Therefore, a systematic review and meta-analysis were conducted to comprehensively identify potential correlations.Ambient air pollution has been identified as a primary risk factor for mental disorders. In recent years, the relationship between exposure to ambient nitrogen dioxide (NOI2 over 50%).A literature search in 3 international databases was conducted before December 31, 2022. Relative risk (RR) and corresponding 95% confidence intervals (CI) were calculated to evaluate the strength of the associations. Summary effect sizes were calculated using a random-effects model due to the expected heterogeneity . However, the heterogeneity was high for the summary estimates, reducing the credibility of the evidence. In 2-pollutant models, results for NO2 increased by 0.3%, 0.2% and 2.3%, respectively, after adjusting for PM2.5, PM10 and SO2.A total of ten eligible studies were included in the meta-analysis, including 1,412,860 participants. The pooled analysis found that an increased risk of HAs for schizophrenia was associated with exposure to each increase of 10 μg/m2 exposure significantly increases the risk of hospital admission for schizophrenia. Future studies are required to clarify the potential biological mechanism between schizophrenia and NO2 exposure to provide a more definitive result.This study provides evidence that NO It affects more than 24 million people worldwide and is among the top 15 leading causes of disability in the world.,3 Empirical evidence shows that people with schizophrenia have impaired daily living skills and a higher risk of premature death than the general population. In addition to its impact on individuals, schizophrenia imposes a significant burden on society and the economy. People with schizophrenia, or those at risk of developing it, are more likely to engage in aggressive behavior towards others, potentially leading to violent crimes. Moreover, schizophrenia is one of the most socially and economically costly mental disorders. A comprehensive review of 56 studies indicated that the economic burden of schizophrenia ranged from 0.02% to 1.65% of GDP in different countries. Unfortunately, the prevalence of schizophrenia is on the rise in many countries, such as China and Korea.,8 Many studies suggest that the primary contributors to schizophrenia include genetic, socioeconomic, environmental, and behavioral risk factors.,9 The relationship between air pollution and schizophrenia has recently been highlighted.Schizophrenia is identified as a severe mental disorder characterized by abnormalities in thought and cognition. Exposure to particulate (PM2.5 and PM10) and gaseous pollutants  may trigger systemic and neuroinflammatory responses, possibly leading to psychopathology through altered neurotransmission and neurodegeneration.–13 Therefore, it has been plausibly hypothesized that air pollution exposure may contribute to schizophrenia pathogenesis. Nitrogen dioxide (NO2) is a gaseous air pollutant produced by fossil fuel combustion in transportation. In studies that determine the association between gaseous pollutants and schizophrenia, NO2 has received relatively high attention from researchers, but the results remain controversial. Some studies reported a positive correlation between them,,14 and others found no association.,16 We, therefore, performed a systematic review and meta-analysis of original research articles to further clarify the potential associations between NO2 exposure and schizophrenia.Air pollution represents the most significant environmental health risk globally. According to the World Health Organization, over 90% of the world's population resides in areas where air pollution levels exceed the recommended limits.2 on schizophrenia can be classified into short-term and long-term effects, where the latter relates to cumulative exposure while the former pertains to an individual acute response. This study examines the association between short-term NO2 exposure and schizophrenia, with daily NO2 concentrations serving as the independent variable, and the risk of hospital admission for schizophrenia as the dependent variable. Furthermore, the results from the 2-pollutant models reported in the included studies were analyzed separately to control for the potential impact of other pollutants  on the findings.The effects of NOThe systematic review and meta-analysis have been registered and published in PROSPERO, with the assigned registration number CRD42022378942.In light of the fact that all analyses were conducted on previously published studies, and no patient consent or ethical approval was required.2” OR air pollutants) AND (“schizophrenia” OR “schizophrenics”) AND . The reference lists of eligible studies and other related reviews were also screened to identify additional studies.This study was performed according to the preferred reporting items for systematic review and meta-analysis (PRISMA) statement (see Guidelines Checklist). The literature search of the PubMed, Embase and Web of Science electronic databases was independently conducted by 2 authors to identify any eligible epidemiological studies published up to December 31, 2022. A search strategy was detailed as following terms: (“nitrogen dioxide” OR “NO2 (<30 days); (C) the study provided quantitative effect estimates with 95% CIs (or standard errors) by comparing humans exposed to lower air pollution levels with humans exposed to greater levels; and (O) schizophrenia confirmed by clinical assessment of the International Classification of Diseases (ICD). Studies that did not report the effect of short-term NO2 exposure on the risk of hospital admission for schizophrenia were excluded. Reviews, non-English studies, and animal experiments were also excluded.Based on the predesigned PECO framework, the following eligibility criteria were selected in this study: (P) the study was performed among human participants; (E) the study focused on short-term exposure to NOAfter deduplication, 2 coauthors screened titles and abstracts for eligibility and retrieved the full texts of eligible studies for further assessment. Any disagreements in the process were resolved through group discussions until consensus was reached. The detailed process of eligible study selection is shown in Figure Two coauthors independently extracted the following elements from eligible studies. They entered the data into a predesign Excel spreadsheet, including first-author name, publication year, country of origin, study design, study period, outcome definition, study participants, exposure assessment, adjustment variables, and main results. Any discrepancy was resolved by discussion with a third coauthor. The establishment of this quality assessment scale is based on previous successful experience, in particular the selection of several items from the New Castle Ottawa and Cochrane Risk of Bias Tools. This scale evaluates 3 items: validation of schizophrenia , the quality of NO2 concentration measurements , the quality of the adjustment for confounders . A study with a score of 0 was categorized as “low quality,” and as “high quality” if it achieved a score of 5 (the highest score). All remaining study scores are classified as “medium quality.”The study design of eligible studies included in this analysis included both time-series and case-crossover studies. To the best of our knowledge, there are currently no valid scales to assess the quality of these 2 types of studies. The scale suggested by Mustafic was used to assess their quality. Additionally, the extraction effect estimates per unit increase in NO2 exposure to a 10 μg/m3 increment were standardized prior to formal analysis. When studies reported NO2 concentration in ppb, the data were converted using 1 ppb NO2 = 46/22.4 μg/m3. Afterwards, RR for each study was standardized according to the following formula.To ensure comparability of outcomes across different studies, it was necessary to transform various types of effect sizes into relative risks (RR). As not all studies reported RR values, we converted the outcome of change rate of morbidity by dividing it by 100 and adding 1, thus obtaining the RR value. For regression coefficients, exponential transformation was used to derive the RR.In short-term exposure studies, schizophrenia admission risks with different lag patterns  may be reported. To facilitate pooling across studies, lags were selected according to the following criteria: if only 1 lag estimate was provided, the estimate was selected; or if multiple lags were provided, in order of preference, the lag that researchers focused on or preferentially stated was chosen, the lag that was statistically significant, or the lag with the largest effect estimates.I2 statistics. A P value of Cochran Q <0.1 was considered statistically significant for heterogeneity. The I2 statistic provides quantitative indicators of heterogeneity and inconsistency between studies. According to the experience of previous studies, I2 is equal to 0% to 25%, 25% to 50%, 50% to 75%, and 75% to 100% representing no heterogeneity, mild heterogeneity, severe heterogeneity, and extreme heterogeneity, respectively. Due to the considerable heterogeneity of this study, a random-effects model was chosen to pool effect sizes. A subgroup analysis was then conducted to explain the source of heterogeneity. Publication bias was visually assessed using a funnel plot for asymmetry and Egger test (P < .1 indicated the existence of publication bias). Additionally, the trim-and-fill method was used to test for contributions of publication bias to the overall effect. The meta-analyses were performed using STATA version 13.0 .Standardized RR values and 95% confidence intervals for each eligible study were selected for meta-analysis. Heterogeneity between studies was assessed using Cochran Q and The search strategy identified 517 potentially relevant studies in 3 electronic databases. The full texts of 34 relevant articles were retrieved for further selection after removing duplicates, animal experiments, and reviews. Finally, eleven eligible studies were identified after excluding studies with non-short-term effects and did not report relevant outcomes , 2 in the USA, and 2 in South Korea. Most of these studies were performed in a time-series design (n = 9), and the remaining 2 used a case-crossover design, while the sample size of these studies ranged from 3218 to 649,052. All studies used data from national or regional ambient monitoring sites/centers for exposure measures. Three studies used chemiluminescence methods to measure NO2 concentration. Ten studies reported single-pollutant analysis (NO2) results, and 7 studies reported results from 2-pollutant models (NO2 plus other pollutants). For the diagnosis of schizophrenia, 7 and 3 studies used the ICD-10 and ICD-9 codes, respectively.Table 2 exposure with hospital admissions for schizophrenia. Under the random-effects model, NO2 exposure is significantly associated with an increased hospital admission risk for schizophrenia . In the subgroup analyses , PM10  and SO2 .Figure http://links.lww.com/MD/J691 respectively.All eligible studies were assessed for methodological quality. Six studies were of high quality, and 5 were of intermediate quality due to unadjusted holidays, influenza epidemics, etc. The quality assessment results and details are shown in Table P = .006 <0.1). The trim-and-fill analysis identified 4 missing studies for the analysis, and the adjusted estimate was not substantially changed .Funnel plots and Egger test were applied to assess potential publication bias Fig. . There i2 exposure and the risk of hospital admission for schizophrenia. Each 10 μg/m3 increase in NO2 concentrations is significantly associated with a 2.9% increased risk of hospital admission for schizophrenia. However, the results must be cautiously interpreted due to the high heterogeneity among the studies. By subgroup and trim-and-fill analyses, this correlation is unaffected by publication bias and heterogeneity. In a sense, this study provides synthesized evidence for previously inconsistent conclusions.In the present systematic review and meta-analysis, ten studies from different countries were investigated to examine the correlation between short-term NO2, providing essential evidence for the effects of NO2 exposure on mental disorders and the effect of environmental factors on schizophrenia. The results of the 2-pollutant model also confirm that the association was robust to co-pollutants  adjustment. Similarly, several previous meta-analyses found short-term NO2 exposure to be an independent risk factor for depression among air pollutants.,29 However, another previous