to completely rule out, and these participating confounders may confound the final results. Fourth, this study focused only on meta-analyses that had already been published and may have missed associations that were not assessed in other systematic reviews or meta-analyses. Fifth, because of the level of evidence, an environmental factor or biomarker with a strong effect may be underestimated, such as early life food sensitization, since fewer than 1000 studies would be graded as class IV evidence. Finally, the umbrella review inherited most of the study limitations of the included studies. For example, if the latter evaluates the relationship between the study factors and morbidity rather than causation, then the umbrella review can also only evaluate the relationship between the study factors and morbidity but not causation.In this umbrella review, a total of 76 potential environmental risk factors, environmental protection factors and biomarkers for AR were established, forming a complete hierarchy of evidence. Among them, tic disorders (class I), early-life antibiotic use, exposure to indoor dampness, acetaminophen exposure, childhood acid suppressant use to exposure to indoor, coronavirus disease 2019 and prolonged breastfeeding (class II) were rated as high credibility. However, we could not infer causality for these associations, which would require a more rigorous design and high-quality studies to confirm this finding.Supplementary file1 (PDF 6487 KB)Below is the link to the electronic supplementary material.