MicroRNA-423 (miR-423) rs6505162 polymorphism is found to be associated with breast cancer (BC) risk. However, the results were inconsistent. This study meta-analyzed the literature on possible association between rs6505162 polymorphism and BC risk.  PubMed, Embase, Google Scholar, and the Chinese National Knowledge Infrastructure (CNKI) databases were systematically searched to identify relevant studies. Meta-analyses were performed to examine the association between rs6505162 polymorphism and BC. P=0.85; recessive model, OR 0.99, 95% CI 0.72–1.38, P=0.97; dominant model, OR 0.93, 95% CI 0.72–1.21, P=0.60; homozygous model, OR 1.04, 95% CI 0.66–1.65, P=0.87; and heterozygous model, OR 1.07, 95% CI 0.90–1.28, P=0.45. Similar results were obtained in subgroup analyses of Asian, Chinese, and Caucasian patients.  None of the five genetic models suggested a significant association between rs6505162 polymorphism and BC risk: allelic model, OR 1.02, 95% CI 0.18–1.28,  The available evidence suggests no significant association between rs6505162 polymorphism and BC risk. These conclusions should be verified in large, well-designed studies. Breast cancer (BC) continues to disrupt the lives of millions of women. For many years, BC has consistently ranked among the top cancers in the women, both in terms of incidence and mortality . As we amiR-423 is located in frequently amplified region of chromosome 17q11.2 and can produce two mature sequences: miR-423-3p and miR-423-5p . Recent As some new studies published, we conducted this meta-analysis of all relevant literatures to provide comprehensive and reliable insights. To the best of our knowledge, this is the first meta-analysis especially concerning rs6505162 polymorphism and BC risk, and it has the largest sample at present, compared with those published ones.microRNA-423; miR-423; rs6505162; these three terms in combination with polymorphism, polymorphisms, SNP, variant, variants, variation, genotype, genetic, or mutation; and all of the above terms in combination with breast cancer, mammary cancer, or mammary adenocarcinoma. Reference lists in identified articles and reviews were also searched manually to identify additional eligible studies.All clinical and experimental case-control studies of polymorphisms in the miR-423 gene and BC published through May 15, 2021, were identified through systematic searches in PubMed, Embase, Google Scholar, and the Chinese National Knowledge Infrastructure (CNKI) databases, without language restrictions. The search terms used were: To be included in our review and meta-analysis, studies had to (1) have a case-control design for assessing the association between rs6505162 polymorphism and BC risk; (2) be accessible as a full-text article and report sufficient data for estimating odds ratios (ORs) with 95% confidence intervals (CIs); (3) report genotype frequencies; and (4) involve humans rather than animal models.P value for Hardy–Weinberg equilibrium (HWE) in controls, control source, sample size, matched parameters, and numbers and genotypes of cases and controls. Discrepancies were resolved by consensus. Only those studies that met the predetermined inclusion criteria were included.Two authors (ZL and LJD) independently extracted the following data from included studies: first author's family name, year of publication, ethnicity, testing methods, NOS score, To assess the quality of the studies included in this analysis, the Newcastle–Ottawa Scale was applied independently by two assessors (ZL and LJD)  Table 1Table 1. Z test, with P < 0.05 defined as the significance threshold. Meta-analysis was conducted using a fixed-effect model when P > 0.10 for the Q test, indicating lack of heterogeneity among studies; otherwise, a random-effect model was used. All these statistical tests were performed using Review Manager 5.3 (Cochrane Collaboration).Unadjusted odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association between rs6505162 polymorphism and BC risk based on genotype frequencies in cases and controls. The significance of pooled ORs was determined using the P < 0.05 considered statistically significant.Publication bias was assessed using Begg's funnel plots and Egger's weighted regression in Stata 12.0 , with P > 0.05) in all but one study [In the end, 12 studies , 17–27 wne study . The oveP=0.85 (P=0.97 (P=0.60 (P=0.87 (P=0.45 (The meta-analysis of a possible association between rs6505162 polymorphism and BC risk is summarized in P=0.85 ; recessi (P=0.97 ; dominan (P=0.60 ; homozyg (P=0.87 ; and het (P=0.45 .P=0.56; recessive model, OR = 1.10, 95% CI = 0.75–1.61, P=0.64; dominant model, OR = 0.81, 95% CI = 0.63–1.03, P=0.09; homozygous model, OR = 1.20, 95% CI = 0.69–2.08, P=0.52; and heterozygous model, OR = 1.20, 95% CI = 0.92–1.56, P=0.18.Next we meta-analyzed data for subgroups based on ethnicity. Meta-analysis of 9 studies –27 involP=0.13; recessive model, OR = 1.13, 95% CI = 0.95–1.35, P=0.18; dominant model, OR = 0.81, 95% CI = 0.54–1.22, P=0.32; homozygous model, OR = 1.29, 95% CI = 0.85–1.95, P=0.24; and heterozygous model, OR = 1.15, 95% CI = 0.75–1.76, P=0.53.Similarly, no evidence of an association was identified in meta-analysis of 4 studies –22 involP=0.51; recessive model, OR = 0.75, 95% CI = 0.38–1.48, P=0.41; dominant model, OR = 1.11, 95% CI = 0.74–1.66, P=0.63; homozygous model, OR = 0.75, 95% CI = 0.33–1.70, P=0.49; and heterozygous model, OR = 0.98, 95% CI = 0.77–1.24, P=0.84.Also, no evidence of an association was identified in meta-analysis of 3 studies , 17, 18 P=0.78; recessive model, OR = 1.06, 95% CI = 0.66–1.71, P=0.81; dominant model, OR = 1.00, 95% CI = 0.77–1.30, P=0.99; homozygous model, OR = 1.08, 95% CI = 0.52–2.27, P=0.83; and heterozygous model, OR = 0.95, 95% CI = 0.72–1.26, P=0.73.Lastly, no evidence of an association was identified in meta-analysis of 5 studies –21, 27 iP value associated with HWE was less than 0.05. Deleting these data from the meta-analysis did not alter the results obtained using any of the five genetic models, whether for the entire study population or the Asian population.The robustness of the meta-analysis of 12 studies examining a possible association between rs6505162 polymorphism and BC risk was assessed by repeating the meta-analysis after excluding a study  in whichP values for Begg's funnel plots and Egger's tests were all greater than 0.05. These results suggest no potential publication bias.Potential publication bias in this meta-analysis was assessed using Begg's funnel plot and Egger's test. In any of the five genetic models, respectively, no obvious asymmetry was observed in Begg's funnel plots Figures  and EggeIn order to investigate the relationship between rs6505162 polymorphism and BC risk, a few recent meta-analyses , 28–30 hThose previous meta-analyses did not specially focus on BC, much less on BC by subgroup analysis by ethnicity. In order to evaluate available evidence on the possible association between rs6505162 polymorphism in miR-423 promoter and BC risk, a more detailed meta-analysis was performed. Results showed that miR-423 rs6505162 might not be associated with BC risk, regardless of ethnicity. Even though our results supported previous studies , 29, givP value for HWE in one study [Although null results were obtained in the current study on rs6505162 polymorphism with larger sample, we really hope they would provide a reference for future studies. Nonetheless, the work still has several limitations that may affect interpretation of the results. Firstly, the ne study  was lessne study –21, 27 oIn conclusion, this study performed an extensive assessment based on a larger sample size than the previous pooled analysis and suggested no significant association between miR-423 rs6505162 polymorphism and BC risk. These conclusions should be verified in large, well-designed studies.


