Genetic factors contribute to susceptibility and resistance to fluoride exposure. The aim of this systematic review was to identify alleles/genotypes of single nucleotide polymorphisms (SNPs) associated with dental fluorosis (DF) and to identify them as protective or risk factors. PubMed, ScienceDirect, Cochrane Library, Scopus and Web of Science were searched for articles; the last search was performed in August 2022. Human studies that analyzed the relationship between SNPs and DF published in English were included; systematic reviews and meta-analyses were excluded. Methodological quality was graded using the Joanna Briggs Institute checklist and risk of bias was assessed using the Cochrane Collaboration’s tool. Eighteen articles were included, 44% of which showed high methodological quality and data from 5625 participants aged 6 to 75 years were analyzed. The SNPs COL1A2, ESR2, DLX1, DLX2, AMBN, TUFT1, TFIP11, miRNA17, and SOD2 were considered risk factors, and ESR1, MMP20, and ENAM were considered protective factors. In conclusion, there are alleles and genotypes of different single nucleotide polymorphisms involved in increasing or decreasing the risk of developing dental fluorosis. At low concentrations, fluoride is considered a compound necessary for human health . It is uDental fluorosis (DF) is an undesirable defect in tooth enamel development attributed to an above-optimal systemic exposure to fluoride during critical amelogenesis periods . The sevFluoride triggers actions that contribute to the development of DF, including direct effects on ameloblasts and the development and processing of the matrix . By compAnimal studies have determined the involvement of genes in the etiology of DF. It has been shown that genetic factors underlie susceptibility/resistance to dental fluorosis ,10. In aThe identification of SNPs of different genes involved in DF susceptibility and resistance could be a valuable contribution to dental fluorosis prevention strategies. The aim of the present study was to perform a systematic review of current knowledge of the alleles/genotypes of SNPs associated with DF, and to identify them as protective or risk factors.The protocol was registered in the database of the International Prospective Register of Systematic Reviews (PROSPERO)  with theWe used the following PECO strategy : P = humWe included articles that met the following criteria: (1) studies that evaluated the relationship between SNPs and DF; (2) original studies performed on humans; (3) studies in the English language. We excluded case reports, pilot studies, books and/or book chapters, systematic reviews, and meta-analyses.A digital search was carried out in the PubMed, ScienceDirect, Cochrane Library, Scopus, and Web of Science (WOS) databases. A manual search was performed on the bibliographic references of the selected articles to identify additional studies. The search began in September 2021 and ended in August 2022.The keywords that were employed for the advanced search in each database were: dental fluorosis, gene, genetic, skeletal fluorosis, and enamel fluorosis. These words were combined with the Booleans AND NOT as follows:  AND (gene) AND (genetic)), ((gene) AND  NOT ), ((genetic) AND  NOT ), ((enamel fluorosis) AND (gene) AND (genetic)), ((gene) AND (enamel fluorosis) NOT ), ((genetic) AND (enamel fluorosis) NOT ). In PubMed, the search was conducted on the titles and abstracts of the articles and the “human” filter was used. In ScienceDirect, Scopus, and Cochrane Library, the search was conducted on the title, abstract, and keywords of the articles. In WOS, the search was conducted on the abstracts of the articles. No publication date restriction was applied in any database, and thus all articles published up to the date of the search were eligible. Articles with restricted access were retrieved through institutional access.First, duplicated articles were excluded. Then, the titles and abstracts of each article were analyzed and the articles containing relevant information were selected in accordance with the eligibility criteria. Finally, the selected articles were evaluated through full-text analysis in order to determine which of them would be useful for the elaboration of the systematic review. Each reviewer made a list of the articles, which was updated in every step described until they had defined the relationship of the included studies. Two of the reviewers selected the abstracts according to the above criteria, and the concordance of the classification was checked for 20% of the randomly selected publications with a kappa statistic of 0.99 intra-examiner and 0.97 inter-examiner. In the case of a disagreement between the reviewers, a third reviewer was brought in to resolve it.The data required for the systematic review were collected according to standardized forms that contained the most important variables for analysis. Two reviewers performed this process independently, and in the case of a disagreement a third reviewer was brought in to resolve it.