meta-analysis reported that NO2 exposure was a protective factor for anxiety disorder. The results of these studies reveal that the effects of NO2 exposure on various mental disorders may differ. There was empirical evidence of the long-term effects of NO2 exposure on individuals developing schizophrenia. Two national cohort studies have demonstrated that higher concentrations of residential NO2 exposure during childhood were associated with an increased risk of later developing schizophrenia.,31 The underlying pathophysiological mechanisms linking environmental pollutant exposure to schizophrenia remain unclear. However, Alan S. Brown et al have proposed the gene-environment interplay hypothesis to elucidate this association. This hypothesis builds upon the premise that genetic factors are the primary cause of schizophrenia and suggests that environmental factors increase an individual risk of developing schizophrenia through intermediate pathways such as oxidative stress, apoptosis, inflammation, and the HPA axis. Potentially, 3 pathways can be considered, gene-environment interactions, genes as antecedents of environmental exposure, and epigenetic effects.This study is the first comprehensive analysis to identify the association between schizophrenia and short-term exposure to NO,34 Secondly, Tongling economy is comprised primarily of copper mining and planting, which means many outdoor employees are exposed to air pollution for extended times, thereby increasing the risk of hospital admissions for schizophrenia. Thirdly, exposure level estimation errors vary due to differences in the density of ambient monitoring stations across studies , which may be an essential source of heterogeneity.High heterogeneity is found among the ten studies included in this meta-analysis. After subgroup analysis, heterogeneity was primarily from the 6 studies within China. Studies in different countries also contributed a lower proportion of heterogeneity. Such heterogeneity is considered from the following perspective. The 6 studies from China (including 9 study cities), reports from Shenzhen (RR = 1.08), Hong Kong (RR = 1.08), and Tongling (RR = 1.12) had higher effect sizes than other cities. Firstly, socioeconomic factors between the different cities may contribute to this difference. In China, Shenzhen and Hong Kong are the main cities experiencing environmental stresses, including higher competitive pressures, more immigration, lower social cohesion and social support, and higher housing values, which have all been associated with developing schizophrenia. compared to 65% to 8.3% in China,37) and severe air pollution due to rapid industrialization. Secondly, although the methodological quality assessment scale employed in this study has been previously used in systematic reviews, its validity has not been scientifically established. Thirdly, publication bias may have resulted in an overestimation of the true effect size, as studies reporting non-significant effects may have remained unpublished. However, the trim-and-fill method did not reverse the initial outcomes. Fourthly, exposure assessment in all included studies was based on data from stationary ambient monitoring stations, which may have led to exposure misclassifications and information bias. Finally, differences in the intensity of air pollution exposure among individuals from different socioeconomic backgrounds within the same region may exist. Most of the included studies did not adjust for these factors, which may have influenced the study results.Several limitations need to be acknowledged in this study. Firstly, data were obtained from only 3 countries, with the majority of studies (7/11) being conducted in China, which may restrict the generalizability of the findings. This limitation may be attributed to local contextual factors and publication bias, where studies with negative results are less likely to be prioritized for publication. It is noteworthy that China has been reported to have a higher prevalence of schizophrenia (2.64% globally,39 Additionally, public health campaigns can raise awareness about the adverse effects of air pollution on mental health, encouraging individuals to take measures to reduce their exposure to pollutants. In terms of healthcare policy, our findings underscore the importance of early detection and treatment of schizophrenia. Policy-makers should prioritize the development of accessible and effective mental health services, including screening programs, early intervention programs, and evidence-based treatment options.This finding has significant policy implications for public health, as it highlights the need for preventive measures and interventions to reduce the incidence of this debilitating mental illness. Policy-makers should consider implementing targeted interventions aimed at reducing air pollution levels in areas with high population density or high levels of industrial activity. These interventions may include stricter regulations on industrial emissions, as well as the promotion of clean technologies and renewable energy sources, such as carbon neutrality policy.2 and HAs for schizophrenia. However, given the limitations identified in the study, further research is necessary, particularly from countries with high levels of ambient air pollution, such as Africa and India, to clarify the plausibility of this association. Moreover, it is recommended that future studies adjust for potential confounding factors, such as holidays, meteorological factors, and flu epidemics, to provide insight that could benefit relevant public and health policies.In summary, this systematic review and meta-analysis suggests an association between short-term exposure to NOConceptualization: Jiating Xu, Zhihua Zhang.Data curation: Zhiyong Lan, Penghao Xu.Formal analysis: Jiating Xu, Zhiyong Lan, Penghao Xu.Methodology: Zhiyong Lan, Penghao Xu, Zhihua Zhang.Visualization: Zhiyong Lan.Writing – original draft: Jiating Xu.Writing – review & editing: Penghao Xu, Zhihua Zhang.


TNF-α gene (rs1800629) is associated with an increased TNF-a production. However, several previous association studies of TNF-α G-308A polymorphism and IgAN rendered contradictory findings. The objective of the present study is to shed light on these inconclusive results and clarify the role of TNF-α and any possible contribution of this factor in the development and progression of sporadic IgAN. Therefore, a meta-analysis of all available genetic association studies relating the TNF-α G-308A polymorphism to the risk for development and/or progression of IgAN was conducted. Seven studies were included in the meta-analysis. Three of them included populations of European descent (Caucasians) and four involved Asians. The generalized odds ratio (ORG) was used to estimate the risk for the development and/or progression of the disease. Overall, the meta-analysis did not detect any significant association between the G-308A variant and both the risk of developing IgAN and the risk for progression of IgAN. In conclusion, these results suggest that TNF-α does not constitute a key component in the genetic architecture of sporadic IgAN. However, further evidence deciphering the influence of TNF-α on IgAN is still needed.Tumor necrosis factor-α (TNF-α) is a potent pro-inflammatory cytokine, involved in the pathogenesis and progression of immunoglobulin A nephropathy (IgAN). A bi-allelic polymorphism in the promoter region, at position -308 (G/A) of the  Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis for which only supportive care is available up to date . It is cFCRL3, DUSP22.IRF4, and PADI4, three HLA polymorphisms and two variants harbored in the MHC region as susceptibility genes of IgAN  (accessed on 24 June 2023).In order to clarify the contribution of The retrieved publications were thoroughly reviewed to evaluate their eligibility. All references of the eligible studies were scrutinized to identify articles not indexed in the aforementioned databases. Abstracts, case reports, editorials, review articles, in vitro studies, as well as family-based studies were excluded. It is important to note that the search included only articles in English. Two investigators (M.T. and I.S.) evaluated the eligibility of the articles, and any disagreements were resolved through consensus.In the association studies, that were eligible for meta-analysis concerning progression of IgA nephropathy, both cases and controls were patients with sporadic IgA nephropathy. Patients with a progressive IgAN were considered as cases (progressors) and those with stable nephropathy as controls (non-progressors). Eligibility was not dependent on a specific prefixed definition of IgAN progression. The definition of progression used in each study was accepted and is presented in The following details were extracted from each study: the primary author, publication year, racial background of the study participants, selection criteria, demographic information, and complete genotype counts. Allele frequencies were calculated from genotype counts.2 metric . Similarly, no significant association was detected in sensitivity analysis in which only studies confronted with HWE were included [ORG = 0.94 (95% CI 0.70–1.26)] ] .2 = 71.92% and 61.83%, respectively) between the studies with a polled ORG of 0.74 (95% CI 0.44–1.26) and 0.85 (95% CI 0.50–1.43), respectively ] (G = 1.19 (95% CI 0.74–1.92)] .The main analysis included five studies and did not detect any significant association between G-308A polymorphism and the risk for progression of sporadic IgAN [OR4–1.73)] . Similar4–1.92)] . Both maG = 1.16 (95% CI 0.61–2.23) and ORG = 0.85 (95% CI 0.37–1.93), respectively  found that G-308A polymorphism was not correlated with disease progression and long-term outcome and did not also correlate with disease activity, except for gross hematuria in Asians, suggesting that TNF-α may not play an important role in disease progression [IL1b2, IL1RN and TNF-α because it was found that the carriage of both IL1b2 and IL1RN*2 together with the non-carriage of TNF-α -308A allele increased the risk of IgAN fivefold [TNF-α G-308A polymorphism was not associated with either the susceptibility or progression of sporadic IgAN, either in the main analysis or in sensitivity and subgroup analyses.On the basis of the available data about gression . In contgression . Howevergression . It is nfivefold . The stufivefold . Anotherfivefold . Anotherfivefold . In addifivefold . Yamamotfivefold . Finallyfivefold  which waThese conflicting results are difficult to interpret. The discrepancy in results could be related to racial differences. More specifically, it is known that the prevalence of IgAN is very high in East Asians, intermediate in European Caucasians and low in Africans . It is aUnfortunately, there is no specific treatment for IgAN to date. Patients with IgAN receive treatment that applies to virtually any glomerular disease . More spThe second category of therapeutic interventions of IgAN involves immunosuppressive agents. According to the KDIGO guidelines, IgAN patients who continue to be at a high risk of disease progression even after receiving optimized supportive care for at least 90 days should contemplate undergoing a six-month regimen of systemic corticosteroid therapy . NeverthIt is noteworthy to mention that many ongoing trials are performed in an effort to develop new therapeutic agents for the treatment of IgAN and new pathogenetic pathways are revealed ,50,51,52G) to estimate the magnitude of the association. This metric overcomes the problem of multiple comparisons of the different genetic models  by utilizing the full genotypic counts and prevents confusion in cases when more than one genetic model is significant. Therefore, the interpretation of the results is straightforward and more robust. In addition, the choice of a specific genetic model a priori is not required. This metric has been used in various studies of other diseases, like diabetic nephropathy [In this study, we used the generalized odds ratio (ORhropathy ,56,57,58In conclusion, the current meta-analysis reviews the latest genetic epidemiology findings regarding the contribution of G-308A polymorphism in the risk of developing IgAN and the progression of IgAN. Since this meta-analysis did not detect any significant association of G-308A polymorphism with risk for the development or progression of IgAN, we conclude that this genetic component does not constitute a key genetic component in the pathogenesis of sporadic IgAN at least alone. However, the results should be interpreted with caution because the number of studies in the meta-analysis is relatively small.