Migraine is a complex neurological disorder that is considered the most common disabling brain disorder affecting 14 % of people worldwide. The present study sought to infer potential causal relationships between self-reported migraine and other complex traits, using genetic data and a hypothesis-free approach.We leveraged available summary statistics from genome-wide association studies (GWAS) of 1,504 phenotypes and self-reported migraine and inferred pair-wise causal relationships using the latent causal variable (LCV) method.ever feeling unenthusiastic / disinterested for a whole week, a phenotype related to the psychological well-being of individuals, was a potential outcome of migraine.We identify 18 potential causal relationships between self-reported migraine and other complex traits. Hypertension and blood clot formations were causally associated with an increased migraine risk, possibly through vasoconstriction and platelet clumping. We observed that sources of abdominal pain and discomfort might influence a higher risk for migraine. Moreover, occupational and environmental factors such as working with paints, thinner or glues, and being exposed to diesel exhaust were causally associated with higher migraine risk. Psychiatric-related phenotypes, including stressful life events, increased migraine risk. In contrast, Overall, our results suggest a potential vascular component to migraine, highlighting the role of vasoconstriction and platelet clumping. Stressful life events and occupational variables potentially influence a higher migraine risk. Additionally, a migraine could impact the psychological well-being of individuals. Our findings provide novel testable hypotheses for future studies that may inform the design of new interventions to prevent or reduce migraine risk and recurrence.The online version contains supplementary material available at 10.1186/s10194-021-01284-w. Migraine is a complex neurological disorder characterised by intense, debilitating headaches on one side of the head, and it is often accompanied by nausea, vomiting, numbness, and sensitivity to light and sound. Migraine is the most common disabling brain disorder, affecting 14 % of the population .A migraine episode is commonly composed of three stages , 3, 6, 7Migraine is a heritable trait, with heritability estimated between 30 and 60 % . Genome-As an alternative to Mendelian randomisation, the latent causal variable method (LCV) was developed to provide an opportunity to investigate potential causal associations with a different approach see  10]. Ad. Ad10]. N = 1,504) of GWAS summary statistics to conduct a hypothesis-free phenome-wide screening of traits causally associated with migraine using the latent causal variable (LCV) method. Our results generate testable hypotheses for future studies and provide novel insights into the relationship between migraine and overall health.Despite extensive efforts to understand migraine’s aetiology, there is still a growing need to generate investigation lines that can successfully incorporate results and hypotheses from genetic studies of migraine into clinical practice. That could enable the identification of disease-modifying traits and pinpoint the underlying causes of this complex neurological disorder. Here, we conduct a multi-trait analysis of GWAS with samples for self-reported migraine in the 23andMe cohort and chronic headaches in the UK Biobank. Then, we leverage an extensive collection  of the UK Biobank participants included in the analysis were considered cases for chronic headaches.p-value < 1 × 10− 5). After quality control exclusions, a total of 11,172,285 single nucleotide polymorphisms (SNPs) remained in the analysis. Subject data were excluded if their genotype-derived principal components 1 and 2 were further than six standard deviations away from 1000 Genomes European sample population. Sex, age, genotyping array, and the top 10 principal components derived from genetic data were used as covariates for the association analysis. After quality control, a total of up to 441,088 individuals remained in the GWAS.Chronic headache was defined using the item “Have you had headaches for more than three months?” (Field-ID: 3799), which could be answered with “Yes”, “No”, “Do not know”, or “Prefer not to answer”. Individuals that selected “Yes” were defined as cases, whereas those who selected “No” for headaches for more than three months were defined as controls. GWAS was performed using REGENIE (v1.0.6.2), a method that implements a logistic mixed-effects model. This approach models genetic relationships between individuals as a random effect to account for cryptic relatedness. Quality control consisted of excluding variants with minor allele frequency (MAF) < 0.005, imputation quality < 0.6 and those deviating from Hardy–Weinberg equilibrium (G=0.83 s.e.=0.05). Because the current study’s scope is migraine, we focused on the output specific to migraine, which had > 35 genome-wide significant loci.Given that chronic headaches and self-reported migraine represent highly related but not the same trait, we performed a multi-trait analysis of GWAS (MTAG) analysis . This aphttps://genoma.io/) [www.nealelab.is/uk-biobank/) [The Complex Traits Genomics Virtual Lab   has madeiobank/) , and theiobank/) , 19. Foriobank/) .A genetic correlation indicates the extent to which genetic effect sizes at common genetic variants are shared between two different phenotypes , 20. We https://github.com/lukejoconnor/LCV). Further, to ensure consistency of alleles and variants across GWAS summary statistics, data was formatted using munge_sumstats.py, which is available by the LD-score software and extracted hapmap SNPs using the provided list of SNPs (w_hm3.snplist) (https://github.com/bulik/ldsc/wiki). In the present study, we uploaded GWAS summary statistics for migraine onto CTG-VL. Then, we performed the phenome-wide analysis pipeline to estimate genetic correlations and GCP estimates with LD-score regression and LCV, respectively. Finally, we used causal architecture plots to illustrate our results. A detailed and illustrated description of this approach is available in previous studies [We estimated the genetic causal proportion (GCP) between migraine and 1,504 other phenotypes using the phenome-wide analysis pipeline in the CTG-VL as described in previous studies –14 to as studies , 13.Regarding correction for multiple comparisons, we applied the LCV method to estimate the GCP for all phenotypes with evidence of a genetic correlation with self-reported migraine at Benjamini-Hochberg’s False Discovery Rate (FDR < 5 %). Then, FDR < 5 % was used to account for multiple comparisons and identify those traits that had evidence of a potential causal relationship based on their GCP.L, assumed to be the causal constituent mediating the genetic correlation between both traits, to estimate the genetic causality proportion (GCP) [LCV leverages GWAS summary statistics to estimate a genetic correlation and relies on a latent variable on (GCP) , 13, 21.on (GCP) , 12, 13.on (GCP) . MultiplWe identified 510 significant genetic correlations of which 17 were found to be potential causal associations with self-reported migraine , ventral hernia , and benign neoplasm of colon, rectum, anus and anal canal   such as 0 such asParacetamol . In contrast, a higher self-reported migraine risk is influenced by traits involving the use of various medications such as, Clopidogrel, which is an antiplatelet drug, and Felodipine commonly prescribed for hypertension   and pulmonary embolism  appear to increase self-reported migraine risk, as do some phenotypes diagnosed by a doctor, including a blood clot in leg  and stroke  , whilst ever feeling unenthusiastic / disinterested for a whole week  was a putative migraine consequence.For psychiatric-related phenotypes, self-reported migraine was a potential outcome of stressful life events such as worked with paint, thinner or glues  and being at a workplace that had a lot of diesel exhaust  potentially increase self-reported migraine risk  has been associated with a higher risk for chronic diseases , 40. Fordeath of a close relative in the last two years, which is considered a major stressful life event that can lead to depression or anxiety [ever feeling unenthusiastic / disinterested for a whole week was identified as a putative consequence of self-reported migraine. Thus, our results show that stressful life events can be a risk factor for migraine, while migraine holds an impact on the psychological well-being of individuals, which in turn suggests that identifying psychological vulnerabilities among migraineurs is of great importance.The relationship between migraine and emotional distress has been described before; however, it has not been fully elucidated. For instance, several studies point out that migraine is associated with psychiatric disorders such as depression and anxiety , 47, whi anxiety , was potWe note that statistical methods used in genetic epidemiology such as LCV and Mendelian randomisation test the potential causal effect of the genetic liability for a disease on the outcome . MigrainWe highlight the importance of triangulating results from multiple study designs, of which at least one should be an interventional study . However, interventional studies can be expensive, time-consuming, or unethical to perform. Therefore, identifying potential causal associations using statistical methods in genetic epidemiology could be the best option available. We suggest that the inferred causal relationships identified through LCV analyses should be testable hypotheses for future observational and genetic studies.Important limitations of this study must be acknowledged. For instance, given that previous studies have highlighted racial and ethnic differences in migraine , and ourG=0.83 s.e.=0.05).It is fundamental to consider potential biases in the design of the GWAS involved. Although the self-reported migraine sample used in the present study has been previously included in a large migraine meta-analysis, comprising ~ 52 % of the cases which allowed the identification of ~ 40 independent loci associated with migraine , we noteFelodipine, a proxy for hypertension, which could be indicative of a putative causal association between hypertension and secondary-type headache.Future studies should aim to assess whether the potential causal associations identified in the present study could be specific to a particular type of migraine and if they can be observed for secondary type headaches. As previous studies have noted , we suggWe provide evidence for potential causal relationships between self-reported migraine and 1,504 different phenotypes. Our findings uncovered changes in blood vessels, particularly vasoconstriction and platelet clumping, potentially increasing migraine risk. Further, we show the putative influence of workplace environments increasing migraine risk and reveal emotional stress as a risk factor for migraine. Also, we reveal migraine’s potential impact on the psychological well-being of individuals. In addition, we raise the possibility of abdominal pain influencing a higher migraine risk. Altogether, our results confirm some causal associations contemplated in previous studies and point out testable hypotheses that, if confirmed, may open novel avenues in the understanding of migraine, which in turn can provide opportunities to improve the design of emerging treatments and drug targets.Additional file 1: Supplementary File 1. LCV output for migraine.


APOE polymorphism and MI, and to provide evidence for the etiology of MI.Myocardial infarction (MI) remains the leading cause of death and disability among cardiovascular diseases worldwide. Studies show that elevated low-density lipid protein cholesterol (LDL-C) levels confer the highest absolute risk of MI, and Apolipoprotein E (ApoE) is implicated in regulating levels of triglycerides (TGs), cholesterol, and LDL-C. Our study aimed to evaluate the association between Case–control studies on the association between APOE polymorphisms and the risk of myocardial infarction were included by searching PubMed, Web of Science, and CNKI, and this meta-analysis was written in accordance with PRISMA guideline statement. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using either random-effects or fixed-effects models by R software.ApoE epsilon 2 and epsilon 4 alleles. The results showed that patients with MI had a low frequency of the ε2 allele  and a high frequency of the ε4 allele .A total of 33 eligible articles involving 13,706 cases and 14,817 controls were finally selected. The pooled analysis based on the total eligible articles showed that the risk of MI was associated with APOE ε2-involved genotypes may be protective factors for MI; in contrast, ε4-involved genotypes  may be risk factors for MI.The online version contains supplementary material available at 10.1186/s12872-022-02566-0. Myocardial infarction (MI) remains the leading cause of death and disability among cardiovascular diseases worldwide . Blood lEpidemiological findings show that the impact of myocardial infarction on global health is significant, with more than one-third of deaths in developed countries . Today, The study showed that, regardless of age, more women than men died within one year of the first acute myocardial infarction (AMI) (26% of women and 19% of men respectively) and more women than men died within 5 years of the first AMI (47% of women and 36% of men). At 5 and 10 years after AMI, women had a higher unadjusted mortality rate compared to men and had a 30% readmission rate within 30 days of the first hospitalization, partly due to differences in age, MI risk factors, clinical presentation, and treatment. Women also have a higher prevalence of heart failure and diabetes mellitus (DM) compared to men. A meta-APOE has two single nucleotide polymorphisms (SNPs) (rs7412 and rs429358). The two SNPs are used to define the three major alleles of APOE . Allele ε3 possesses cytosines in the amino-acid-coding positions corresponding to rs7412 and rs429358, conferring APOE3 with arginine at residue 158 and cysteine on residue 112 . Apart from methods that Qi et al. used [53], we adopted TSA additionally. Simple sizes reached RIS, and Z-curves crossed the trial sequential monitoring boundaries, documenting that the association of the genotype ε2/ε2 with MI risks is robust  may be implicated in MI as risk factors. Luc et al. conducted their meta-analysis based on a multicenter population-based case–control study [Both the meta-analysis of Luc  and our ol study . Populatol study , 29, 40.ε4/ε4 had no significant association with MI risks [ε2 allele and ε2-involved genotype (ε2/ε2 and ε2/ε3) had no significant association with MI risks [APOE ε2 allele and with genotypes  is weaker in Asian than that in other ethnicities. Furthermore, we performed sensitivity analyses and TSA to obtain a reliable conclusion.Wang et al. observed the genotype MI risks . In addiMI risks , 40. BecMI risks , 31, 40.APOE polymorphism and MI risks, rather than a causal relationship. Third, we did not retrieve other confounding factors, such as the low-density lipoprotein receptor gene, lifestyle, and gene–gene or gene-environment interactions, because the articles included in this meta-analysis did not provide any information about the other confounding factors.Our study has some limitations. First, despite subgroup analyses and regression, the main sources of heterogeneity remain difficult to identify. Second, our study focused on articles based on case–control design, merely providing the associations between APOE polymorphism and MI risks. Second, the result of sensitivity analysis documented that our conclusions are stable and reliable. Third, in contrast to previous meta-analyses on the association between APOE gene polymorphism and MI risks, this is the first study to use TSA to further build reliable evidence to draw conclusions.Despite the limitations above, our study has some strengths. First, up-to-date articles were collected extensively, conferring our study more statistical power to draw valid conclusions on the associations between ε2 allele and ε2-involved genotypes, as protective factors, have been implicated in MI. However, the ε4 allele and ε4-involved genotypes  may perform as risk factors for MI.In conclusion, the Additional file 1. Figure S1. Funnel plot of the association between APOE gene polymorphism and myocardial infarction. (A) ε2 allele; (B) ε4 allele; (C) ε2/ε2 genotype; (D) ε2/ε3 genotype; (E) ε2/ε4 genotype; (F) ε3/ε4 genotype; (G)ε4/ε4 genotype.Additional file 2. Figure S2. Trial sequential analysis of the association between ApoE gene polymorphism and myocardial infarction. (A) ε2 allele; (B) ε2/ε2 genotype; (C) ε2/ε3 genotype.Additional file 3. Figure S3. Trial sequential analysis of the association between ApoE gene polymorphism and myocardial infarction. (A) ε4 allele; (B) ε3/ε4 genotype; (C) ε4/ε4 genotype.Additional file 4. Figure S4. Trial sequential analysis of the association between ε2/ε4 genotype and myocardial infarction.