® worksheets (2016) in the following order: authors, year of publication of the study, country of the study, study design, range of age of the participants, DF diagnostic index, number of participants, prevalence of DF, extracted samples, laboratory techniques, genes, polymorphisms, alleles, and genotypes.The data analyzed for each article were collected in Microsoft ExcelFor the evaluation of the methodological quality, the tools of the Joanna Briggs Institute (JBI)  were useThe sample sizes ranged from 30 to 1,017 participants and their age ranged from 6 to 75 years. The Dean method (14/18) and the Thylstrup and Fejerskov index (4/18) were used for the diagnosis of DF. A total of 33% of all participants belonged to the case group and 67% to the control group .To our knowledge, this is one of the first systematic reviews to specifically address the relationship between single nucleotide polymorphisms and dental fluorosis. Prior to the extraction and analysis of the data, the seventeen selected articles were evaluated and methodologically qualified. A total of 52 SNPs of 26 candidate genes were studied, of which 18 SNPs of 15 genes were associated with the disease. The SNPs considered risk factors were COL1A2, ESR2, DLX1, DLX2, AMBN, TUFT1, TFIP11, miARN17, and SOD2. On the other hand, those considered protective factors were ESR1, MMP20, and ENAM. In addition, alleles and genotypes of four SNPs were associated without specifying the type of association. No gender differences were mentioned in the results. In comparison with dental caries ,37 and pCollagen type 1 alpha 2 (COL1A2) is a candidate gene for isolated defects, mainly in dentin . Huang eEstrogen, which acts through its alpha (ESR1) and beta (ESR2) receptors, promotes the deposition of calcium and phosphorus in bones and plays an important role in the stimulation of osteoblast activity ,41. The Secretory ameloblasts produce the structural proteins amelogenin (AMELX), ameloblastin (AMBN), and enamelin (ENAM) in the enamel matrix . In relaTuftelin (TUFT1) and members of the microRNA family (miRNA) have already been associated with oral conditions ,48. OtheThe distal-less (DLX) family are expressed during the early stages of odontogenesis and amelogenesis . KüchlerDuring the secretory stage of amelogenesis, matrix metalloproteinase-20 (MMP20) quickly cleaves proteins that are secreted in the enamel matrix . RomualdA considerable difference between investigations is the size of the case and control groups. The case groups represented between 22.4 and 27.3% of participants in the studies carried out in Brazil, between 27.4 and 31.25% in China, between 41 and 50% in India, and, lastly, between 66 and 100% in Mexico. Furthermore, comparing the extremes, we noted that in Brazilian cohorts, populations presented more participants with mild than severe DF, constituting the most important subgroup with phenotypes, and they reported lower fluoride concentrations in drinking water than in studies from other countries. On the other hand, Mexican populations presented more moderate/severe phenotypes than mild forms, and reported higher fluoride concentrations in drinking water than in Brazil. Therefore, despite individual heterogeneity, it is suggested that for extreme DF forms the relationship between the concentrations of fluoride in drinking water the ion and the severity of the disease are directly proportional.Some articles reported incomplete data , which could influence the results reported, and prevents us from discussing them in detail. In addition, another limitation of the present study is that there is a high methodological variability  between studies included here that makes it difficult to precisely compare the results.The relevance of the present systematic review lies in strengthening the evidence of the influence of genetic factors on the etiology of dental fluorosis. It is of utmost importance to encourage further research to improve our understanding of the mechanisms of dental fluorosis and thus strengthen prevention strategies for this disease, which covers both oral health and general health.Scientific evidence confirms the involvement of single nucleotide polymorphisms in the development of dental fluorosis. Some alleles/genotypes are risk factors, and others are protective factors. Therefore, genetic factors should be considered protagonists in the etiology of this disease, and the continuation of its study is fundamental.


Casein hydrolysate has various biological functional activities, especially prominent are angiotensin I-converting enzyme inhibitory activities. Increasing evidence has reported the prominent hypotensive effect of casein hydrolysate. However, the effects of casein hydrolysate on cardiovascular risk factors remain unclear and require more comprehensive and detailed studies. Here, we conducted a systematic review and meta-analysis on eligible randomized controlled trials (RCTs) to summarize the effects of casein hydrolysate supplementation on blood pressure, blood lipids, and blood glucose. In the pooled analyses, casein hydrolysate significantly reduced systolic blood pressure by 3.20 mmHg (−4.53 to −1.87 mmHg) and diastolic blood pressure by 1.50 mmHg (−2.31 to −0.69 mmHg). Supplementation of casein hydrolysate displayed no effect on total cholesterol , low-density lipoprotein cholesterol , high-density lipoprotein cholesterol , triglycerides , or fasting blood glucose  compared with the placebo diets. Collectively, this study indicated that supplementation of casein hydrolysate displayed decreasing effect on blood pressure without affecting blood lipids or glycemic status. With the aging of the world population, cardiovascular disease (CVD) has become an increasingly prominent public health problem globally. CVD remains the leading cause of mortality worldwide . AccordiNutritional and lifestyle risk factors such as suboptimal diet, smoking, alcohol consumption, physical inactivity, and other metabolic diseases  were identified to be major risk factors for CVDs , among wEvidence from randomized controlled trials (RCTs) indicated that milk protein supplementation was an effective diet approach for reducing blood pressure (BP) ,9 specifCasein-derived hydrolysate has various biological functions including, but not limited to, anti-inflammatory, antioxidant , and antContradictory results have been reported on the