Accumulating observational studies have indicated that vitamin D deficiency (serum 25-hydroxyvitamin D (25OHD) < 50 nmol/L) is common in women with polycystic ovary syndrome (PCOS). However, the direction and causal nature remain unclear. In this study, we aimed to investigate the causal association between PCOS and 25OHD.A bidirectional two-sample Mendelian randomization (MR) study was used to evaluate the causal association between PCOS and 25OHD. From the publicly available European-lineage genome-wide association studies (GWAS) summary statistics for PCOS  and 25OHD , we selected 11 and 102 single nucleotide polymorphisms (SNPs) as instrumental variables (IVs), respectively. In univariate MR (uvMR) analysis, inverse-variance weighted (IVW) method was employed in the primary MR analysis and multiple sensitivity analyses were implemented. Additionally, a multivariable MR (mvMR) design was carried to adjust for obesity and insulin resistance (IR) as well.P = 0.008). However, mvMR found the causal effect disappeared when adjusting the influence of obesity and IR. Both uvMR and mvMR analysis didn’t support the causal effect of 25OHD deficiency on risk of PCOS .UvMR demonstrated that genetically determined PCOS was negatively associated with 25OHD level (IVW Beta: -0.02, Our findings highlighted that the casual effect of PCOS on 25OHD deficiency might be mediated by obesity and IR, and failed to find substantial causal effect of 25OHD deficiency on risk of PCOS. Further observational studies and clinical trials are necessary. Accumulating observational studies have indicated that vitamin D deficiency [serum 25OHD < 50 nmol/L ] is commMendelian randomization (MR) can strengthen inferring causality and give a robust estimation between a risk factor and an outcome of interest . Compare22.1via exposure. In this study, SNPs were employed as IVs to perform bidirectional two-sample MR to explore the causal association between PCOS and 25OHD.The bidirectional two-sample MR study was conducted in the framework shown in 2.22.2.1The GWAS summary statistics of PCOS were obtained from the latest and largest published GWAS meta-analysis, including 4,890 patients with PCOS and 20,405 health controls of European ancestry, and were adjusted for age  Supple, Rotterd2.2.2The GWAS summary statistics of 25OHD were obtained from 417,580 European UK Biobank participants with available serum 25OHD levels , and adj2.3Our MR study was performed using publicly published studies or shared datasets, which had acquired ethical approval and informed consent. No additional ethics statement or consent was required.2.4p < 5 × 10–8, and none of which surpassed the limited value  in linkage disequilibrium (LD) analysis (F statistics (F = Beta2/SE2) (F statistics<10). The proportion of variance of the exposure explained by SNPs was evaluated by R2. R2 of each SNP was calculated by the following formula: 2 × EAF × (1-EAF) × Beta2, and summed them up to calculate the overall R2, where EAF represents the effect allele frequency of the SNP  . Finally the SNP .F statistics of all selected SNPs ranged separately from 30.84 to 57.66 and 30.07 to 1,468.55, demonstrating that all selected SNPs had sufficient validity. Moreover, the total variance explained by the genetic instruments was 6.23% and 2.71%, respectively. The detailed information of all selected SNPs of PCOS and 25OHD was presented in Eventually, 11 SNPs for PCOS and 102 SNPs for 25OHD were separately extracted from the GWAS summary statistics. The 2.5https://gwas.mrcieu.ac.uk/ ), for which details were shown in Fixed-effect inverse-variance weighted (IVW) method was conducted as the primary methods for uvMR estimates . The IVWP < 0.05.MR analyses were performed using the packages “TwoSampleMR”  . All other MR estimates were consistent with the direction of the main IVW estimate (P > 0.05), and no outlier SNPs were observed in the MR-PRESSO analysis. However, there were some SNPs crossing the zero line in leave-one-out sensitivity analysis, which suggested potential heterogeneity (P = 0.710).The results of the uvMR analyses were shown in P > 0.05) (P < 0.001), which was in keeping with previous MR study  and IR (represented by fasting insulin) in mvMR analysis, we found that it was disappeared for the causal relationship between genetically predicted PCOS and 25OHD  with the main method in the opposite direction. There was no evidence suggested the possible causal relationship between genetically predicted 25OHD and PCOS. Leave-one-out sensitivity analysis (P > 0.05). Besides, no outlier SNPs were observed in the MR-PRESSO analysis.As shown in P > 0.05), which was consistent with the results of univariable MR , so did fasting insulin .Adjusting the influence of confounders including obesity and IR in mvMR analysis, we still found no causal relationship between genetically predicted 25OHD and PCOS (4This study explored the relationships between PCOS and 25OHD using a bidirectional two-sample MR design for the first time, which adopted the strong IVs from the largest GWAS of respective phenotypes in European populations. Our study found that genetically predicted PCOS was weakly inversely associated with deficiency of 25OHD. However, the casual association may be unstable and would disappear after correcting the influence of obesity and IR. The effects of PCOS on 25OHD might be accounted for obesity and IR. Meanwhile, our study didn’t support the causal effect of 25OHD on PCOS.Previous observational studies have found that there seems to be a link between PCOS and 25OHD, while the causality is still not yet fully clear. Some studies reported that PCOS was a risk factor for vitamin D insufficiency –30. ReceThe real relationship between PCOS and 25OHD might be interpreted as follows: An increasing body of clinical evidence , 34, 35 Seeing that observational design is susceptible to reverse causality and potential confounders, current results of clinical studies between PCOS and 25OHD may bias the true relationship. For instance, most of the included studies were lack of control of BMI and IR. Obesity and IR have been confirmed to be important pathogenic factors of PCOS  and coulNonetheless, several limitations in our study cannot be ignored. Firstly, the proportion of PCOS cases was relatively low and could bring compromised statistical power, failing to detect true causal relationship. Secondly, we failed to evaluate the causality between different clinical phenotypes of PCOS on 25OHD, due to the lack of GWAS data of PCOS phenotypes. We were not able to further stratify our outcomes and identify the risk of each phenotype, although there was great heterogeneity between different phenotypes of PCOS. Therefore, without further stratification, the causal relationship between PCOS and 25OHD obtained may be mixed and inaccurate. Thirdly, although many methods were used to control and evaluate the pleiotropy, the bias caused by gene pleiotropy could not be completely ruled out. Finally, the participants involved in our study were all from European ancestry. Therefore, it should take care when extending our conclusions to people of other ancestry.5In summary, our results highlighted that the causal effect of PCOS on 25OHD may be mediated by the negative effect of obesity and IR on 25OHD. Future studies with larger MR studies, clinical trials and further observational studies are highly warranted to confirm the results of our present study.The original contributions presented in the study are included in the article/Conception and design: NZ; data curation: HZ and FJ; analysis: SZ and YY; software and visualization: CW and WZ; writing—original draft, review and editing: NZ and YL; funding acquisition: TC and XL. All authors contributed to the article and approved the submitted version.