The relationship between 100% fruit juice (100%FJ) consumption and cardiovascular risk is object of debate: indeed, recently published investigations provided new but discrepant evidence on this important question and International dietary guidelines are not in agreement on recommendations about fruit juice consumption. Therefore, we performed a meta-analysis of the prospective studies and the randomised controlled trials (RCTs) that explored the relationship between 100%FJ intake, cardiovascular risk profile and risk of cardiovascular events.We performed a systematic search of publications up to August 2019. Summary relative risks and exploration of linearity of the association were estimated for prospective studies and summary mean differences (MDs) calculated for RCTs.p for non-linearity < 0.05). No significant association was found for coronary heart disease and diabetes risk. In RCTs, a favorable and significant effect of 100%FJ intake was detected on blood pressure , arterial compliance  and endothelial function . Neutral effects were found on body weight, blood lipids and glucose metabolism.A total of 21 prospective studies and 35 RCTs met the inclusion criteria. Dose–response analysis detected a significant inverse association between low-moderate 100%FJ consumption and risk of stroke (up to 200 ml/day) or total CV events (up to 170 ml/day) compared with no consumption, with a non-linear relationship .The online version of this article (10.1007/s00394-020-02426-7) contains supplementary material, which is available to authorized users. The pivotal role of fresh fruits and vegetables in a healthy diet is universally acknowledged and increased consumption of these foods is recommended by all the international guidelines for prevention of cardiovascular (CV) disease , 2. On tThe aim of the present study was thus to perform a comprehensive systematic review and subsequent meta-analysis of the prospective studies and the randomised controlled trials (RCTs) that explored the relationship between 100%FJ intake, CV risk profile and risk of CV events, aiming at clarifying the shape and strength of the dose–response relationship for these associations, if at all possible. As for prospective investigations the majority did not specify the type of fruit drink consumed by participants, we performed separate analyses of the few studies dealing with 100%FJ only but for completeness we also added an analysis including all the other studies available.This meta-analysis was planned, conducted and reported according to the PRISMA statement . The stuThe data selection was conducted and reported in accordance with the PRISMA statement  by L.D.,To be included in the meta-analysis a published study had to meet the following criteria, stratified by study design:Prospective studies (a) Original articles, (b) studies with a prospective design, (c) studies involving the adult population, (d) studies involving the assessment of 100% fruit juice (100%FJ) [(100%FJ)  or of unIntervention studies (a) Original articles, (b) randomized controlled trials (RCTs), (c) studies involving the adult population, (d) studies in which there is an indication of the difference in outcomes—among which CV risk factors  or CV damage —between the intake of 100% FJ [ 100% FJ  and of cThe risk of bias of the studies included in the meta-analyses was assessed according to established criteria : the NewThe quality of the entire body of evidence was evaluated using the GRADE  methodology . EvidencQ-test.Meta-analysis on the prospective evaluation: the assessment of linear and non-linear association between 100%FJ or unspecified fruit drink consumption and outcomes was carried out. The possibility of non-linear relationship was explored by modelling 100% FJ or unspecified fruit drink consumption using restricted cubic splines with three knots at fixed percentiles  of 100% FJ distribution. Departure from linearity was assessed by testing the null hypothesis that the coefficient of the second spline was equal to zero. A two-stage dose–response random-effects meta-analysis was performed , 30, whin < 10), sensitivity, publication bias, sub-group and meta-regression analysis were not performed.Due to the small number of studies included in the prospective evaluation —and standard errors (SEs)—of the defined outcomes were extracted from the selected publications. The pooled weighted MD and 95% CI were estimated using a random-effect model. If these were not available, MD and SE were calculated from the comparison of the outcomes of 100% FJ and control drink intake . The infn < 10).Subgroup and meta-regression analyses were used to identify associations between risk of cardiovascular risk factors and relevant study characteristics as possible sources of heterogeneity: total participants, age, gender, BMI, country, year of publication, length of intervention, underlying disease status, baseline value of the outcome and variables potentially involved, serving size, type of 100% FJ, study design, comparator, level of feeding control, energy intake, energy difference between intervention and comparator, domains of risk of bias, and assessment methods for arterial stiffness. The additional analyses were not performed if there was a small number of cohorts for single outcome exploration .Of a total of 16,762 publications retrieved, 21 prospective studies (8 reporting 100%FJ and 13 unspecified fruit drinks) , 32–45  . On the other hand, a not significant effect of higher levels of reported 100%FJ intake over 170 ml per day was apparent compared with no 100% FJ consumption.The analysis of the two studies that investigated the consumption of 100%FJ and total CV events , 14 . A level of consumption up to 200 ml per day was significantly associated with lower risk of stroke compared with no consumption, with lowest risk at 100%FJ consumption of 78 ml per day  . By contrast, there was no significant effect of higher levels of reported 100%FJ intake, above 200 ml per day, compared with no 100%FJ consumption.Two studies were available for the analysis of 100%FJ intake and risk of stroke , 14 (ovep for non-linearity = 0.01). Fruit drinks intake was significantly and inversely associated with risk of stroke at moderate consumption . The analysis did not detect significant heterogeneity (p = 0.88).Separate analysis of the studies with unspecified fruit drink intake , 12 (ovep for non-linearity = 0.15) . A further study evaluated CHD risk for 100%FJ intake, but there were no data available for dose–response analysis [The analysis of the two studies that investigated the association between 100%FJ intake and CHD , 14   and no evidence of heterogeneity among studies (p = 0.83). Other two studies not specifying the type of fruit drink consumed analysed the risk of CHD [Separate dose–response analysis of the studies with unspecified fruit drink intake , 34  . Separate analysis with available data on the relationship between citrus 100%FJ intake and diabetes risk [p for non-linearity = 0.11; heterogeneity, p = 0.40) .The dose–response analysis of the five studies , 44, 45 83) Fig. , withoutp for non-linearity < 0.001) . There was significant heterogeneity among studies (p = 0.02).By contrast, additional analysis of the studies with unspecified fruit drink intake –41, 43 . Only one study provided multiple groups including different categories of patients [patients . Six stuThe quality of the association between 100%FJ intake and arterial stiffness was downgraded from high to moderate level because of heterogeneity among studies. However, the quality level achieved the high GRADE score when the evaluation was performed on only carotid-femoral PWV results.The meta-analysis of the effects of 100%FJ intake on brachial BP included 25 studies , 80, 81 Additional analyses Only the study design was a significant source of heterogeneity for the effect on diastolic BP. Of note, sub-group analysis stratified by type of 100%FJ consumed found that pomegranate juice significantly improved BP .Pooled analysis of the effect of 100%FJ intake on body weight changes showed no significant association for all the specific outcomes considered: weight, BMI, and waist circumference , 75–80 . For allAdditional analyses No study characteristics affected the relationship between 100%FJ intake and body weight changes by meta-regression and subgroup analysis .The analyses of the effect of 100%FJ intake on the lipid metabolic profile did not detect any significant association for total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides , 80, 81 Additional analyses Age and features of the participants, design of the studies, type of comparator used, characteristics of 100%FJ, and diet during the studies were significant sources of heterogeneity on changes of HDL-cholesterol .Pooled analysis of the effect of 100%FJ intake on glucose metabolism showed no significant association for all the outcomes considered: serum glucose, HOMA index, serum insulin, and glycated haemoglobin , 74–81 . Analysis of the features that may affect changes in HOMA index detected only the type and the energy content of the comparator as significant sources of heterogeneity .In the pooled analysis of six RCTs , 75, 81 p = 0.04). In addition, the analysis did not detect heterogeneity among studies .Separate analysis including only the studies using the carotid-femoral PWV changes  , 75, 81 Pooled analysis of four RCTs , 61, 75 Our meta-analysis indicated that 100% FJ consumption is not associated with increased CV risk. Prospective data support a non-linear dose–response association between 