BP lowering effect of casein hydrolysate in RCTs ,27. TherThe systematic review and meta-analysis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.We searched the PubMed and Web of Science databases from 1994 to July 2022 to identify eligible studies. The involved searching keywords were randomized controlled trial, casein hydrolysate, cardiovascular disease, systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and fasting blood glucose (FBG). Two reviewers independently searched and assessed the studies retrieved from databases. Any inconsistency was reexamined by another reviewer and resolved via group discussion.Inclusion criteria were as follows: (1) the study was written in the English language; (2) trials were performed with humans; (3) published RCTs; (4) the intervention diet was casein hydrolysate or lactotripeptides; (5) the study contained a comparable placebo or control group; (6) and reporting at least one CVD risk factor. Exclusion criteria were as follows: (1) the trials involved animals ; (2) no control/placebo group; (3) the intervention diet was not casein hydrolysate or lactotripeptides; (4) no relevant result of CVD risk factor; (5) no result of intervention or control/placebo group; (6) review article. Initially, two reviewers independently screened the retrieved articles based on titles and abstracts to determine whether the studies met the inclusion criteria. The full text was downloaded for detailed examination for eligible or uncertain studies according to titles and abstracts.The following information of eligible studies was extracted: (1) author name; (2) publication year; (3) the study design ; (4) the source of hydrolysate consumed in the intervention diet; (5) the preparation method of hydrolysate; (6) intervention diet; (7) control/placebo diet; (8) outcomes of CVD risk factor before and after control and intervention diet; (9) intervention duration; (10) health status of participants; (11) population size; (12) geographic location; (13) mean age of participants. For subsequent statistical analysis, the units of TG, related cholesterol indicators, and FBG were unified. The TG value (in mg/dL) was divided by 88.57 (in mmol/L). The related cholesterol value (in mg/dL) was divided by 38.67 (in mmol/L). The FBG value (in mg/dL) was divided by 18 (in mmol/L).The risk of bias was assessed by two independent reviewers according to the Cochrane Collaboration Handbook recommendations . Review p < 0.05). The symmetry of funnel plots was also visually judged in evaluating publication bias. Sensitivity analysis was used to assess the existence of a small study effect and the reliability of the results. Review Manager 5.4 was used to evaluate the effects of casein hydrolysate on CVD risk factors. It also showed the risk of bias and visual funnel plots of the included studies. Review Manager 5.4 was used to generate a forest plot. Stata 15 was used to perform Egger’s linear regression test and sensitivity analysis. p < 0.05 was considered as a statistically significant difference.The change value of indicators (endpoint minus baseline) used in the analysis were presented as means and standard deviations (SDs). A random-effects model was applied to assess the effect sizes. The evaluated effect sizes were presented as weighted mean difference (WMD) and 95% confidence intervals (CIs) according to the Cochrane Handbook . Meta-reThe screening process for eligible studies is shown in In total, 30 trials consisting of 1824 participants reported SBP; 29 trials consisting of 1743 participants reported DBP; 13 trials consisting of 648 participants reported TC; 7 trials consisting of 386 participants reported LDL-C; 11 trials consisting of 641 participants reported HDL-C levels; 14 studies trials consisting of 678 participants reported TG; and 7 trials consisting of 396 participants reported FBG. The detailed characteristics of included studies are described in p < 0.00001) compared with control diets (p = 0.01)  . However = 0.01) .p = 0.0003) (p = 0.03)  B. Public = 0.03) . Sensiti = 0.03) .p = 0.17), LDL , HDL , and TG    were assessed. It was shown that casein hydrolysate had no significant effect on blood lipids: TC  . The fun= 0.473) . Sensiti= 0.473) .p = 0.90) compared with the control diets (p = 0.430) was observed  and DBP  compared to participants with normal BP  (p = 0.008) and DBP  compared to the older participants  (p = 0.0001) and DBP  compared with the long-term intervention  (p = 0.01) and DBP  compared with enzymatic preparation method   and the participants with blood pressure disorders   . Younger= 0.003) . Short-t = 0.02) . Ferment = 0.04) . In addi= 0.006) . Taken tTo further assess the effect of casein hydrolysate on blood lipids and blood glucose, we conducted a stratified analysis for extracted data . We analp < 0.00001) and DBP  compared with control diets, but no effect on TC , LDL-C , HDL-C , TG , or FBG . Furthermore, no difference in reducing BP was observed among participants stratified by different baseline BP, age, duration of the intervention, preparation methods, and disease status. Consistent with the BP results of stratified analyses, no significant difference was observed in blood lipids and blood glucose among participants stratified by age, duration of the intervention, preparation methods, and disease status. To our knowledge, this is the first systematic review comprehensively assessing the overall effects of the available RCTs of casein hydrolysate supplementation on CVD risk factors. Our study possesses several strengths. First, our analysis reflected the most updated and comprehensive assessment of the effects of casein hydrolysate on multiple CVD risk factors. Second, we provided