The recurrence rates after catheter ablation (CA) and direct current (DC) cardioversion remain high, although they have been established treatments of rhythm control of atrial fibrillation (AF). This umbrella review systematically appraises published meta-analyses of both observational and randomized controlled trials (RCTs) for the association of risk and protective factors for arrhythmia recurrence after CA and DC cardioversion of AF.Three bibliographic databases were searched up to June 2021. Evidence of association was rated as convincing, highly suggestive, suggestive, weak, or not significant with respect to observational studies and as high, moderate, low, or very low with respect to RCTs, according to established criteria. Thirty-one meta-analyses were included. Of the 28 associations between CA and the risk of arrhythmia recurrence, none presented convincing evidence, and only the time from diagnosis to ablation over 1 year provided highly suggestive evidence. The association between hypertension and metabolic profile provided suggestive evidence. The associations of Class IC and III antiarrhythmic drugs use with the recurrence after DC cardioversion were supported by an intermediate level of evidence.Although AF is a major health issue, few risk- and protective factors for AF recurrence have been identified. None of these factors examined were supported by convincing evidence, whereas established factors such as female gender and left atrial volume showed only weak association. An early CA strategy combined with treatment of metabolic syndrome and hypertension prior to CA may reduce the risk of arrhythmia recurrence. The use of antiarrhythmics can increase the success rate of DC cardioversion.PROSPERO registry number: CRD42021270613. Our study is the first umbrella review to systematically appraise published meta-analyses of both observational and randomized controlled trials for the association of risk and protective factors for arrhythmia recurrence after catheter ablation (CA) and direct current (DC) cardioversion of atrial fibrillation (AF).Few risk- and protective factors of arrhythmia recurrence after CA and DC cardioversion of AF have been identified.None of the factors examined showed association with AF recurrence supported by convincing evidence.An early CA strategy and management of metabolic syndrome and hypertension prior to CA can reduce the risk of arrhythmia recurrence.The use of antiarrhythmic drugs, mainly amiodarone, flecainide, and propafenone, can increase the success rate of DC cardioversion.1 These numbers are influenced by both unmodifiable factors such as advancing age and modifiable risk factors associated with modern lifestyle such as high body mass index (BMI), physical inactivity, hypertension, obstructive sleep apnoea syndrome (OSAS) and psychosocial stress.2 Atrial fibrillation is associated with an increased risk of death, primarily from heart failure (HF) and stroke.3The prevalence of atrial fibrillation (AF) among adults aged older than 55 years of age in the European Union was estimated at ∼8.8 million in 2010. An increase to around 14 million is forecast by 2060.4Currently, stroke prevention with oral anticoagulation has reduced the risk of death in patients with AF. However, many patients remain symptomatic as well the risk of HF.5 Direct cardioversion terminates AF in over 90% of cases with rare complications.6 Nevertheless, the recurrence rate of AF is high, approximately 50% in the first two weeks and 65% in the first year after cardioversion.7 Consequently, various alternatives such as the ‘wait and see’ approach in patients with recent-onset AF and the use of hybrid treatment, combining DC cardioversion with pre-treatment with antiarrhythmic drugs (AADs) have been proposed.7 Identifying predictors of successful DC cardioversion is crucial. So far, age, functional class of the patients, and eventual prior treatment with AAD have been identified as predictors of successful cardioversion.6Synchronized direct current (DC) cardioversion is an integral part of rhythm control in patients with AF.8 Pulmonary vein isolation (PVI) has been the basis of CA procedures for AF since the pioneering observation of induction of AF by ectopic beats from the pulmonary veins.10 CA has evolved substantially over the past few decades, with several different tools becoming accessible and different approaches being adopted. To date, none of the novel approaches have been proven superior to PVI alone.11 Success rates vary between 50 and 80%, depending on the type of AF .12 The likelihood of successful CA is related to both procedure and patient characteristics.13 Given the moderate success rate of CA in patients with AF, several studies have explored different factors such as gender, AF duration, age, as predictors of recurrence post-CA of AF.14–16 No study has yet collectively summarized, evaluated, and graded the evidence of the clinically applicable research on this topic.Catheter ablation (CA) is an established and safe treatment option for rhythm control in patients with symptomatic AF.18The aim of this paper is to summarize the existing evidence on risk and protective factors associated with the risk of recurrence after CA and DC cardioversion of AF across published meta-analyses through an umbrella review. Following best research practices, the evidence from the available meta-analyses on this topic was ranked based on sample size, the strength of the association, and the presence of various biases.19 reporting guidelines and the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines20 (see Appendix S1 in the Supplement) were used in this study. The study protocol was registered in the PROSPERO database. (CRD42021270613).The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)Appendix S2 in the Supplement). The reference lists of eligible studies were also examined to identify additional studies.Bibliographic databases  were searched up to May 28, 2021, to identify systematic reviews with meta-analysis of observational or randomized controlled trials (RCTs) that examined associations between non-genetic risk or protective factors, with the risk of recurrence after CA or/and DC cardioversion of AF as a primary or secondary endpoint. Our search strategy was broad to identify all eligible studies using terms related to AF and meta-analysis  independently conducted the initial search for relevant articles. The full texts of the retrieved articles were further examined for eligibility by the same researchers. Records of any discrepancies regarding the eligibility for inclusion were reviewed by a third investigator (E.C.), and disagreements were resolved through discussion.21 All reported outcomes for eligible meta-analyses were considered for inclusion.We included only peer-reviewed meta-analyses of RCTs or observational studies with either a cohort, case-control, or nested case-control study design and examined any association between recurrence of AF after CA or DC cardioversion and risk- or protective factors. In the case of multiple meta-analyses evaluating the same risk and/or protective factors, we kept the meta-analysis with the largest number of included studies.Appendix S3 in the Supplement).Meta-analyses were excluded for (i) study designs other than those mentioned above ; (ii) a non-systematic selection of observational studies or RCTs and non-systematic reviews; (iii) examining genetic variants as risk factors for recurrence after CA or DC cardioversion; (iv) studies published in languages other than English; (v) insufficient data for quantitative synthesis were provided; or (vi) they presented study-specific effects estimates other than odds ratio (OR), hazard ratio (HR), or relative risk (RR), i.e. mean difference. Reasons for exclusion after full-text assessment were listed in the supplementary material  independently performed data extraction from each eligible article using a predefined extraction form (EXCEL 365). Any disagreements were resolved through discussion. For each meta-analysis, the collected variables included: first authors’ name, year of publication, journal, standard identifier (DOI), number of primary studies, total sample size, and risk or protective factors assessed. For each primary study, we collected: the first authors´ name, year of publication, study design, sample size (exposure and non-exposure), and relative risk estimates  with the subsequent 95% confidence interval (CI).https://amstar.ca/Amstar-2.php). This tool was designed to assess meta-analyses of both randomized and non-randomized studies and applies criteria within ten original domains. The RoB assessment was performed by two reviewers  and checked by two others .22Risk of bias (RoB) was assessed using the AMSTAR2 tool  per association. A P-value ≤ 0.10 was considered statistically significant for excess significance bias.27 All analyses were performed using Stata 17.0  and R v.4.0.3 .The effect size (ES) of different studies reported in each meta-analysis was extracted for each association. We re-measured the pooled effect sizes and 95% CIs employing random-effects modelsAppendix S4 in the Supplement), consistent with previous umbrella reviews.28Suitable associations from observational studies were categorized into five classes, according to the power of the evidence of possible risk or protective factors: convincing (Class I), highly suggestive (Class II), suggestive (Class III), weak (Class IV), and not significant (NS) , 95% prediction interval (excluding the null or not), presence of large heterogeneity (I² >50%), small study effects (P < 0.10), and excess significance (P < 0.10).29 Additionally, GRADE  levels of evidence (GLE) using a modified concrete set of rules was also employed as previously described.31 Four areas were evaluated: (i) imprecision, by the number of participants in the pooled analysis ; (ii) RoB original study quality, by the proportion of RCTs included in the pooled analysis with low RoB for randomization and observer blinding ; (iii) inconsistency, by heterogeneity ; and (iv) RoB review quality, by the responses to AMSTAR2 questionnaire . Then, reviews were classified as high, moderate, low, or very low according to GLE .Regarding RCTs, the credibility of evidence was categorized according to the summary effect (Appendix S3), and 31 articles were included for analysis. Twenty-six studies evaluated risk and protective factors for recurrence of AF post-CA and reported 28 associations, while six studies assessed risk- and protective factors for AF recurrence after DC cardioversion and reported 25 associations . Background factors of the included studies are presented in Appendix S5 in the supplement.The initial search yielded 4179 publications. After title