100% FJ consumption and the rate of incident stroke and total CV disease, with evidence of a statistically significant beneficial effect at low-moderate intake (~ 80 ml/day). There was no significant association between 100% FJ consumption and risk of CHD or diabetes. The results of the RCTs support a beneficial effect on CV risk due to the favourable impact of 100% FJ intake on BP levels, arterial compliance and endothelial function. A neutral effect was detected on body weight, lipid profile and glucose metabolism. The results were supported by the GRADE categorization that detected high quality of the results for RCTs and moderate quality for prospective studies.The results on CV risk were strengthened by no evidence of heterogeneity among studies. While, in general, our results are consistent with the trend found by a previous systematic review , relevanOur results are also substantially in agreement with a recent study of a European population , 83 showBy contrast, they are at variance with another recent study on a large American population, in which a very high 100% FJ intake was associated with significantly higher CHD death rate . The latThe beneficial effect of moderate 100%FJ intake on CV risk, in particular on the risk of stroke, is supported by the results on BP. Pooled analysis of a large number of studies showed that 100% FJ intake was associated with a reduction of more than 3 mmHg for systolic and approximately 2 mmHg for diastolic BP. Compared with previous meta-analyses of the effects of 100%FJ intake on BP, our study used more stringent inclusion criteria and adopted a robust methodology for the assessment of potential sources of heterogeneity, potential publication bias, robustness and quality of results. Furthermore, we explored for the first time the effect of 100% FJ intake on arterial stiffness, an expression of CV organ damage , found aUnfortunately, only two studies explored the risk to develop hypertension as a function of the consumption of fruit drinks , 37  may contribute to the cardiovascular benefit, in particular by modulation of the nitric oxide (NO)–cGMP pathway. These compounds may regulate the levels and the activity of endothelial NO synthase and therefore NO bioavailability , 91, 92,2+ . Polyphe2+ , oxidati2+  and lipi2+ –97. In a2+ , 99, red2+ .Also the antioxidant activity of vitamins may support the beneficial CV effect of 100% FJ intake. Vitamin A and derivatives were reported to reduce coronary heart disease risk  and thisBased on the available evidence and on the results of our analyses, a biphasic dose–response relationships apparent, where the beneficial effect detected at low-moderate 100% FJ consumption may be explained by the favourable health effect of “low dose” bioactive substances . On the Although there is an almost complete lack of studies comparing the effects on health outcomes of low-moderate consumption of 100%FJ with those of equivalent amounts of fresh fruit , it is i100%FJ intake in our study appeared to have a neutral effect on adiposity in all its expressions. Noteworthy, none of the included RCTs show significant changes in body weight upon 100%FJ consumption. These results are in line with the recent prospective study by Garduño-Alanís et al. in 5000 Russian individuals indicating no significant BMI increase after 3 years of follow-up in 100%FJ consumers . LikewisOther experimental investigations, in particular those on citrus 100%FJ, did not indicate a detrimental effect on body weight and actually suggested that citrus extracts may induce lipolysis , 116 andOur systematic review did not detect a significant association between 100% FJ consumption and risk of diabetes and in this respect our results are in general consistent with those of previous meta-analyses , 120. OnThe exploration of the lipid profile showed no significant effect of 100% FJ intake in our meta-analysis. Previous systematic reviews as well as some experimental study reported a beneficial effect on lipid profile with consumption of 100% FJ –123.This study has several strengths: (a) the evaluation of both prospective and intervention studies; (b) the stringent inclusion criteria; (c) a large number of participants for prospective evaluation and a large number of studies for intervention assessment; (d) the robustness of the findings by sensitivity and sub-group analysis; (e) the comprehensive exploration of possible sources of heterogeneity; (f) the substantially low heterogeneity among studies and no evidence of publication bias; (g) the evaluation of shape and strength of the dose–response relationship; (h) the assessment of overall quality of evidence using the GRADE assessment approach.On the other hand, the study also has limitations. For prospective studies, their observational nature impairs conclusions about possible cause-effect relationships.Also the questionnaire to assess the extent of 100%FJ consumption is subject to limitations in prospective studies both in the administered and the self-administered version, because of potential misclassification of quantity and quality of 100%FJ consumption.The heterogeneity in the characteristics of the included studies is an important limitation, in particular for the RCTs, which varied for age, health status, type of 100%FJ utilized, serving size and comparator, length of intervention. This limitation was explored by sub-group and meta-regression analysis, which in general found little evidence of subgroup differences. However, in some subgroup analyses, the test was performed including relatively few studies in one of the subgroups, hence in those cases definitive conclusions cannot be reached. In the analysis of prospective studies, an important source of heterogeneity may be the different serving size due to geographical location, but this limitation was dealt with by dose–response analysis. Furthermore, although all the included prospective studies adjusted for several relevant confounding factors , residual confounding by other potential factors cannot be ruled out.This meta-analysis was not able to detect consistent effects of individual types of 100% FJ, apart for the effect of pomegranate juice on BP, because of the low number of studies in each subgroup. Of note, a focused evaluation of the citrus/orange 100% FJ effect, the most popular juice worldwide, suggests substantial similar results of this type of juice as compared to the unspecified 100%FJ both for CV outcomes , 14 and Also, because few studies evaluated the effect of 100%FJ on CV organ damage, only the effect on arterial stiffness was explored by this meta-analysis. About CV organ damage, our systematic search detected only two studies that examined the effect of 100% FJ on other outcomes  , 125. OnFinally, further limitations are given by the relatively small number of prospective studies and cohorts available, by the residual possibility of publication bias and by the difficulty to draw definitive conclusions with regard to the interaction with age, gender and race given the peculiar composition of the study cohorts available. This notwithstanding, the observational design and the process of meta-analysis, with the calculation of a pooled estimate of the effect and the dose–response analysis in a large number of participants, are functional to overcome at least in part this problem.The results of our study show that low-moderate 100% FJ consumption is not associated with increased risk of CV disease and that actually it is associated with apparent benefit against the development of CV events through a non-linear relationship. The positive changes in BP, arterial compliance and endothelial function may help explain the effect of 100% FJ intake on risk of CV disease, in particular on stroke risk. These findings are in keeping with the inverse association also occurring between regular fresh fruit consumption and risk of CV disease.Given the importance of CV diseases , 127 andBased on recent data, the overall average consumption of 100% FJ is 38 ml per day , with woInternational dietary guidelines are not in agreement on recommendations about 100%FJ consumption. In the United States, the Guidelines for Healthy Eating recommend the daily consumption of two cups-equivalent of fruit (one cup = 237 ml), of which less than half can be taken as 100% FJ . For theWhile fresh fruit in the proper amounts cannot be surrogated by processed fruit consumption, the results of our study indicate no harm for the adult population from low-moderate 100% FJ consumption and suggest that low-moderate consumption of 100% FJ in the context of a balanced diet and as an alternative to sugar-sweetened beverages needs not to be discouraged. Although these results also show that high levels of 100% FJ intake were not associated with a detrimental CV effect, it would be hazardous to try to reach any conclusion on “safe levels” of intake, given the few prospective data available and the high heterogeneity of the level of consumption between trials and prospective studies. Therefore, only general consideration can be made. Indeed, it seems reasonable to suggest particular caution by overweight and obese individuals and by anyone else at higher risk of diabetes mellitus. Furthermore, more research is warranted to compare the effects on health outcomes of low-moderate consumption of 100% FJ with that of equivalent amounts of fresh fruit, given the almost complete lack of sound information available in this respect , 133.Supplementary file1 (PDF 279 kb)Supplementary file2 (PDF 705 kb)Below is the link to the electronic supplementary material.