stratified analyses to identify potential covariates modifying the effect of casein hydrolysate supplementation on CVD risk factors. Third, a detailed sensitivity analysis and publication bias analysis were performed to ensure the robustness of the results. The findings of this study had several public health implications. For instance, our findings supported the consumption of casein hydrolysate in the population at risk for the prevention of CVDs.To determine the association between casein hydrolysate consumption and different CVD risk factors, the current systematic review and meta-analyses evaluated the effects of casein hydrolysate on SBP, DBP, TC, LDL, HDL, and FBG. Twenty-six RCTs were included to investigate the effect of casein hydrolysate supplementation on multiple CVD risk factors. Casein hydrolysate significantly reduced SBP  and DBP . In another study, subgroup analysis only included a small number of participants, which may lead to a biased conclusion [p = 0.0017) in European subjects. Compared with these published meta-analysis articles, our review conducted pooled and detailed subgroup analyses of casein-derived hydrolysate supplementation on multiple CVD risk factors. We also incorporated recent published RCTs investigating the effect of casein hydrolysate on BP (see There are published systematic reviews and meta-analyses investigating the influences of casein hydrolysate supplementation on BP and other CVD risk factors ,31,56,57nclusion . Two stun BP see . AlthougReviewing the RCTs articles that met inclusion criteria, few articles investigated the effects of casein hydrolysate consumption on blood lipids or blood glucose in humans . JauhiaiLimitations still exist in the present study. First, several results were obtained from a small number of RCTs, especially in some stratified analyses, which may lead to biased results. Second, although the risk of bias in all eligible studies was adequately represented in the figures, some included RCT studies did not report sufficient information on the random sequence generation and allocation concealment. Third, some results may have significant heterogeneity and publication bias, which potentially influences the reliability of the results. Fourth, the BP reduction in casein hydrolysate may be also attributed to weight loss ,60. CaseIn conclusion, our study supports the beneficial role of casein hydrolysate intake in improving blood pressure. Unlike casein protein, casein hydrolysate displayed no effect on blood lipids and fasting blood glucose. Large-scale and long-term studies are still warranted in the future to validate the effect of casein hydrolysate on CVD incidence and the findings obtained in this study. In addition, our findings of this systematic review and meta-analysis have certain public health implications, and casein hydrolysate combined with other food-effective nutrients may generate potential synergistic effects on improving human health.


Background: Allergic rhinitis (AR) is an especially common disorder associated with both environmental and genetic factors, and a lot of researchers have attempted to find polymorphisms which predisposed to the disease. We conducted a meta-analysis of the most frequently researched polymorphisms to find those genes which may be susceptible to AR and then may be of value in diagnosis.Methods: Pubmed and China National Knowledge Infrastructure (CNKI) databases were searched to screen out eligible studies focusing on the correlation between polymorphisms and AR susceptibility, and then polymorphisms cited in at least 3 studies were selected.Results: The 142 papers originally selected cited 78 genes. Twelve genes (coinciding with 23 polymorphisms) were reported in more than three papers. Twenty-three polymorphisms were involved in the meta-analysis. Among the 23 polymorphisms, only 4 were found to be related to the risk of AR: IL-13 rs20541, CTLA-4 rs11571302, IL-4R RS1801275 and ACE (I/D). The remaining 19 of the 23 polymorphisms were not associated with AR.Conclusion: We found polymorphisms that could be used for AR diagnosing and those that were unrelated to AR. This may be the first step in detecting polymorphic combinations susceptible to AR . In addition, our results may improve AR diagnosis and contribute to the intensive study of AR. Allergic rhinitis (AR) is a chronic inflammatory disorder of the nasal mucosa mediated by allergic hypersensitivity responses to environmental allergens . As repoTo solve the limitations of individual researches, a comprehensive evaluation of the relationship between SNPs and vulnerability to AR is required in synthesized studies. The purpose of this study was, first, to provide a detailed review of the SNPs researched in AR, and second, to evaluate the correlation between the most frequently reported SNPs and the susceptibility to AR by meta-analysis, so as to further understand the molecular mechanism of this disease and provide underlying therapeutic targets or approaches for the reuse of existing drugs.We performed a exhaustive literature search on PubMed and CNKI, with the search strategies being  and (“mutation” or “polymorphism”). The detailed search strategy is supplied in In order to gain the credibility of our results and restrict the amount of meta-analyses completed, only the genes and polymorphisms reported in at least three diverse studies were considered in the analysis.For meta-analysis, studies must conform to the following inclusion standard: 1) original case-control studies of AR; 2) An association between AR and at least one polymorphism was reported and sufficient data were available to calculate odds ratio (OR) and corresponding 95% CI; 3) Genotype frequency did