and abstract assessment, 96 eligible articles were identified. Then 65 articles were excluded after a full-text review (see Table 1 and Appendix S5 in the Supplement). The median number of studies included in the original meta-analyses was six (IQR = 5–10), the median number of patients was 1304 (IQR = 639–3806), and the median number of incidences of recurrence was 454 (IQR = 291–932).The quality score of the meta-analyses of observational studies on risk and protective factors for recurrence of AF post-CA, following AMSTAR2, was low and critically low in 14 studies, moderate in six and high in six (P ≤ 0.05) under the random-effects models, and four of these (15%) achieved a P-value <10−6. Sixteen associations (62%) had more than 1000 cases per association. Thirteen associations (50%) showed considerable heterogeneity (I2 > 50%), and 24 of 26 associations had a 95% prediction interval that excluded the null value. In 17 associations (65%), the ES of the largest study had a nominally statistically significant effect (P ≤ 0.05). Finally, small-study effects were found in seven associations (27%), and excess significance bias was found in eleven associations (42%).In the meta-analyses of observational studies, 21 of the 26 associations examined (73%) had a nominally statistically significant effect (Table 1). The remaining 16 (76%) statistically significant associations between risk or protective factors and recurrence after CA of AF presented weak evidence (Table 1), while five associations were not significant (Table 1). Interestingly, when the criterion of associations with more than 1000 cases per study was excluded, three associations upgraded from low to highly suggestive level of evidence  and five more from a low to suggestive level of evidence, including high BMI and P-wave duration. (Table 1).When the credibility of evidence was assessed, no association presented convincing evidence. Only one association provided highly suggestive evidence (diagnosis of AF to ablation time), and two suggestive (hypertension and metabolic syndrome) (Table 2). The association between short-term AADs and late recurrence after CA of AF was non-significant, whereas the association between short-term antiarrhythmic use with the short time recurrence presented moderate GLE. No signs of heterogeneity or small study effects were found (Table 2).Only one meta-analysis of RCTs with two associations concerning protective factors of recurrence post-CA of AF was found. The analysis evaluated short-term AADs prior to CA of AF and the early and late recurrence risk. The quality of this meta-analysis was high according to AMSTAR2. It included six studies with 2655 participants (Table 1 and Appendix S5 in the Supplement). The median number of studies included in the meta-analyses was nine, with a median of 682 participants and 347 recurrences. All associations were statistically significant, with no evidence of heterogeneity (I2 < 30%). In one of three associations, the ES of the largest study had no statistically significant effect, and there was evidence of small-study effects. The prediction interval did not exclude the null value in two of three associations and there were signs of excess significance. All associations presented a low level of evidence. When the restriction of 1000 cases per association was withdrawn, the association of high-sensitive CRP (hs-CRP) with the risk of recurrence after DC cardioversion was upgraded to a highly suggestive level of evidence, and one of the statins and the CHA2DS2-VASc score were also suggestive (Table 1).Overall, only three meta-analyses of observational studies on risk and protective factors of recurrence after DC cardioversion were found. All of them were of low quality according to the AMSTAR2 scoring system (Table 2 and Appendix S5) The median number of studies included in meta-analyses of RCTs was 5.5 (IQR = 2.75–11.5), the median number of participants was 1430 (IQR = 730–2787), and the median number of cases was 1006 (IQR = 434–1388). Overall, 6 of 23 reported associations were non-significant (P < 0.05). Thirteen associations presented high heterogeneity (I2 > 50%), four showed small study effects, and three showed excess significance bias. When the RCT credibility criteria were applied, 14 associations between protective factors and recurrence of AF after CA of AF presented moderate GLE and one low. GLE (Table 2). These associations included using different AADs and RAAS blockers as protective factors against AF recurrence after DC cardioversion (Table 2).We found three meta-analyses of RCTs using 23 associations between protective factors and recurrence after DC cardioversion. The quality of the included meta-analyses according to the AMSTAR2 score was high in 20 meta-analyses of RCTs and low in only three.  or were not statistically significant. These risk factors need to be re-evaluated by larger cohort studies and should not currently be considered to select patients with AF for CA.15 Previous studies have shown that the longer the AF persists, the more significant the risk of progressive atrial structural and electrical remodelling, and the higher the risk of unsuccessful CA.32 Implementing an early rhythm control therapy in patients with AF, either with AADs or CA, results in a reduced risk of adverse cardiovascular outcomes, including death from a cardiovascular cause.33The most important protective factor for AF recurrence after CA was the short duration (<1 year) between the time of AF diagnosis and AF ablation .34 Metabolic syndrome is defined as a combination of central obesity, hypertension, dyslipidemia, and glucose intolerance.35 The mechanism behind recurrence after CA and metabolic syndrome is not precise. However, metabolic syndrome has been associated with atrial conduction disturbances of conduction and refractoriness between the right and left atria,37 whereas obesity is associated with a shortened effective refractory period in the pulmonary veins.38 Furthermore, the use of CPAP in patients with OSAS, appears to protect them from AF recurrences after CA . However, the level of evidence for this association was low due to the small number of of identified cases, which is why more extensive studies are required.Other modifiable risk factors for AF recurrence after CA identified in the study were metabolic syndrome, obesity, and hypertension.P = 1.8 × 10−20) risk factor for AF recurrence after CA , supported by suggestive evidence.39 The mechanism of this association is unclear; however, it has been suggested that depression may be associated with chronic inflammation and can increase sympathetic activity, both factors that can mediate atrial modelling in patients with AF.41Depression was a highly significant (P = 4.3 × 10−11) and was supported by highly suggestive evidence when the criterium of >1000 cases per association was not considered. Thus, larger studies are needed to confirm this association. Other factors, such as the use of adenosine to unveil reconnections in pulmonary veins after CA, proved to be non-significant. Regarding the risk of recurrence after DC cardioversion of AF, meta-analyses of RCTs showed that the use of AADs were significant protective factors supported by a moderate level of evidence. Several AADs, mainly belonging to pharmacologic classes IC and III, proved to maintain sinus rhythm after electrical cardioversion of AF. Depending on the drug, the recurrence of AF was reduced by 30 to 80% compared with controls. However, the success rate of DC cardioversion remained low, around 30% for the whole population.43 The level of evidence for these associations was moderate, mainly due to the high risk of bias of the original studies. This issue can be explained by the fact that most of the RCTs included in the original meta-analyses were implemented >10 years ago. The use of other drug categories such as b-blockers and omega-3 fatty acids also failed to achieve significance level.Regarding procedural related predictors of recurrence of AF after CA ablation, non-inducibility of AF with burst-pacing was highly significant (3 CA is proposed as a safe and superior treatment option compared with AADs for rhythm control in patients with AF. However, it is pointed out that a more objective method of patient selection is needed. This umbrella review of meta-analyses is the first to provide data on the associations of various risk and protective factors with the risk of recurrence after CA of AF. The results of the study indicate the lack of associations with convincing evidence. Thus, no causality between meta-analyzed risk or protective factors and recurrence after CA or DC cardioversion can be reported. Larger cohort studies and RCTs are needed to improve the evidence base. The study also indicates that waiting time before implementing CA, obesity, and suffering from hypertension and metabolic syndrome or depression increase the risk of AF recurrence after CA. The use of burst pacing to check AF inducibility after CA can be considered. Finally, in patients undergoing DC cardioversion of AF, use AADs such as amiodarone and flecainide can decrease the risk of recurrence.In the current guidelines,This umbrella review has several limitations. Initially, only meta-analyzed associations or meta-analyses with sufficient data were included. Therefore, other key factors might not have been considered, as they have not been evaluated in published meta-analyses. Second, the results from the primary analyses may have been affected by various unidentified covariates. Third, potentially meaningful subgroup analyses for different age groups, gender, and type of AF were not addressed. Finally, the grading system used can only provide indications of systematic biases but no proof of their nature and extent.This study reviewed and evaluated the literature of the epidemiological evidence for factors associated with recurrence of AF after CA and DC cardioversion. Although AF is a significant health issue, few risk and protective factors for AF recurrences have been identified, none of which supported by convincing evidence. An early CA strategy appears to reduce the risk of recurrence. Addressing comorbidities such as obesity, depression, metabolic syndrome, and hypertension prior to CA can increase the success of the intervention. The use of AADs, mainly amiodarone, flecainide, and propafenone, may increase the success rate of DC cardioversion. This study suggests that the factors with borderline significance and low level of evidence need to be analyzed further to achieve genuine associations. Further investigation of new predictors for successful CA procedures and DC cardioversions is needed.Europace online.euac143_Supplementary_DataClick here for additional data file.