To determine the prevalence of food allergy (FA) and factors associated with these occurrences in different populations from different regions.2<50%), the fixed effect model will be analyzed, otherwise, random effects model analysis will be performed. When the heterogeneity is large (I2≥50%), Meta regression will be used to explore the sources of inter-study heterogeneity. When the heterogeneity is large (I2≥50%) and the results are statistically significant (P<0.05), subgroup analysis will be analyzed based on age, gender, race/region, literature quality and other factors. Funnel plots will be used to reflect reporting bias and the Begg’s test will be used to test the symmetry of the funnel plots. When publication bias occurs, “cut-and-fill” method will be adopted to adjust publication bias. And sensitivity analysis will be performed for all outcome indicators.The literature search will be conducted via Pubmed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), Vip and Wanfang databases. Ratio rate (RR), odds ratio (OR) and 95% confidence intervals (CIs) will be adopted to evaluate prevalence and factors for FA in different populations from different regions. When the heterogeneity is small (IThis meta-analysis will evaluate the prevalence of FA and factors associated with these occurrences in different populations from different regions on the basis of existing evidences. Our study may be crucial to analyze similarities and differences regarding FA between different individuals from diverse regions and eventually define preventive or diagnostic approaches specifically tailored to certain populations and regions.10.17605/OSF.IO/VQXU9OSF registration number:  Food allergy (FA) is defined as an abnormal immune response to antigens introduced into the body through food, with wide spectrum of clinical manifestations, ranging from mild skin problems to severe systematic reactions . The preDespite the increasing prevalence of FA and its attributed public health burdens, estimating the incidence and prevalence of FA faces a huge challenge. The gold standard of FA diagnosis is the double-blind, placebo-controlled food challenge (DBPCFC) –8. NeverHerein, we plan to present a systematic and meta-analysis to provide a comprehensive report on sociodemographic, and regional patterns of FA based on different populations from different regions. We will also identify factors associated with FA in the different populations from diverse regions. This study will provide combined values and interval estimates for the prevalence of FA in different population groups and geographic regions, which may improve the prevention and control strategies of high-risk groups and high allergenic food.To determine the prevalence of FA in global context.To identify potential influencing factors of FA.https://osf.io/registries), and the registration number is 10.17605/OSF.IO/VQXU9. This protocol for systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) statement.Prospective registration of this study has been approved by Open Science Framework (OSF) registries , Embase , Cochrane Library , Web of Science , China National Knowledge Infrastructure (CNKI) , Vip  and Wanfang  databases. Search terms will be “Food Hypersensitivit*” OR “Hypersensitivity, Foo*” OR “Allerg*, Food” OR “Food Allerg*” AND “Prevalenc*” OR “Period Prevalenc*” OR “Prevalence, Perio” OR “Point Prevalenc*” OR “Prevalenc*, Point” AND “Factor, Ris*” OR “Risk Facto*” OR “Health Correlat*” OR “Correlat*, Health” OR “Risk Scor*” OR “Scor*, Risk” OR “Risk Factor Scor*” OR “Scor*, Risk Factor” OR “Populatio* at Risk”. The search strategy is displayed in Inclusion criteria: (1) people with FA; (2) observational studies include cohort studies, case-control studies, and cross-sectional studies; (3) Chinese and English literature.Excluded criteria: (1) the number of people with FA cannot be quantified; (2) animal experiments; (3) food intolerance , poisoning (food poisoning), pharmacological adverse reactions ; (4) other researches not related to the research topic; (5) case reports, editorial materials, meeting abstracts, letters, protocols, reviews, and meta-analysis.For cohort studies and case-control studies, literature quality will be assessed using a Newcastle-Ottawa Scale (NOS) with a total score of 10, 1–4 being low quality and 5–10 being high quality. For cross-sectional studies, the quality of the literature will be assessed using the Joanna Briggs Institute (JBI) scale, which had a total score of 20 on a scale of 0–14 as low quality and 15–20 as high quality.The data will be extracted independently by two reviewers (H Feng and XJ Xiong) after the final qualified study is selected, which containing the first author’s name, year of publication, the country/region/ ethnicity, the study design, population source, sample size, age, gender, food type, number of FA events, and influencing factors of FA, etc. If information is lost, an attempt will be made to contact the original study author for relevant information. If not, the missing information will be calculated from the relevant data in the study if possible. The data extraction tables of the two authors (Z Chen and QY Xu) will be cross-checked to verify the accuracy and consistency of the extracted data. Any differences in the above process will be resolved through discussion between two authors (ZH Zhang and JG Feng), and any further differences will be arbitrated by a third author (YN Wu).Outcome evaluation of the literature will be from two aspects. The first one will be the prevalence of FA, that is, the proportion of people with FA in different population groups and geographic regions. The second will be factors that may affect FA, such as gender, and genetic factors , and specific genes, etc.), some potential risk factors that can be used to reduce/prevent FA, such as atopic disease manifestations (complicated with atopic dermatitis), hygiene Conditions improved, vitamin D deficiency, reduced antioxidant intake, increased use of antacids , obesity (in a state of inflammation), timing and pathways of food exposure  and so on.P<0.05 will be considered statistically significant. Heterogeneity tests will be performed for each outcome effect size. Heterogeneity statistic I will be calculated by Q test to quantify the magnitude of heterogeneity. When the heterogeneity is small (I2<50%), the fixed effect model will be used, otherwise, random effects model analysis will be performed.Stata15.1 software  will be used for statistical analysis. For FA prevalence, ratio rate (RR) will be adopted as the effect indicator. For factors influencing FA, the odds ratio (OR) will be used as the effect indicator for enumeration data. Each effect size will be expressed by 95% confidence intervals (CIs), and 2≥50%), Meta regression will be used to explore the sources of inter-study heterogeneity. When the heterogeneity is large (I2≥50%) and the results are statistically significant (P<0.05), subgroup analysis will be analyzed. Subgroup analyses will be performed by regions , populations , diagnosis modes, etc.The potential sources of heterogeneity will be investigated by subgroup and meta-regression analyses. When the heterogeneity is large  worldwide prevalence of FA; (2) geographical differences in prevalence of FA and related food allergens; (3) most frequent symptoms associated with specific foods; (4) risk factors associated with FA; (5) prediction of the degree of risk of the FA. Our results will potentially allow drawing conclusions about general and specific aspects of FA in various populations and diverse geographical regions. This information may be crucial to analyze similarities and differences regarding FA between different individuals from diverse regions and eventually defining preventive or diagnostic approaches specifically tailored to the certain populations and regions.S1 Checklist(DOC)Click here for additional data file.


Background: A large body of evidence suggests that epigenetic modification including DNA methylation plays a critical role in BD's pathogenesis while the identification of methylation quantitative trait loci (meQTLs) shed light on the interpretation of the function of genetic variants in non-coding regions. The intronic single nucleotide polymorphism (SNP) rs10994336 within the ANK3 has emerged as one of the most replicated risk variants for bipolar disorder (BD) in genome-wide association studies. Whether rs10994336 functions as a meQTL to mediate the association between genotype and phenotype remains unclear.Method: A total of 154 patients with BD and 181 healthy controls (HC) were recruited. The genotypes of rs10994336 and methylation levels of CpG sites within ANK3 were tested. Executive functions were assessed using a computerized version of the Wisconsin Card Sorting Test (WCST).Results: Bipolar disorder patients with the risk-T allele of rs10994336 scored lower on tests of executive function compared to homozygous CC carriers, after controlling for age, gender, and education level. No significant difference was found in HC individuals. The risk-T allele is associated with a lower methylation level of CpG site cg02172182 in HC after multiple corrections and replicated in the BD group in the same direction. Further mediation analysis revealed that the cg02172182 methylation significantly mediated the association between the polymorphism rs10994336 and PE index of WCST in patients with BD.Conclusion: Our study suggests that BD-related genetic variant rs10994336 in ANK3 impacts executive functions by modulating ANK3 methylation, supporting the theory that methylation acts as a mediator between genotype and phenotype. Bipolar Disorder (BD) is one of the most prevalent mental illnesses characterized by mood swings between episodes of mania or hypomania and depression  rs10994336 within the ANK3 gene are considered a risk allele for BD in genome-wide association studies (GWAS) , and examine whether rs10994336 polymorphism functions as a meQTL and changes the site methylation to mediate the influences of rs10994336 on executive functions.A total of 335 participants between the age of 13 and 60 years were included in this study, including 154 with BD and 181 HCs. All participants with BD were recruited from the inpatient and outpatient service at the Department of Psychiatry, First Affiliated Hospital of China Medical University and Mental Health Center of Shenyang. The recruitment interval was from April 2011 to May 2019. In adult participants (≥18 years old), the Axis I diagnosis (or its absence) were made by two experienced clinical psychiatrists using the Structured Clinical Interview Diagnostic (SCID) and Statistical Manual of Mental Disorder, Fourth Edition (DSM-IV). In participants younger than 18 years, the diagnosis (or absence) of Axis I Disorder were conducted using the Schedule for Affective Disorder and Schizophrenia for School-Age-Children-present (K-SADS-PL) by two experienced child psychiatrists. All the participants with BD in this study met the DSM-IV diagnostic criteria for BD and had no other Axis I Disorder. HC participants were recruited from Shenyang, China and surrounding cities by publicly posted advertisement. All HC participants had no current or lifetime history of an Axis I disorder or a history of psychotic, mood, or other Axis I Disorder in first-degree relatives, as determined from a detailed family history. Participants were excluded if they met any of the following criteria: (1) any history of major medical disease; (2) any history of moderate or severe head injury, head trauma, neurological disorder, or mental retardation; (3) lifetime substance/alcohol abuse or dependence; and/or (4) the presence of a concurrent and major physical illness that could lead to mood disorder symptoms. The current study was approved by the Ethics Committee of the First Affiliated Hospital of China Medical University (Shenyang China). Each participant provided a written informed consent after a complete description of the study. If their age were <18 years, they, as well as their parental/legal guardian, provided a written informed consent.Venous blood samples were collected from the participants for DNA extraction pursuant to the standard procedures. Genotype information of rs10994336 was extracted from the results of the Illumina Global Screening Array-24 v1.0 BeadChip. Participants were further divided into two groups: a CC group  and risk T-carrier group . Genotype frequencies were consistent with Hardy-Weinberg equilibrium (HWE) expectations.DNA methylation level was assessed using the Infinium Human Methylation850 (850K) Beadchip array  Heaton, , the most-tests or the chi-square tests were employed