not deviate from Hardy-Weinberg equilibrium (HWE) significantly; 4) Based on the symptoms and allergen tests or confirmed histologically, people were diagnosed as AR. Duplicate researches and researches with overlapping data were excluded. We also excluded retrospective studies, systematic reviews, and meta-analyses.Exclusion criteria were as follows: 1) not a case-control study; 2) irrelevant to SNPs and AR risk; 3) Lack of detailed data.One investigator (FX) extracted the data from every eligible study, which was checked by the second investigator (LW). Divergences were settled by consultation with the third researcher (YP). For each study, the following data were collected: the title, the authors, the journal, the year of publication, the country of study team, the sample capacity, and the method of diagnose.p > 0.05)  values of the involved publications. Before merging the publications, heterogeneity needs to be found correctly and effectively, that is, heterogeneity test. I2 test is the heterogeneity evaluation index proposed by  > 0.05) . If not,The publication bias was judged intuitively by drawing a funnel plot. The funnel plot symmetric, no publication bias was found; otherwise, publication bias existed. Besides, publication bias was quantitatively estimated by the Egger’s Test. For every polymorphism involved in this research, articles search was conducted to identify prior meta-analyses. And our results were compared with the prior results to identify potential records.After screening , a totalt = −0.4; p = 0.717)  variants, of which only TNF RS1800629 was considered in our work. Five literatures were included in this meta-analysis (30/59/102/103/104). We didn’t observe significant associations  applying a random-effect model , and pub= 0.717) .t = −0.51; p = 0.659) (Four studies of the Transforming growth factor β1 (TGFβ1) rs1800469 polymorphism were included (32/65/104/141). We didn’t observe significant associations  applying a fixed-effect model  and publ= 0.659) .Thirteen full-text articles on Interleukin-13(IL-13) SNPs of interest were selected. Two genetic variants of IL-13 were analyzed: rs1800925 , rs20541t = 0.01; p = 0.994) (IL-13 _ rs1800925 (-1112C > T/1055). IL-13 _ rs1800925 (-1112C > T/1055) was considered in five studies (41/100/107/117/118) and meta-analysis was completed on them. We didn’t observe significant associations  in a fixed-effect model , and pub= 0.994) .t = 1.19; p = 0.262) (IL-13_rs20541 (130/ + 2044G > A). Twelve studies dealing with the IL-13_rs20541 A allele were considered (42/100/105/107/108/110/111/113/116/117/118/119) for the meta-analysis. An association was observed  applying a fixed-effect model  without = 0.262) .After screening, four of the nine main allelic mutants of Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) were analyzed: rs3087243 , rs23172t = −3.7; p = 0.168) (CTLA-4 _ rs3087243. Three studies were included (12/94/106). We didn’t observe significant associations  applying a fixed-effect model . And asy= 0.168) .t = -4.81; p = 0.13) (CTLA-4 _ rs231725. Three studies (12/94/106) were involved in the meta-analysis. We didn’t find significant associations  applying a random-effect model , and pub = 0.13) .t = −10.67; p = 0.059) (CTLA-4 _ rs11571302. CTLA-4 variant (rs11571302) was considered in three studies (12/94/106). When we considered the A allele as the risk allele, a correlation was found  in a fixed-effect model  with no = 0.059) .t = 4.29; p = 0.146) (Three studies were considered (12/94/106). We didn’t observe significant associations  in a fixed-effect model , and pub= 0.146) .In the 8 studies of AR and Interleukin-4(IL-4) polymorphisms five IL-4 variants were reported. Only three of them were considered.t = 0.71; p = 0.506) (IL-4 _ rs2243250 (−590C > T/589). IL-4 _ rs2243250 was considered in eight studies (107/108/109/110/112/113/114/115). When we considered the T allele as the risk allele, associations were not identified  in a random-effect model , and pub= 0.506) .t = 1.64; p = 0.349) (IL-4 _ rs2227284 (T2979G). Three studies was also considered (112/114/115) and meta-analysis was completed on these studies. We didn’t find significant associations  in a random-effect model , and pub= 0.349) .t = −2.24; p = 0.267) (IL-4 _ rs2070874(C-33T). Three studies (109/112/114) were included in this meta-analysis. We didn’t observe significant associations  applying a random-effect model , and pub= 0.267) .t = 1.71; p = 0.126) , and we didn’t find significant associations (OR 0.93 95% IC0.78–1.12) applying a random-effect model , as well= 0.126) .Two of the four primary genetic variants of forkhead box P3(FOXP3) were analyzed: rs3761548  and rs22t = 0.12; p = 0.910) (FOXP3_ rs3761548 (−3279A > C). Five studies (50/84/125/126/127) were considered for meta-analysis. Association wasn’t identified  employing the random-effect model  and publ= 0.910) .t = 0.82; p = 0.498) (FOXP3_ rs2232365 (−924A > C). Four studies (125/126/127/128) were involved . We didn= 0.498) .Seven Interleukin-18(IL-18) variants were reported. Only three of them were considered.t = 2.96; p = 0.098) (IL-18_ rs1946518 (−607C/A). meta-analysis was completed with data of four publications (73/129/130/131). We didn’t find significant associations  applying a fixed-effect model , and pub= 0.098) .t = 2.96; p = 0.098) (IL-18 _ rs187238 (−137G/C). Three relevant studies were considered in this meta-analysis (129/130/131). We didn’t observe significant associations  in a fixed-effect model , and pub= 0.098) .t = 10.68; p = 0.059) (IL-18 _rs360721(C133/140G). Three studies (129/130/131) were involved in the meta-analysis. We didn’t observe significant associations  applying the fixed-effect model . No