AA = −0.577, p < 0.01; rω-6 LCPUFA = −0.626, p < 0.001). Moreover, Mendelian randomization analyses revealed that genetically predicted AA and gamma-linolenic acid (GLA) were protective factors against schizophrenia . In addition, no significant relationships were observed between schizophrenia and docosahexaenoic acid (DHA) or other ω-3 PUFAs. These findings show that the deficiencies of ω-6 LCPUFAs, especially AA, are associated with schizophrenia risk, which sheds novel insight into the etiology of schizophrenia and a promising diet supplementation for the prevention and treatment of schizophrenia.Polyunsaturated fatty acids (PUFAs), especially long-chain PUFAs (LCPUFAs), are crucial for both the structural and functional integrity of cells. PUFAs have been reported to be insufficient in schizophrenia, and the resulting cell membrane impairments have been hypothesized as an etiological mechanism. However, the impact of PUFA deficiencies on the onset of schizophrenia remain uncertain. We investigated the associations between PUFAs consumption and schizophrenia incidence rates through correlational analyses and conducted Mendelian randomization analyses to reveal the causal effects. Using dietary PUFA consumption and national schizophrenia incidence rates in 24 countries, we found that incidence rates of schizophrenia were inversely correlated with arachidonic acid (AA) and ω-6 LCPUFA consumption (r Schizophrenia is a complex psychotic disorder characterized by a bundle of neuropsychiatric manifestations, including cognitive impairment, apathy and social withdrawal . The onsAn especially important nutrient group for the course of brain development is polyunsaturated fatty acids (PUFAs). PUFAs are essential fatty acids that are mainly obtained from the diet. The dietary intake of PUFAs varies widely due to geographic and cultural differences across countries . LinoleiOur study aims to investigate the associations between PUFAs and schizophrenia risk. Correlations between PUFA dietary consumption and national incidence rates of schizophrenia are evaluated from an epidemiological perspective, and Mendelian randomization (MR) analysis is conducted to address the causative relationships and evade residual confounding. We specifically hypothesize that lower LCPUFAs would be associated with an increased schizophrenia risk.Our study consists of cross-national correlation analysis and MR analysis. A schematic diagram of our study design is shown as below .The incidence rates of schizophrenia were obtained from published epidemiological studies. We included studies published between January 1975 and December 2021, which were identified through the search terms (incidence (Title/Abstract) AND schizophrenia (Title/Abstract)) applied in MEDLINE, PsychINFO and EMBASE, as well as the literature referred to in systematic reviews . As the Dietary consumption data of PUFAs were obtained from the Food and Agriculture Organization of the United Nations and the Australian Food Composition Database . The method of calculations followed the methodological process of establishing a global database of nutrients . BrieflyA twenty-year lag interval was introduced to evaluate the causative relationships between PUFA intake in early life and schizophrenia risks in consideration of an adequate time span for the onset of psychiatric symptoms. Since PUFA consumption is correlated with economic development, we used the GDP per capita to account for the socioeconomic differences, paralleling previous studies ,20,21,22In the cross-national association study, seventeen individual PUFAs and four summary PUFA groups were included for analyses. The analysis involved simple Pearson’s product moment correlation and partial correlation analyses adjusting for economic factors. These statistical procedures were conducted in SPSS 20.To investigate the potential causal associations between PUFAs and schizophrenia, we applied a two-sample MR approach by using summary data from genome-wide association studies (GWASs). Ethical approval was obtained in all original studies.We obtained published association results for genetic instruments of ω-6  and ω-3 http://pgc.unc.edu, accessed on 28 January 2021).We obtained the summary statistics data on genetic associations for schizophrenia from Psychiatry Genomics Consortium (PGC) . To mitip < 5 × 10−8). Bias in effect estimates of MR analysis can be induced by correlation between SNPs. In order to minimize this bias, our genetic instruments used in each PUFA were limited to independent SNPs without linkage disequilibrium (R2 < 0.1). We calculated F statistics to assess the strength of each instrument. If F > 10, there is sufficient strength to avoid weak instrument bias in the MR analysis. The F statistics were computed by the formula F = (N-k-1) × R2/(1 − R2), in which R2 = 2 × MAF × (1 − MAF) × β2. N and k refer to the sample size and numbers of the instrument separately. All SNPs used in univariable MR analysis satisfied the MR criteria (F-statistic > 10) [In this MR analysis, four ω-6 PUFAs  and four ω-3 PUFAs  were included. All included SNPs were significantly associated with PUFA levels at the genome-wide significance level (ic > 10) . In addiic > 10) .p < 0.05 as statistical significance criteria to classify SNPs as potentially influential. Two-sample MR analysis was implemented by using the “MendelianRandomization” package in R 4.0.We harmonized the summary-level data to ensure that the allele for each SNP corresponded between each PUFA and schizophrenia. In the main analysis, we used the fixed-effects inverse-variance-weighted (IVW) method to assess the causal effects between exposure and outcome. The odds ratio (OR) of schizophrenia was calculated per 1 SD increment in genetically predicted plasma fatty acid levels. We applied We also conducted two-sample multivariable MR analysis to simultaneously estimate the direct effect of ω-3 and ω-6 PUFAs on schizophrenia in consideration of their nexus in metabolism. Considering the tight relationships between ω-3 and ω-6 PUFAs of sharing the same metabolic enzymes, multivariable MR analysis focused on estimating LA (18:2 ω-6) and ALA (18:3 ω-3) effects in comparison to each other, as well as AA (C20:4 ω-6) and EPA (C20:5 ω-3) effects in comparison to each other. Links regarding other PUFAs in equivalent positions in the synthesis pathway were not evaluated due to the lack of GWAS summary data from the same GAWS study. A total of eight SNPs related to ω-3 and ω-6 PUFAs were extracted from the CHARGE consortium. The final instrument set contained 5 SNPs due to linkage disequilibrium clumping. The schizophrenia outcome data were previously described. Multivariable MR was conducted using the R package “Mendelian Randomization”. The F-statistic was calculated to assess instrument strength, which was performed using the “MVMR” package.We also considered potential biological and socioeconomic confounders that may affect the associations between PUFAs and schizophrenia risk. We explored the effect of some potential confounders such as C-reactive protein (CRP), educational attainment, and vitamin D levels ,32,33. AInitially, 41 potentially related papers were collected based on the strict inclusion criteria described above to obtain national incidence rates of schizophrenia ,76,77,78Eating habits vary across different countries and cultures, leading to a global difference in the major dietary PUFA categories and a wide range of PUFA intake. The NUTTAB included 17 dietary PUFAs, and the scales of the dietary PUFAs differed by two orders of magnitude; on average, LA accounted for 88.3% of the total PUFA intake, whereas adrenic acid  accounted for only 0.08%. AA and DHA were the major individual LCPUFAs among most countries . PUFA coAA = −0.577, p < 0.01)  A. Moreov < 0.01) B. Given ω-6 LCPUFA = −0.626, p < 0.001)  C, wherea< 0.001) D. In add< 0.001) .Taken together, these results suggest that the high intake of ω-6 LCPUFAs, especially AA, would decrease the risk of schizophrenia onset.AA = 0.986, p = 0.030; ORGLA = 0.148, p = 0.004), whereas ω-3 LCPUFAs showed only protective tendencies without statistical significance   A. Single= 0.072) B,C.FADS1 and rs16966952 in NTAN1/PDXDC1. These genes are strongly connected with fatty acid metabolism. FADS1 is involved in the desaturation of LA and ALA, contributing to the biosynthesis of LCPUFAs such as AA and DHA. PDXDC1 expression level appeared to be changed in mice fed with a high-fat diet.These associations were driven by the SNP rs174547 in 2 < 0.1), which implied that CRP is not genetically related to AA , whereas no statistically significant evidence was found with EPA    . Given t= 0.002) .Overall, the MR analyses indicate that AA and GLA are protective factors against schizophrenia. Consistent with our cross-national correlation results, insufficient AA may be a potential causal factor leading to the onset of schizophrenia.In this study, we aimed to investigate the relationships between PUFAs and schizophrenia risk using epidemiological methodology and Mendelian randomization analysis. Our results showed that ω-6 LCPUFAs, especially AA, are potential protective factors against schizophrenia. A higher intake of AA and ω-6 LCPUFAs, according to measures of food consumption, was significantly correlated with a lower incidence rate of schizophrenia across countries. Consistently, a genetically predicted low level of AA was revealed to increase schizophrenia risk by the MR analysis. In contrast, ω-3 LCPUFAs, including DHA and EPA, showed only a slight tendency to be protective against schizophrenia risk, which was an effect without statistical significance.FADS1 gene in LCPUFA synthesis, was reported to influence IQ performance, illustrating the crucial effects of PUFAs on early brain development [N-terminal asparagine amidase that is related to social behavior and memory [Both ω-3 and ω-6 LCPUFAs are rich in seafood and animal food. Previous studies have focused on the correlational relationships between the prevalence of affective disorders and seafood consumption ,84 and felopment . NTAN1 id memory . The resAlthough both ω-6 and ω-3 LCPUFAs are critical in brain function and development, our results show that ω-6 LCPUFAs, but not ω-3 LCPUFAs, function as protective factors against developing schizophrenia. Our findings provide supportive evidence for the hypothesis that the onset of schizophrenia might be determined by insufficient AA, a major ω-6 LCPUFA in the brain; this is released for the production of its eicosanoid metabolites to support adequate signal transduction , and wheLpiat1−/− mice, a model of AA deficiency in phosphatidylinositol synthesis, died within a month after birth and showed atrophy of the cerebral cortex and hippocampus [AA deficiency impairs normal brain function  and contpocampus . M. Maekpocampus . Meanwhipocampus  found thpocampus ,10 and apocampus ,92,93. Apocampus . These fIn contrast to AA and ω-6 LCPUFAs, we found that ω-3 LCPUFAs were not significantly related to schizophrenia risk. Several cross-national studies reported strong relationships between fish consumption and mood disorder ,84,94, wIn conclusion, our findings, combining the results of diet-dependent epidemiological analyses and gene-dependent MR analyses, show that AA and ω-6 LCPUFAs are protective factors against schizophrenia risk. These results imply diet enrichment might help prevent the onset of schizophrenia. Studies on AA supplementation for individuals with ultra-high risk for psychosis would help further characterize the nature of the AA and schizophrenia associations.