to investigate differences in the demographic and clinical data between the TT/TC group and CC group in participants with BD or HC participants. Continuous variables were presented as mean ± SD. The threshold for significance level was defined as P < 0.05.Independent two-sample P < 0.05.For all the participants who completed the WCST measures, we conducted one-way ANOVA with age, gender, and education years as covariates to explore the effect of genotype on the five indices in WCST. Statistical significance was set at two-tailed p < 0.05. A Benjamin–Hochberg false-discovery rate-corrected (FDR) correction was used to avoid type I error.A total of 160 CpG sites of ANK3 were included and all the corresponding β-values were calculated for each individual. The association between the TT/TC and CC groups of rs10994336 and each methylation level of the 160 CpG sites was tested by a linear regression model adjusted with age and gender as covariates in HC participants and medication factor added as an extra covariate in the BD group. The significance level for the association analyses was set at To test whether the effect of rs10994336 genotype on cognition was potentially mediated by the methylation level of ANK3, we conducted mediation analysis on PE index using the PROCESS macro for SPSS, with a 5,000 bias-corrected bootstrap sample for significance testing. The mediation analysis was comprised of three steps of regression. In the first step, the outcome variable (PE index of WCST) was regressed on the independent variable (rs10994336 genotypes), which indicates the total effect of the predictor on the outcome variable. In the second step, the mediator variable (cg02172182 methylation) was regressed on the independent variable (rs10994336 genotypes), and in the final step, the outcome variable (PE index of WCST) was regressed on the mediator (cg02172182 methylation) and the independent variable (rs10994336 genotypes). An indirect or mediating effect is supported when the significant association between the independent variable (rs10994336 genotypes) and outcome variable (PE index of WCST) diminishes after introducing a third variable, the mediator. In addition, age and gender were included as covariates in all mediation models and the study variables were standardized.http://cran.r-project.org) for multiple repeated tests.All the statistics analyses were conducted using the SPSS software except the association analysis between rs10994336 genotypes and methylation level of ANK3 which was performed by the R statistical package  in BD and HC, respectively. After correcting for multiple tests, two CpG sites  showed a significant association with the genotype in BD participants, while eight CpG sites  were associated significantly with the genotypes of rs10994336 in HC participants. The results of the association between the genotypes of rs10994336 and methylation level of CpG site cg02172182 were consistent in patients with BD  and in HGiven the significant effect of polymorphism rs10994336 on executive functions in the BD group and that rs10994336 was detected to be a meQTL by influencing the methylation level of CpG site cg02172182 both in the HC and BD groups, we assessed whether the methylation level of cg02172182 mediated the association between rs10994336 and executive functions. The results showed that the methylation level of cg02172182 had a significant mediation effect on the association between ANK3 rs10994336 genotypes and PE index of WCST in the BD group . In stepIn the present study, we found that the risk T-allele carriers of rs10994336 showed a worse WCST performance compared to those with homozygous CC genotype in the BD group. Moreover, rs10994336 affects the methylation level of specific CpG site within ANK3 as a meQTL in the BD and HC groups, which mediates the effect of rs10994336 on executive functions. To the best of our knowledge, it is the first study to document the mediation effect of ANK3 methylation between BD-related genetic variant rs10994336 within ANK3 and executive functions in BD.Our results suggest that the risk allele of rs10994336 of ANK3 is associated with a poor executive performance in patients with BD after adjusting for age, gender, and education. This is consistent with the result of a previous study conducted among 173 patients with first-episode psychosis showing that the polymorphism rs1938526 of ANK3 gene, which was in high linkage disequilibrium with rs10994336, was associated with cognitive domains of reasoning and problem solving, though at a marginal significance  which could affect DNA methylation considering that our sample size was not large enough. However, age and medication use were adjusted in our linear regression models and the effect of rs10994336 polymorphism on cg121722182 methylation remained significant. Future studies with larger samples could further exclude those confounders. Finally, a potential limitation is that the precise mechanism by which methylation of cg121722182 influences executive functions is unclear since it locates at the gene body of ANK3 while the role of methylation in gene bodies is not well-established, but some evidence indicates that methylation in gene bodies is associated with the activation of genes in contrast to the methylation observed in promoter regions which are generally considered to be involved in the content of silence of genes (Greenberg and Bourc'his, In summary, using executive functions as a highly heritable endophenotype and combining genetic and epigenetic data, we found that allelic variation of rs10994336 in ANK3 impacts executive functions by moderating methylation, supporting the theory that methylation acts as a mediator between genotype and phenotype. This provides insights into the mechanism of how intron risk variants associated with BD contribute to disease susceptibility.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethics Committee of First Affiliated Hospital of China Medical University. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.YT and FW contributed to the conception and design of the study and provided the technical support. LT performed the data analyses and wrote the manuscript. LT, JL, YW, YZ, JD, and YC contributed to acquisition of data and manuscript preparation. XG helped perform the analysis with constructive discussions. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The consumption of dairy is associated with decreased risk of colorectal cancer (CRC), but few studies have assessed the relationship between dairy consumption and precursors of CRC. Therefore, we performed the first meta-analysis to further evaluate this association.  PubMed, Embase, Scopus, and Web of Science databases were searched through July 2020 for observational studies. Study-specific risk estimates for the highest versus lowest category were pooled using the random-effects and fixed-effects model. The methodological quality of included studies was assessed using the ROBINS-I Scale.  A total of 12 studies were included (3 cohort studies and 9 case-control studies). Compared with the lowest level consumption, fermented dairy products had a decreased risk of precursors of CRC in both cohort (RR = 0.92 95% CI: 0.87–0.97) and case-control studies (RR = 0.98 95% CI: 0.96–0.99). Total dairy (RR = 0.80 95% CI: 0.68–0.96) and cheese (RR = 0.96 95% CI: 0.93–0.99) consumption was inversely associated with the risk in case-control studies whereas yogurt consumption was inversely associated with the risk in cohort studies (RR = 0.91 95%CI: 0.86–0.96). No significant associations were found for consumption of total milk and non/low-fat milk. For dose-response analyses, evidence of linear association was found in total dairy and yogurt consumption. The risk decreased by 12% for an increment of 200 g/d total dairy consumption (RR = 0.88 95% CI: 0.81–0.95) and decreased by 8% for an increment of 50 g/d yogurt consumption (RR = 0.92 95% CI: 0.85–0.99).  Fermented dairy products, specifically yogurt and cheese, were significantly associated with decreased risk of conventional and serrated precursors of colorectal cancer. According to GLOBOCAN 2018, colorectal cancer (CRC) is the third most frequently diagnosed cancer and the second leading cause of cancer death. It is estimated that there will be over 1.8 million new CRC cases and 881,000 deaths in 2018 , 4. In aAdenomas  and a subset of serrated lesions  and sessile serrated adenoma/polyp (SSA/P) are two major subtypes of the precursors of CRC. A previous meta-analysis has shown an increased risk of colorectal adenoma (CRA) with the intake of red and processed meat , 8; a deThe protocol of this meta-analysis was registered in PROSPERO (CRD42020192846). This study was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines . The comWe searched PubMed, Embase, Scopus, and Web of Science database in English until April 2020. The following search terms were used: “dairy” or “dairy products” or “fermented milk products” or “cultured milk products” or “fermented dairy products” or subtypes of dairy products  to exclude irrelevant articles. Then, the full texts were retrieved to further increase the potentially relevant articles.Inclusion criteria: (1) adult participants>18 years of age; (2) cohort studies, case-control studies, or cross-sectional studies that investigated the association between dairy consumption and risk of conventional adenomas and serrated lesions; (3) diagnosis: colorectal adenomas and serrated lesions that were determined by histology; (4) studies that reported the risk estimates (relative risk (RR), odds ratio (OR), or hazard ratio (HR)) with their corresponding 95% confidence interval (CI) or available original data allowing us to compute the 95% CI; (5) if the published studies reported data for specific subgroups, results for the whole population were considered in this meta-analysis; (6) if the original publications provided several independent studies, they were considered as separate studies in the following data analysis.Exclusion criteria: (1) animal studies; (2) studies conducted on children, adolescents, or pregnancy women; (3) nonoriginal papers ; (4) meta-analysis studies; (5) studies that did not provide enough data on dairy products consumption and risk estimates; (6) duplicate reports and abstracts; and (7) studies that investigated the risk of CRC or the recurrence of colorectal adenomas or serrated lesions.The data extracted from each study included the name of first author, publication year, study region, study design, sample size, type of colorectal lesion, dairy products categories, the risk estimates with their 95% CIs for each category of exposure variables and adjusted covariates in the multivariable analysis. We extracted the risk estimates that reflected the greatest degree of adjustment for potential confounders.Dose-response analysis requires the distribution of cases and controls, person-years or noncases, and risk estimates with 95% CIs for at least three quantitative categories of exposure to dairy. The median or mean level of dairy intake for each category was assigned to the corresponding RR for every study. The interval size of the open-ended highest category was assumed as the closest interval while the lowest was considered as zero [Two investigators (Weiwei Chen and Kaiyin He) independently assessed the study quality based on the Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) tool which contains seven domains. According to ROBINS-I guidance, the study judged to be at low risk in all seven domains was considered as low risk of bias; the study judged to be at low or moderate risk in all domains was considered as moderate risk of bias; the study judged to be at serious risk or critical risk in at least one domain was considered as serious risk of bias or critical risk of bias, respectively .The definition of the dairy category  in this P < 0.05 was considered statistically significant. Cochran's Q-test and I2statistics were used to assess the heterogeneity of individual studies. I2 > 50% and P < 0.1 were considered as statistically significant heterogeneity [The results were expressed in terms of RR and 95% CI for the highest versus lowest category of dairy products consumption. The standard error of the logarithmic OR/RR of each study was calculated and taken as the estimated variance of the logarithmic OR/RR. The inverse variance method was adopted  . Dose-reogeneity . Fixed-eP < 0.05. The trim and fill method was used to reduce the potential influence of publication bias [The subgroup analyses were performed according to study design, geographic location, patient sex, number of cases, size of adenoma, type of