pote= 0.059) .After screening, only one of the main allelic mutants of T cells immunoglobulin domain and mucin domain protein-3(Tim-3) were analyzed.t = 2.84; p = 0.105) (Tim-3_ rs10515746 (−574G/T). Four studies (6/44/49/132) were involved in this meta-analysis. We didn’t find significant associations  in a fixed-effect model , and pub= 0.105) .AFTER our data screening, both of the primary allelic mutants of IL-4R were analyzed.t = 2.62; p = 0.034) (IL-4R_ rs1801275 (Q576R/Gln551Arg). Nine studies (35/36/43/107/109/113/116/117/142) were considered in this meta-analysis. We observed significant associations  applying a random-effect model , and a p= 0.034) .t = 0.51; p = 0.699) . Three studies (113/117/142) were included for this variant. No association was identified   with no = 0.699) .t = 1.25; p = 0.301)  . And pub= 0.301) .t = −0.57; p = 0.627) , we didn’t find significant associations  in a random-effect model  and no p= 0.627) .t = 0.00; p = 0.999) (TAP1_637G/D. Of the four selected studies for TAP1_637G/D (21/56/137/138), meta-analysis was completed with information of these publications, and we didn’t find significant associations  employing a random-effect model , as well= 0.999) .The aim of this research was to offer a detailed review of polymorphisms about AR and to conduct a meta-analysis of those most frequently studied polymorphisms. Finally, 23 polymorphisms (in 12 genes) were meta-analyzed. Four polymorphisms were identified to be significantly related to the risk of AR. Thus, we were allowed to identify those polymorphisms that had the potential to constitute a screening test for AR and put forward combinations of SNPs that could prerecognize AR: IL-13 rs20541, CTLA-4 rs11571302, IL-4R rs1801275 and ACE (I/D).To be as detailed as possible, we conducted extensive PubMed and CNKI search queries. The amount of 142 papers (involving 78 genes) were found to be related. To increase efficiency, only the genes that had been researched in three or more studies was considered in our study. Of the 142 publications cited in the Results section, 38 was augmented manually for the reason that the keyword “AR” was missing. The manual augment of references was not unexpected, because we were allowed to find relevant data quickly and accurately by our strategy.To the best of our knowledge, our study is the first to have emphasized the potential association between AR and the CTLA-4 rs11571302 polymorphisms through meta-analysis . The CTLInflammation and immunization are known to be involved in the pathogenesis of AR. The Type 2 cytokines  are the initiating factors of airway inflammatory response . SeveralNo associations with AR were detected here for IL-4 rs2243250, IL-4 rs2227284 and IL-4 rs2070874. In contrast, one previous study reported that the IL-4 rs2243250 genotype is associated with AR susceptibility . We exclAll biological functions of IL-4 are mediated by effector IL-4R, including mediating Th1/Th2 imbalance, promoting B cell proliferation and IgE synthesis, which play a crucial role in allergic rhinitis . Our resACE I/D polymorphism may influence the strength of immunological response and has been reported to be associated with atopic disorders, inflammatory diseases . Our resTNF-α functions as a pro-inflammatory cytokine involving in T cell activation and cytokine release, recruitment of neutrophils, macrophages and monocytes, and increased histamine release from airway mast cells. Here, we ensured the known result of association previously shown by another meta-analysis . We founTGF-β is known to be involved in AR, which can induce initial CD4 + T cells to differentiate into CD4 + CD25 + Treg cells and stabilize the immune function of the body . ElevateStudies have shown that CD14/-159 may influence the regulation of CD14 gene expression and thus modulate the influence of CD14-mediated events on innate and adaptive immune responses . CD14 spFOXP3, as a specific transcription factor of Treg cells, is involved in the development and functional maintenance of Treg cells . CompareTim-3 has a negative regulatory effect on Th1 cell and causes Th1/Th2 imbalance, which is required for the development of AR . It was Inhaled antigen is presented to CD4 + T cells in AR, and TAP1 gene encodes molecules involved in endogenous antigen processing . TAP genIn the end, this study has several limitations. Firstly, for greater efficiency, it only considered the polymorphisms cited in more than three various studies, which may miss some significant associations to AR. Thus, to confirm the underlying correlations between the remaining polymorphisms and the susceptibility of AR, more studies will be necessary. Second, the susceptibility to AR is not only related to heredity, but also to race, age, sex and so on. However, due to the small number of studies and small samples in the present analysis, stratifications for race, age and sex were not performed. Besides, the susceptibility to AR may be affected by multiple gene loci, which coordinate with each other to offset the genetic susceptibility to developing AR. These may be the reasons why only 4 SNPs were observed to have an association with the risk of AR in this study.As mentioned above, four of the polymorphisms could be analyzed simultaneously as they were associated with AR. For the few polymorphisms not involved in this study, that is, those showing a positive correlation based on two studies, further research is needed. This work allow researchers begin to find the underlying markers for developing a diagnostic method for AR patients. The panel of these polymorphisms exhibits the potential in forming a genetic screening test about AR and may thus lessen the time used in diagnosing AR.