Observational studies have linked hyperuricemia with venous thromboembolism (VTE). We aimed to investigate whether there are causal relationships between uric acid levels and VTE and its subtypes, including deep venous thrombosis (DVT) of the lower extremities and pulmonary embolism (PE).p < 5 × 10−8) with uric acid from the CKDGen consortium and UK biobank, respectively. Genetic associations with the risk of VTE, DVT, and PE were obtained from the FinnGen biobank. We used the inverse-variance weighted method as the preliminary estimate. Additionally, we employed MR-Egger, weighted median, and Mendelian randomization pleiotropy residual sum and outlier method as complementary assessments. Sensitivity analyses were performed to test for pleiotropic bias.We utilized Mendelian randomization (MR) analysis to estimate the causal association in European individuals. We extracted two sets of polygenic instruments strongly associated (The genetically instrumented serum uric acid levels had no causal effects on VTE, DVT, and PE. Two sets of polygenic instruments used for exposure, along with three complementary MR methods, also yielded no significant association.Our MR analysis provided no compelling evidence for a causal relationship of serum uric acid with the risk of VTE. This suggests that uric acid-lowering therapies in patients with hyperuricemia may not be effective in reducing the likelihood of developing VTE.The online version contains supplementary material available at 10.1186/s13075-023-03115-6. Venous thromboembolism (VTE) is a chronic condition that manifests as either deep vein thrombosis (DVT) or pulmonary embolism (PE), depending on the location of the clot . With anUric acid (UA), the end product of purine breakdown, has been shown to modulate the interplay between compromised endothelial function, inflammatory response, and thrombogenicity . Most obMendelian randomization (MR) is a valuable statistical technique that employs genetic variants as instrumental variables (IVs) to establish causal relationships between risk factors (exposure) and diseases (outcome). MR is particularly useful when randomized controlled trials (RCTs) are infeasible or unethical . In the MR utilizes single-nucleotide polymorphisms (SNPs) as IVs, which should satisfy the three core assumptions . First, https://gwas.mrcieu.ac.uk/datasets (ID: ukb-d-30880_irnt).Summary data for UA were obtained from the Chronic Kidney Disease Genetics (CKDGen) consortium, which conducted the most recent genome-wide association study (GWAS) of urate levels in 288,649 European participants . To valihttps://r8.finngen.fi/) , DVT , and PE . Despite significant pleiotropy and heterogeneity being identified by MR-Egger regression and Cochran’s Q test , suggesting the associations between UA and VTE observed in epidemiological studies may not indicate causality.Additional file 1:Supplementary Table 1. Genetic variants used in the MR analyses. Supplementary Table 2. SNPs associated with VTE risk factors . Supplementary Table 3. MR Analysis after adjusting for potential VTE risk factors. Supplementary Table 4. Pleiotropy tests of urate instrumental variables after adjusting for potential VTE risk factors in GWAS for VTE and its subtypes.Additional file 2:Supplementary Figure 1. The plots of “leave-one-out” analysis method to show the influence of individual SNP on the causal effect of genetically predicted uric acid (CKDGen consortium) on venous thromboembolism. Supplementary Figure 2. The plots of “leave-one-out” analysis method to show the influence of individual SNP on the causal effect of genetically predicted uric acid (UKB) on venous thromboembolism. Supplementary Figure 3. The plots of “leave-one-out” analysis method to show the influence of individual SNP on the causal effect of genetically predicted uric acid (CKDGen consortium) on deep venous thrombosis. Supplementary Figure 4. The plots of “leave-one-out” analysis method to show the influence of individual SNP on the causal effect of genetically predicted uric acid (UKB) on deep venous thrombosis. Supplementary Figure 5. The plots of “leave-one-out” analysis method to show the influence of individual SNP on the causal effect of genetically predicted uric acid (CKDGen consortium) on pulmonary embolism. Supplementary Figure 6. The plots of “leave-one-out” analysis method to show the influence of individual SNP on the causal effect of genetically predicted uric acid (UKB) on pulmonary embolism.


Many studies have investigated the etiology of acute leukemia, one of the most common types of cancer in children; however, there is a lack of clarity regarding preventable risk factors. This systematic review and meta-analysis aimed to summarize the current evidence regarding the role of maternal dietary factors in the development of childhood leukemia. All epidemiological studies published until July 2022 that evaluated maternal dietary risk factors for childhood acute leukemia were identified in two electronic databases (PubMed and Web of Science) without limits of publication year or language. A total of 38 studies  were included. The published risk estimates were combined into a meta-analysis, using the Generic Inverse Variance method. The maternal consumption of fruits (two or more daily servings vs. less) was inversely associated with acute lymphoblastic leukemia , whereas maternal coffee intake (higher than two cups per day vs. no consumption) was associated with an increased risk of acute lymphoblastic leukemia . Despite these findings, more high-quality research from cohort studies and the identification of causal factors are needed to develop evidence-based and cost-effective prevention strategies applicable at the population level. Review Registration: PROSPERO registration no. CRD42019128937. Acute leukemia is one of the most frequently diagnosed cancers among children and adolescents. Its worldwide incidence is approximately 46 cases per million per year in children aged 0–14 years and approximately 29 cases per million in adolescents aged 15–19 years [The etiology of childhood acute leukemia is linked to X-ray radiation exposure, specific forms of chemotherapy and some genetic syndromes . HoweverConsidering the differential incidence of acute leukemia by geographic region worldwide, the potential roles of lifestyle and environmental factors in its etiology have been proposed . A peak The current systematic review and meta-analysis focused on the role of maternal diet in the risk of childhood acute leukemia. It provides an overview of existing data linking the influence of maternal diet, supplementation and the consumption of non-alcoholic beverages to the development of acute leukemia in children. We used combined evidence to assess the potential impact of maternal diet on the risk of childhood acute leukemia. The main outcome of our systematic review is acute leukemia (AL) incidence in children aged 0–14 years and adolescents aged 15–19 years. The leukemia types considered included acute lymphoblastic leukemia (ALL) and acute non-lymphoblastic leukemia (ANLL), mainly acute myeloid leukemia (AML). The exposures included maternal dietary and non-alcoholic drink intake and supplements consumed during the peri-pregnancy period.Details of the protocol for this systematic review were registered on PROSPERO, registration number CRD42019128937. To identify the maternal dietary factors that have been studied in relation to childhood leukemia risk, we performed a multi-tiered electronic search of PubMed and Web of Science. First, an explorative search for studies on leukemia in infants, children and adolescents was conducted in December 2017; this was not restricted by language or publication date. A total of 66 studies were identified in this search. Based on the results of this first search, we were able to narrow down the keywords further and perform a more targeted search in July 2022, which focused on some identified maternal exposures such as dietary intake (food groups and micronutrients), consumption of non-alcoholic beverages  and supplements used during pregnancy, and no limit of publication year or language restriction was used. For all constructs, database-specific thesauri were used to identify the relevant synonyms. The search strategy is illustrated in Studies were eligible for inclusion if they reported effect estimates (relative risk (RR), odds ratio (OR) or hazard ratio (HR) and 95% confidence intervals (CI)) or if they provided sufficient data to calculate the estimates for different levels of exposure. Subsequently, quality control of the selected articles was performed using the checklist by Fowkes et al. to ensure the inclusion of high-quality studies . This chA quantitative analysis of the risk of AL, ALL, or AML in children was performed to determine the risk factors that met the eligibility criteria for the meta-analysis. For each included factor, the choice of performing an additional quantitative analysis was based on the number (at least two studies) and homogeneity of the included studies  and overlapping study data were also excluded. We used the adjusted odds ratio (OR) reported in case-control studies and the relative risk (RR) reported in cohort studies to calculate the overall effect. The analyses were conducted using the Generic Inverse Variance method, in which the weight of each study was equivalent to the inverse of the variance of the effect estimate . A randoThe results of the search strategy and process of selecting studies for review are illustrated in The quality assessment  for the Seven case-control studies ,15,16,17Two studies reported results for AL, one focused on cured meats but their results did not achieve statistical significance  and the Regarding ALL, three consecutive studies ,14,17 coA statistically significant increased risk for AML was reported in one case-control study related to the intake of certain fresh vegetables  , and anoA.CoffeeTwo pooled studies ,19, eighA cohort study  (N = 141p = 0.005) was reported. A meta-analysis of five studies [In a pooled study  of eight studies ,22,23,24Another pooled study  of eightB.TeaTwo pooled analyses ,19 and fOverall, the case control studies ,22,23,24C.Soft drinksThree case-control studies ,16,22 evFour case-control studies ,14,28,29Twenty case-control studies ,43,44,45Folic acid supplementation and the risk of AL have been widely studied ,42,43,45Supplementation with iron during pregnancy and the risk of childhood leukemia in offspring have also been studied ,39,43,45Supplementation with multivitamins during pregnancy has been reported ,42,43,44The main findings of the systematic review suggest that maternal dietary intake rich in vegetables, fruits and protein sources (beans and beef) and supplementation with folic acid and multivitamins during pregnancy could have a protective effect against childhood acute leukemia. The increased intake of cured meats, coffee and/or caffeinated beverages could increase the risk of childhood acute leukemia. Some of these findings were confirmed by our meta-analysis; a higher maternal consumption of fruits was significantly inversely associated with ALL . This association was recently found in a previous meta-analysis  in whichOur meta-analysis also confirmed that regular maternal coffee intake higher than two cups per day was associated with an