colorectal lesion, study quality, and type of food frequency questionnaire (FFQ) with dairy consumption if data were permitted. Sensitivity analyses were conducted to examine the stability of results by omitting one study at a time. Publication bias was assessed with Begg's test and Egger's test if ≥10 studies are available and it was considered to exist when ion bias .Moreover, if ≥3 studies are available, a dose-response meta-analysis was carried out to estimate the trend between different exposure levels of dairy products and precursors of CRC using a random-effects meta-regression. Generalized least-squares trend (GLST) estimation modeling and spline curve modeling (MKspline STATA command) were used to estimate the dose-response relation analysis. Both linear and nonlinear dose-response analyses were performed with data from the included studies. The GLST and variance-weighted least-squares methods require median values for categories of intake levels. When medians and means were not presented, the category mid-point was used. If the dairy consumption was reported in servings/day, we converted it into grams/day as the following standard units: 200 g for total dairy, 200 g for milk (1 glass), 125 g for yogurt (1 cup), and 30 g for cheese . The dosThe 12 included studies, published between 1991 and 2020, had 19957 cases with precursors of CRC. Of the studies, 6 were conducted in Europe, 4 in the United States, 1 in Iran, and 1 in Australia. Tables All 12 studies were assessed to have a moderate risk of bias. As shown in P=0.003; I2 = 4.6%) (P=0.097) when compared with case-control studies .A total of 5 studies assessed the effect of total dairy consumption on the likelihood of colorectal adenomas and serrated lesions, which include 1 cohort study  (516 cas = 4.6%) . EvidencP=0.983; I2 = 32.4%), cohort , and case-control  studies , cohort studies , and case-control studies .A total of 3 studies assessed the effect of non/low-fat milk consumption on the likelihood of colorectal adenomas and serrated lesions, which include 1 cohort study  , cohort studies , and case-control studies   .P=0.029; I2 = 50.2%). Evidence in favor of the association was weaker among case-control studies  when compared with cohort studies   .P=0.017; I2 = 0%) and case-control studies . However, the results from the cohort study showed no significant association   .th, 35th, 65th, and 95th percentiles of the distribution. Combining data from 3 studies [P−nonlinearity = 0.947) and yogurt (P−nonlinearity = 0.794) consumption from linearity. We found that 200 g/d increment in total dairy consumption could decrease 12% risk of colorectal adenomas and serrated lesions using the fixed-effect model with no heterogeneity    . Further= 0.367) .The results of subgroup analyses conducted to explore the sources of heterogeneity were detailed shown in Sensitivity analyses were conducted to evaluate the influence of a single study on the overall risk estimate by omitting one study in each turn . In the By pooling the 12 observational studies (9 case-control and 3 cohort studies) eventually included, this present meta-analysis was the first study that conclusively indicated an inverse association between fermented dairy products including yogurt and cheese and the risk of conventional adenomas and serrated lesions, of which fermented dairy products intake showed a decreased trend in both cohort and case-control studies but cheese and yogurt consumption display an inverse association only in case-control studies or cohort studies. No significant associations were found for the consumption of total milk and non/low-fat milk. Very few studies have evaluated the association between whole milk and cottage cheese with the risk of conventional adenomas and serrated lesions. The negative associations of total dairy, yogurt, and cheese were not supported by cohort studies which may be explained by many reasons such as the differences in study design, study quality, category of the intake frequency, amounts of dairy intake, and potential confounders.CRC is arising through three major pathways, including adenoma-carcinoma sequence, serrated pathway, and inflammatory pathway . It was Dairy foods may decrease the risk of precursors of CRC through several mechanisms. Dairy foods are the main source of calcium in the diet. In the most recent report from the WCRF/AICR, low calcium intake may increase CRC risk. A previous observational study has shown a negative association between supplemental calcium intake and CRC risk . On the β-catenin is modified by calcium supplementation [On the other hand, calcium can have an impact on several intracellular pathways leading to apoptosis in transformed cells and differentiation in normal cells , 40. Theentation , 42. Morentation .Lactobacillus and Bifidobacterium [Streptococcus thermophilus and Lactobacillus delbrueckii subsp. bulgaricus, two lactic acid bacteria used to ferment, may prevent carcinogenesis from initiating [We found that total dairy and fermented dairy products were inversely associated with the risk of the precursors of CRC while total milk was not associated with the risk. There are several mechanisms proposed to explain how fermented dairy food decreases the risk of precursors of CRC. Since the process of fermentation, fermented dairy foods contain plentiful probiotic such as acterium –46. The acterium . In a caacterium . Accordiacterium . Yogurt acterium . Live miitiating . Variousitiating . Furtheritiating , 54.Our systematic review and meta-analysis had several strengths. Most of the current meta-analysis focus on the relationship between dietary factors such as milk or dairy products and the risk of CRC. We conducted the first meta-analysis of the association between dairy consumption and the risk of precursors of CRC including the conventional and serrated lesions, based on highest versus lowest analysis, linear and nonlinear dose-response meta-analysis. We included both cohort and case-control studies through a systematic search. All of the included studies used a validated FFQ to assess dairy consumption. Further, a significantly inverse dose-response relationship was observed between total dairy and yogurt consumption and the risk of precursors of CRC, which may strengthen the reliability of the results of our hypothesis. We also carried out a sensitivity analysis to investigate whether a particular study could explain the results.However, our meta-analysis had several limitations. The main limitation of the study was a small number of included studies and subjects, so further subgroup analyses were not able to perform according to anatomical location and histology type. Dose-response analyses of specific types of dairy products were also limited because a few studies reported the modifiable risk factor with 95% CI to different quantitative categories of exposure to dairy products. Secondly, the observed inverse association between dairy intake and precursors of CRC may be due to unmeasured or potential residual confounding, although the quality of 12 included studies was evaluated to have a moderate risk of bias by ROBINS-I tool. Although some known confounding factors were adjusted in most of the studies, not all potential confounders were adjusted for in every study. We found that the association between total dairy, fermented dairy products, yogurt, and cheese persisted in most subgroups, with adjustment for confounding factors. Thirdly, significant heterogeneity was observed among studies. However, there was no evidence of significant heterogeneity found between subgroups analyses. Fourthly, most of the case-control studies may not avoid recall and selection bias, especially dietary recall bias. Lastly, potential publication bias might have influenced the results.This systematic review and meta-analysis was the first to assess the relationship between different dairy products and the precursor of CRC risk as well as the first to explore a linear association between them. In conclusion, our study suggests an inverse relationship between total dairy, fermented dairy products, yogurt, cheese, and risk of precursors of CRC, though the evidence was limited. However, no harmful effects were found between the intake of total milk and the risk of the precursor of CRC. Knowledge of risk factors associated with the precursors of CRC is important in prevention strategies. More large and precise prospective studies, as well as clinical trials, are needed to further investigate the associations and mechanisms between them. Future studies should also focus on the interactions between gut microbiota and environmental factors and their influences on colorectal carcinogenesis.


Objectives: No earlier study has summarized findings from prospective cohort studies on the association of dietary carbohydrates, sugar, and sugar-sweetened beverages (SSBs) consumption and risk of inflammatory bowel disease (IBD). The current study was done to quantitatively summarize earlier information from prospective cohort studies on the link between dietary carbohydrates, sugar, and SSBs intake with risk of IBD.Methods: Relevant studies published up to June 2021 were searched through PubMed, Medline, SCOPUS, EMBASE, and Google Scholar with the use of relevant keywords. All prospective cohort studies investigating the association of dietary carbohydrates, sugar, and SSBs consumption with risk of IBD were included.Results: Combining 5 effect sizes from 4 cohort studies, no significant association was found between dietary intake of carbohydrates and risk of ulcerative colitis (UC) . The same findings were obtained for risk of Crohn's disease (CD)  based on 4 studies with 5 effect sizes. A significant positive association was observed between sugar intake and risk of UC , as well as CD  when 5 effect sizes from 4 cohort studies were combined. The overall effect size, based on 4 estimates, revealed no significant association between SSBs consumption and risk of UC  and CD .Conclusions: Summarizing earlier studies, sugar intake was found to be associated with increased risk of IBD and its subtypes. Any significant association between dietary intake of carbohydrates and SSBs and risk of IBD and its subtypes was not found. Inflammatory bowel disease (IBD) is a chronic, progressive inflammatory disorder of the gastrointestinal tract with a peak onset in adolescence and early childhood. It is associated with an enormous burden on health care system –3. AlthoAlthough the exact pathogenesis of IBD is not fully understood, available evidence suggested that both genetic and environmental factors play a role in IBD development . BreastfIn a previously published meta-analysis in 2017, the investigators focused on total carbohydrates intake and found no significant positive association between dietary carbohydrates intake and risk of ulcerative colitis (UC) incidence. However, a positive association between sugar intake and UC incidence was achieved . Zeng etLiterature databases including PubMed, MEDLINE, SCOPUS, EMBASE, and Google Scholar were searched until June 2021. The following keywords including those from the medical subject headings (MESH) database and non-MESH keywords, were used in this search: (“sucrose” or “sugar” or “carbohydrate” or “sugar-sweetened beverage” or “soft drink”) and (“inflammatory bowel disease” or “Crohn disease” or “ulcerative colitis”). No language or time limitations were performed. In addition, references from the extracted articles and reviews were also reviewed to avoid missing any publication. Unpublished studies, congress abstracts, dissertations, and patents were not included in this meta-analysis. Duplicate citations were removed. This meta-analysis has been conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines .All prospective cohort or nested case-control studies that reported hazard ratios (HRs) or relative risks (RRs) or odds ratio (OR) and 95% Confidence Intervals (CIs) for IBD across categories of dietary carbohydrates, sugar, and sugar-sweetened beverages intake was included. If several publications were reported based on the same dataset, only the most complete one was included. In addition, if a study had reported data for specific subgroups, results for the whole population were included.p-values and did not provide any measures enabling us to calculate the effect size for the association. After these exclusions, nine papers remained for systematic review in the present study. Flow-diagram of study selection is shown in Studies were excluded if they: (1) were done on animals, pregnant women, or children, (2) had cross-sectional or case-control designs or were clinical trials, (3) had examined dietary patterns, and (4) had reported only From each eligible study, two independent reviewers extracted the following information: first author's name, publication year, country, age range of study participants, participants' sex, sample size, number of cases with IBD, follow-up duration, type of exposure, methods used to assess exposure, methods used to assess outcome, relevant effect sizes  with 95% CIs for IBD, and the covariates that were adjusted for.The Newcastle-Ottawa Scale (NOS)  adapted Q-test and I2 statistic. Subgroup analysis was not performed due to the limited numbers of included articles. All statistical analyses were conducted using STATA version 19.0 software . P < 0.05 were considered statistically as significant.To compute overall effect size, the log HRs, RRs or ORs and its standard error were calculated based on reported HRs, RRs, or ORs, and their 95% CIs. The pooled effect size was calculated using random-effects model, which takes between-study variation into account. Between-study heterogeneity was examined using Cochran's The characteristics of nine studies included in this systematic review are presented in Total carbohydrates, sugar, and sugar-sweetened beverages were considered as exposure in the included studies. Four studies considered total carbohydrates , 16, 28 The outcome of interest in these studies were UC , 29, 34,I2= 45.2%, p = 0.12; I2 = 7.2%, p = 0.36; I2 = 36.4%, p = 0.17; Combining five effect sizes from four cohort studies, no significant association was found between dietary intake of carbohydrates and risk of UC , which can, in turn, regulate gut immune and barrier function and suppress inflammation through suppression of NF-kB –41.Total carbohydrates intake was considered as one of the exposures in the current study. However, it seems that type of dietary carbohydrate is more important in determining the risk of IBD than total amount of carbohydrates. In this study, it was found that high sugar intake was associated with an increased risk of IBD. Experimental studies have indicated that consumption of a high-sugar diet promotes intestinal dysbiosis, the expansion of bacterial pathobionts, and inflammation. Exposure to a high sugar diet increases susceptibility to colitis by reducing SCFA production and increasing gut permeability. It is also noted that high levels of luminal sucrose might have direct effects on loss of intestinal barrier function , 41, 42.Along with several strengths, this study has some limitations as well. The analysis was confined to prospective cohort studies because findings from case-control and cross-sectional studies are subject to bias. Using the estimates with a maximum adjustment was another strength of the study. One limitation of the current meta-analysis is that the included studies have used different dietary assessment tools to examine total carbohydrates, sugar, and SSBs intake. Despite the use of FFQ in most studies, it must be kept in mind that dietary data from FFQ might be overestimated. Additionally, misclassification of study participants in terms of dietary intakes is always a problem in these studies. Moreover, most studies had considered baseline dietary intake of participants as the main exposure rather than the average of repeated assessments. Included studies had used different diagnostic criteria for defining IBD. The inconsistent adjustment for potential confounders among included studies might also contribute to between-study heterogeneity. The OR, HR, or RR was extracted with the maximum adjustment for potential confounders. However, the extent to which these estimates were adjusted and the residual confounding by other unmeasured factors should be considered.In conclusion, summarizing earlier studies, it was found that sugar intake was associated with increased risk of IBD and its subtypes. Any significant association between dietary intake of carbohydrates and SSBs, and risk of IBD and its subtypes was not found. Further studies, especially of prospective design from developing countries, are needed to expand the current knowledge in this regard.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.ZK and AM contributed to design, search, statistical analyses, and manuscript drafting. AM and BL contributed to design and statistical analyses. AE supervised the study. All authors approved the final manuscript for submission.This study was supported by Research Council of School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The precise etiology of multiple myeloma remains elusive, but both genetic and environmental factors have been suggested to contribute to disease risk. Several occupational categories and toxic agents have been implicated as potentially causative, yet findings from the literature are inconsistent. The aim of this review was to summarize and critically comment on the accumulated epidemiological evidence, across published meta-analyses, about the association between occupational exposure and risk of multiple myeloma. Overall, results from eleven meta-epidemiological studies underscore a significantly increased risk for firefighters, hairdressers, and employees exposed to engine exhaust, whereas farming and methylene chloride exposure have been non-significantly correlated with the disease. Further epidemiological studies are of utmost importance whilst emphasis should be placed on occupational hazard surveillance, as such studies will obtain a more accurate picture of disease occurrence in working populations, and will enable both the implementation of preventive actions and the evaluation of their effectiveness. Multiple myeloma (MM), a proliferative disease of immunoglobulin-secreting mature B cells, known as plasma cells, is the second most frequent hematologic malignancy, accounting for approximately 13% of neoplastic diseases of the blood and 1% of all cancers ,3,4. In Although the precise etiology of the disease has not yet been established, the asymptomatic, premalignant monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are thought to be precursor states of MM ,9, whereEnvironmental epidemiology of MM is an increasingly investigated, yet controversial, field. Numerous systematic reviews and meta-analyses for multiple environmental and occupational risk factors associated with MM have been published. Thus far, a systematic review of meta-analyses conducted by Sergentanis T. N. et al.  in 2015 A comprehensive review of published literature was conducted to evaluate associations between occupational risk factors and MM. Eligible studies were systematically sought in MEDLINE/PubMed database up to 31 July 2021. Relevant keywords for the search algorithm were (myeloma OR ‘’multiple myeloma’’) AND  AND .The full text of potentially eligible articles was scrutinized by two authors (RG and OF), who worked independently and blindly to each other. Eligible studies included meta-analyses examining the contribution of the workplace environment to MM. We excluded meta-analyses that investigated occupational risk factors for other medical conditions including other hematological malignancies, meta-analyses that examined non-occupational risk factors for MM, and meta-analyses of therapeutic regimens for MM. Furthermore, reviews, systematic reviews, and pooled analyses were also excluded. We did not apply any language restrictions in the selection of eligible studies.p value (and/or I2) for heterogeneity, and publication bias.Data extraction and analysis was done independently by two investigators (O.F. and R.G.), and in the case of inconsistencies and/or disagreements the final decision was reached by team consensus. From each eligible meta-analysis, we extracted information on the first author, journal and year of publication, examined risk factors, and number of studies included. We also extracted the number of cases and controls included, the study-specific effect size measure , odds ratio (OR), hazard ratio (HR)) together with their corresponding confidence interval (CI), the From the 37 articles retrieved from our search strategy, nine were deemed irrelevant from their abstracts. From the remaining 28 articles, four were pooled analyses, six were systematic reviews or reviews, one was a retrospective national cohort study, and one evaluated the association between MM incidences and residential exposure to the petrochemical industry. Overall, 11 meta-analyses ,24,25,26Blair A. et al.  conductep = 0.06).The risk of hematologic malignancies in pesticide-related occupations was evaluated by Merhi M. et al. . In theip = 0.21).Perrotta C. et al.  also conp < 0.05). Potential causative compounds include benzene, PAHs, aldehydes, and other organic chemicals.A meta-analysis of eight mortality studies in 2006  revealedp = 0.0001). Frequently used hazardous chemicals among hairdressers include formaldehyde, ammonium compounds, polyvinylpyrrolidone, and organic solvents.Takkouche B. et al.  found thThe meta-analysis of case–control studies conducted by Sonoda T. et al.  indicatep-heterogeneity: 0.94). Consistent findings had been revealed by a more recent study of Karami S. et al. [p-heterogeneity: 0.76).The results from a meta-analysis of seven cohort studies  did not . et al. ; meta-anRegarding exposure to methylene chloride and MM risk, the meta-analysis of Liu T. et al.  includedp = 0.26) and occupational exposure for asphalt workers . Overall, at the sample size of the included studies, a positive correlation between PAHs exposure and MM risk could not be identified, with the effect size commensurate with the power of the studies.Alicandro G. et al.  conducteTo date, results from epidemiological studies of potential risk for MM mediated by occupation exposure have been inconsistent. In particular, several risk factors across five categories, including farming, firefighting, hairdressing, and organic solvents and PAHs exposure have been studied for an underlying causal association with MM. Herein, we provided an overview and appraisal of the occupational epidemiology of MM, presenting data from published meta-epidemiological studies. Since publication of the previous systematic review of meta-analyses by Sergentanis T. N. et al. , four neFindings from studies of farming-related occupations and MM risk have been inconsistent, ranging from positive associations ,37,38,39Moreover, we should also address that in agriculture the range of occupational exposure is quite broad, considering that farmers may use a number of hazardous products, including pesticides, herbicides, engine fuels and exhausts, fertilizers, and other chemical solvents ,53. As aWith regard to firefighting, in a pooled cohort of 30,000 US firefighters, Daniels R. D. et al.  reportedEmployees in hairdressing salons, barbershops, and beauty salons are also exposed to a variety of agents released from hairdressing and beauty products, like hydrogen peroxide, ammonia, formaldehyde, nitrosamines, polyvinylpyrrolidone/polyvinyl-acetate copolymer (PVP-PVA), some of which have been suggested as mutagenic or carcinogenic . In a laBenzene, one of the elementary petrochemicals widely used for the production of polymers, plastics, rubbers, dyes, pesticides, lubricants, and as a component of unleaded gasoline, has been associated with hematopoietic cancer, including MM . The firAdditionally, no supportive evidence for increased MM risk following occupational exposure to TCE  and PAHsOur study has several caveats, which we should critically point out as they reflect key limitations of meta-analyses. Firstly, given the relative rarity of MM, cohort studies may lack adequate statistical power, while case–control studies may suffer from small sample sizes for specific occupational categories ,63. MoreFurthermore, we need to address that overlapping data between specific studies may occur, leading to spurious associations and false positive results. Of note, despite the fact that 14 studies ,76,77,78Moreover, the identification of specific occupational categories related with an increased risk of MM enables public health officials to not only identify populations  in need of earlier and more frequent screening tests , but also implement feasible and effective preventive measures. Thus, large-scale epidemiological studies of high quality are warranted to investigate and further characterize potential workplace hazards related with MM.In summary, the present review focused on the published meta-analyses that summarize current knowledge on occupational risk factors for MM epidemiology. Additional evidence from well-designed epidemiological studies in the near future is anticipated to further shed light on repeatedly reported associations of MM risk with various occupational risk factors.