H. pylori infection (OR 0.56 [0.48–0.66]) and atrophic gastritis (OR 0.51 [0.31–0.86]) are protective towards EE. This study demonstrates that age, ethnicity, unmarried, long-term GERD, metabolic diseases, HH, and NAFLD act as risk factors for EE, whereas H. pylori infection and atrophic gastritis act as protective factors. These findings may enable a better understanding of EE and increase greater awareness to address its growing burden.Erosive esophagitis (EE) is the part of gastroesophageal reflux disease (GERD) spectrum and may progress to esophageal adenocarcinoma. Due to its progressivity and unclear prevalence, we aim to identify the factors contributing in EE to decide the need for further examination. We performed a PRISMA 2020-based systematic search through PubMed and other resources up to June 2, 2022. Study quality was assessed using the Newcastle–Ottawa Scale (NOS). The odds ratio (OR) of each factor and worldwide prevalence of EE were measured. There are 114 observational studies included with a total of 759,100 participants. Out of 29 factors, the significant risk factors are age ≥ 60 y.o. (OR 2.03 [1.81–2.28]), White/Caucasian (OR 1.67 [1.40–1.99]), unmarried (OR 1.08 [1.03–1.14]), having GERD ≥ 5 years (OR 1.27 [1.14–1.42]), general obesity (OR 1.78 [1.61–1.98]), central obesity (OR 1.29 [1.18–1.42]), diabetes mellitus (DM) (OR 1.24 [1.17–1.32]), hypertension (OR 1.16 [1.09–1.23]), dyslipidemia (OR 1.15 [1.06–1.24]), hypertriglyceridemia (OR 1.42 [1.29–1.57]), hiatal hernia (HH) (OR 4.07 [3.21–5.17]), and non-alcoholic fatty liver disease (NAFLD) (OR 1.26 [1.18–1.34]). However,  Long-term exposure to gastric contents may irritate the esophageal epithelium, leading to a spectrum of disease in three different phenotypes—non-erosive reflux disease (NERD), erosive esophagitis (EE), and Barrett’s esophagus (BE)—when inspected through endoscopy and/or histopathology6. Typical clinical presentations of GERD are heartburns and regurgitation, with atypical clinical presentations, such as epigastric pain, odynophagia, dysphagia, nausea, chronic cough, dental erosion, laryngitis, and asthma8.Gastroesophageal reflux disease (GERD) is a condition that develops when there is a retrograde flow of stomach contents back into the esophagus6. However, reports of EE cases around the globe remain unclear, yet experts estimate the number hits approximately 1% of the population7. Aside from the burden on quality of life9, prolonged esophagitis may further induce esophageal epithelium metaplasia and progression of adenocarcinoma10. Due to its long-term morbidity, it is crucial to identify clear-cut risk factors that contribute to the development of EE to decide the need for endoscopy and/or histopathology analysis, to detect an early mucosal erosion, and to prevent its progression to BE and esophageal adenocarcinoma.Approximately 30% of GERD cases may progress to EE, and 1–13% of EE cases may also continue to develop BEGiven the burden on health-related quality of life, it is important for physicians to provide proper management and care from well-established knowledge of EE risk factors. Therefore, this meta-analysis aims to outline the detailed risk factors contributing to the development of EE as the primary outcome from the perspective of demography, comorbidities, and medication history. Furthermore, a secondary outcome of the global, regional, and local prevalence will also be depicted in this study since the exact number of cases reported is still unclear.The initial search yields a total of 3145 studies, out of which, 1636 studies are removed due to duplication of studies. We obtain 306 studies with eligible titles and abstracts and review 253 studies, as the full-texts of 53 studies are irretrievable. Finally, only 114 eligible studies with a total of 759,100 participants are included in this study. The overall process is illustrated in Fig. 12. To avoid proportional bias, we cannot report the gender proportion because 28 studies are missing this information. Among the 114 included studies, 36 are case–control, 11 are prospective cohort, 6 are retrospective cohort, and 61 are cross-sectional studies. In terms of regions, 84 studies are in Asia, 15 studies in America, 11 studies in Europe, and 4 studies in Africa.Approximately 25.53% of participants are diagnosed as EE through upper gastrointestinal (UGI) endoscopy. The mean age is 47.56 years; two studies did not report the mean age of their study population2 = 77%), age (I2 = 96%), race (I2 = 71%), employment status (I2 = 91%), and educational status (I2 = 85%). All heterogeneity tests are performed using REM. Four factors are found as risk factors: (1) Age ≥ 60 y.o. with OR 2.03 ; (2) White/Caucasian race with OR 1.67 ; (3) Being single with OR 1.08 ; and (4) Having GERD ≥ 5 years with OR 1.27 . We define ‘having GERD ≥ 5 years’ as having symptomatic GERD that is not diagnosed by endoscopy for 5 years or more. The rest – being male, employed workers, being students of college or higher educational degree, and study duration ≥ 12 years—are not risk nor protective factors.The demographical