increased risk of ALL . Similarly, in a meta-analysis published in 2014  maternalRegarding maternal tea consumption during pregnancy, our analysis did not find a statistically significant association. These findings are consistent with those of a previous meta-analysis .Regarding soft drink intake during pregnancy, the analysis suggested a possible increased risk for AL, but this finding was not significant. A previous meta-analysis  reportedFolic acid supplementation during pregnancy suggested a modest inverse association with ALL . A recent systematic review reported that the use of maternal folic acid supplementation before pregnancy was associated with a 30% decreased risk of ALL  and the use of vitamin supplements before pregnancy was associated with a 20% decreased risk of ALL  .The inverse association between maternal fruit and vegetable intake and the risk of AL could be explained mainly by the high content of protective bioactive components such as micronutrients and fiber. Some fruits and vegetables that were found to be protective in some studies ,14 are rSome studies suggest the association between the maternal intake of cured meats and the risk of childhood AL. This is because of the presence of N-nitroso precursors in these meats that can be converted to carcinogenic components  by acidsThe decreased risk of ALL associated with the maternal use of vitamin formulations as supplements can be explained by the capacities of the components, including folate and iron, to protect against oxidative damage to lipids, lipoproteins and DNA . On the The increased risk of AL associated with the maternal consumption of coffee and other caffeinated drinks could potentially be explained by the effects of their components (caffeine and chlorogenic acid) in inhibiting Topoisomerase I and Topoisomerase II ,62, whicThe present systematic review and meta-analysis integrated the available published information regarding maternal dietary intake and the risk of childhood AL. Unfortunately, most of the evidence comes from case-control studies  that were conducted more than a decade ago and restricted to high-income countries. It is also important to note that the accurate evaluation of dietary intake is challenging. We also noticed that some studies restricted their search to specific food items  and, givHowever, there are new generation studies  that can support some of these findings. Studies have been conducted to assess the presence of carcinogens  in the maternal diet, which can be found in the placenta, linked to fetal hemoglobin, and can also be found in newborn lymphocytes. Since these biomarkers were also found in healthy children, further studies focusing on genetic variants found some polymorphisms that could affect the expression of enzymes such as folate hydrolase 1. With lower detoxifying activity, DNA damage or the higher activity of carcinogens may occur .Regardless of the limitations of these studies, professionals dedicated to treating childhood cancer have demonstrated a great capacity to collaborate and collect high-quality data and biospecimens. This could lead to improvements in the quantity and quality of future research, for more prospective cohort studies and a more comprehensive and accurate assessment of the role of nutrition in carcinogenesis are needed.This systematic review of the available literature indicates that a maternal diet rich in vegetables, fruits and supplementation with folic acid and multivitamins during pregnancy could be inversely associated with the risk of childhood AL, while a higher intake of coffee and/or caffeinated beverages could increase the risk. Only the results regarding maternal diet rich in fruits and the consumption of coffee in relation with childhood AL were confirmed by the meta-analysis performed on the available published data. Although this review sheds light on the risk factors related to maternal diets and the prevention of cancers in children and adolescents, more studies are needed to confirm causality and the potential mechanisms involved.


Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate’s role in CRC.Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk.We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants  across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia .P-interaction < 5×10-8) of folic acid supplement and variants in the 3p25.2 locus  were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype  but increased CRC risk among those carrying the TA genotype , suggesting a qualitative interaction (P-interaction = 1.4×10-8). No interactions were observed for dietary and total folate.Inverse associations of dietary, total folate, and folic acid supplement with CRC were found  for users compared with nonusers, respectively). Interactions (Variation in 3p25.2 locus may modify the association of folate supplement with CRC risk. Experimental studies and studies incorporating other relevant omics data are warranted to validate this finding. Colorectal cancer (CRC) represents a major public health concern, being the third most common cancer worldwide with nearly 2 million incident cases and the second cause of cancer death in 2020 . Human dUntil recently, more than 200 common genetic variants have been identified in genome-wide association studies (GWASs) of CRC risk, with a total contribution of common variants to the familial risk estimated to be nearly 20% . InvestiGene-by-folate interaction may explain some of the observed inconsistencies and can add biological insights on the role of folate in colorectal carcinogenesis. We therefore performed a genome-wide interaction analysis to identify SNPs that may modify the effects of dietary and total folate and folic acid supplementation on CRC risk. Moreover, by pooling data from 51 studies in the largest sample available to date, we provide the most robust estimate on the marginal associations of folate with CRC risk.We included data from a total of 30,550 cases and 42,336 controls from 51 studies contributing to 3 consortia—the multicentered Colon Cancer Family Registry (CCFR), the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), and the Colorectal Transdisciplinary Study (CORECT) . Control2) and scaled to reflect a 5 kg/m2 increment. Smoking history was defined as never- and ever-smoking.Interviews and/or structured questionnaires were used to obtain information on demographics and environmental risk factors. A multistep data harmonization procedure was carried out at the GECCO coordinating center (Fred Hutchinson Cancer Research Center), reconciling each study’s unique protocols and data collection instruments as described previously . DietaryParticipant characteristics by disease status, for all the different exposures are presented in P value < 1×10-4), and discordant genotype calls within duplicate samples. Genotypes were imputed to the Haplotype Reference Consortium (HRC version r1.1) using the University of Michigan Imputation Server , MTHFR, 5-methyltetrahydrofolate-homocysteine methyltransferase reductase [MTRR], and thymidylate synthetase [TYMS] genes), with no adjustment for multiple comparisons [ADA) in relation to risk of advanced colorectal adenoma [P: 2.37x10-5) and remained statistically significant after a permutation-based adjustment for multiple comparisons [DNMT3A) (locus 2p23.3) with plasma folate, and DNMT1 (locus 19p13.2) with red blood cell folate  [MTHFR, for which an interaction with folate has been suggested [To our knowledge, this is the first study to investigate gene-by-folate interactions on a genome-wide scale. Previous studies were small and most included a few hundred cases, and they focused their investigation on a limited number of genetic loci, typically in the FOCM pathway . These sparisons ,24,26. A adenoma . The assparisons . Another locus 2p.3 with puggested . We failuggested ,28.Among the strengths of our study is the large sample size and the comprehensive analyses for overall CRC and subtypes. Furthermore, novel, sophisticated statistical methods were used to investigate interactions with common variants, which limits the multiple-comparison burden. In addition, strict quality-control protocols were applied from data collection to analysis, including harmonization of the folate exposure data, to minimize potential sources of bias. We acknowledge that measurement error in the self-reported exposure assessments may have occurred. Additionally, because most of the primary studies in our analysis did not have follow-up measurements, we used a single measurement of folate intake  at the reference time for all primary studies; this misses changes that may have occurred over the life course of participants and past exposures . Another limitation is that our analysis is based exclusively on European ancestry populations, which limits the generalizability of the results. No interactions reached statistical significance for dietary and total folate intake, which could be partly attributed to the fact that other exposure variables  or genetic loci  may act as additional effect modifiers and to bioavailability differences of the synthetic folic acid compared with natural folate. Folic acid is often found in multivitamins, and we cannot rule out the possibility that the interaction could be due to some other nutrient in multivitamins or a behavior related to multivitamin use. Exploratory analyses to investigate the above hypotheses would be underpowered  and hence were not included in the present study.The findings of our study suggest that genetic variation in the region of 3p25.2 might modify the association of folate with CRC risk. Experimental studies and studies incorporating other relevant omics data are warranted to validate this finding.Supplementary Acknowledgments &Funding.We are grateful to all the participants who have been part of the project and to the many members of the study teams. For more details, see The authors’ responsibilities were as follows—UP, WJG, LH, KKT: designed research; AEK, YL, JM, EB: analyzed the data; EB, KKT wrote the manuscript; AEK, YL, JM, MD, DA, ELB, JWB, SIB, SAB, TDB, HB, AB, ABH, PTC, RCT, GC, TWC, ATC, JCC, DVC, MC, MD, VDO, ND, DAD, JCF, GGG, SBG, MJG, TAH, AH, MH, JRH, ADJ, ESK, TOK, AK, LLM, JPL, LL, BML, BM, SM, VM, NM, PAN, MOS, JO, JRP, NP, BP, AJP, ARP, EAP, JDP, LQ, CQ, GR, ERN, LCS, SLS, AS, MCS, YRS, CMT, DCT, YT, CYU, FvD, BvG, KV, JW, EW, AW, MOW: reviewed and edited the manuscript; KKT, UP, WJG, LH: had primary responsibility for final content; and all authors: read and approved the final manuscript.The authors report no conflicts of interest.Wereld Kanker Onderzoek Fonds (WKOF) and by World Cancer Research Fund International . Mengmeng Du was funded by P30 CA008748. For more details about the funding of consortia and participating studies, see Supplementary Acknowledgments &Funding.Konstantinos K Tsilidis was funded by Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization.The authors assume full responsibility for all analyses and interpretation of results. The views expressed here are those of the authors and do not necessarily represent the American Cancer Society or the American Cancer Society – Cancer Action Network.Data described in the manuscript, code book, and analytic code will be made available upon request pending application and approval to the GECCO consortium.