factors chosen for this analysis are as follows: sex, age, race, employment status, marital status, educational status, educational duration, and disease duration Table . The for13. However, the pooled effects of two other factors in the leave-one-out sensitivity analyses are changed from significant to nonsignificant after removing one study, either Chung et al.14, Kulig et al.13, Mun et al.15, or Sadiku et al.16, for marital status, and Kulig et al.13 for disease duration. The sensitivity analyses of the remaining demographical factors suggest that the pooled effects are not influenced by any single study.The sensitivity analysis on employment status shows that the pooled effect of EE in employed patients is changed from nonsignificant to significant after removing one study by Kulig et al.H. pylori infection, gastric ulcer, duodenal ulcer, atrophic gastritis, and non-alcoholic fatty liver disease (NAFLD) (Table 2 = 85%), central obesity (I2 = 69%), hypertriglyceridemia (I2 = 70%), hypercholesterolemia (I2 = 67%), high LDL-C (I2 = 69%), low HDL-C (I2 = 56%), HH (I2 = 95%), H. pylori infection (I2 = 91%), gastric ulcer (I2 = 77%), duodenal ulcer (I2 = 61%), and atrophic gastritis (I2 = 84%). All heterogeneity tests are performed using REM. Based on the ORs, eight comorbidities that can be considered risk factors are as follows: (1) general obesity with OR 1.78 ; (2) central obesity with OR 1.29 ; (3) DM or hyperglycemia with OR 1.24 ; (4) hypertension or elevated BP with OR 1.16 ; (5) dyslipidemia with OR 1.15 ; (6) hypertriglyceridemia with OR 1.42 ; (7) HH with OR 4.07 ; and (8) NAFLD with OR 1.26 . On the contrary, H. pylori infection  and atrophic gastritis  act as protective factors. Other factors – hypercholesterolemia, high LDL-C, low HDL-C, gastric ulcer, and duodenal ulcer – are not risk nor protective factors.Fifteen comorbidities are included in this analysis consisting general obesity, central obesity, diabetes mellitus (DM) or hyperglycemia, hypertension or elevated blood pressure (BP), dyslipidemia, hypertriglyceridemia, hypercholesterolemia, high low density lipoprotein cholesterol (LDL-C), low high density lipoprotein cholesterol (HDL-C), hiatal hernia (HH), D) Table . The for17 in the sensitivity analysis of duodenal ulcer, the pooled effect is shifted from nonsignificant to significant. On the contrary, the pooled OR of atrophic gastritis is shifted from significant to nonsignificant following the removal of a study by Ko et al.18. The leave-one-out sensitivity analyses of the remaining comorbidities suggest that the provided overall effects are robust and not affected by any single study.After removing a study by Cho et al.2 = 58%) and H2RA (I2 = 53%) have moderate heterogeneity, while PPI (I2 = 93%) and antacids (I2 = 84%) have high heterogeneity. All heterogeneity tests are performed using REM. There is no medication history considered as risk nor protective factors in the current analysis: NSAID only (OR 1.02 [0.94–1.10]), aspirin only (OR 1.09 [0.96–1.24]), NSAID and/or aspirin (OR 1.21 [0.79–1.86]), PPI (OR 0.65 [0.30–1.39]), H2RA (OR 1.23 [0.63–2.39]), and antacids (OR 1.97 [0.98–3.93]).We include five pharmacological medications: Non-steroidal anti-inflammatory drug (NSAID) only, aspirin only, NSAID and/or aspirin, proton pump inhibitor (PPI), H2 receptor antagonist (H2RA), and antacids , distribution of visceral fat tissues, and body composition between the Western and Eastern populations26. In terms of anatomical differences, previous studies also suggest that the mass of gastric parietal cells of Western population is greater than that in the Asian population, which explains the higher gastric acid production in the Western population25. Moreover, in terms of genetic variance, some previous studies indicate that the difference in the ABH-secretor and Lewis histo-blood group may explain the difference of risk in the Western population. In particular, Wirth et al.25 and Suzuki et al.27 indicate that individuals with group A and non-secretors (common in the Western population) are prone to have EE.Our study shows that the risk of EE in the Western (White/Caucasian) population is approximately two-fold higher than that in the non-White/Caucasian population. Previous studies have suggested that lifestyle factors, anatomical, and genetic variance can also explain the high risk of EE in the Western population. In terms of lifestyle factors, Wirth et al.28. Previous study mentions that the size of the HH is the most important risk factor of EE in individuals with GERD29. Some etiologies, such as pregnancies, surgical history, being elderly, and overweight, may increase the probability of HH31.This study finds that HH increases the risk of EE and this may be explained by anatomical and physiological factors. HH may diminish the augmenting effect of diaphragmatic crus to prevent gastric reflux32. Anatomically, obesity may promote esophagitis by increasing intra-abdominal pressure (IAP) and inducing lower esophageal sphincter (LES) relaxation33. Another evidence also reveals that obesity increases the transvesically-measured IAP34. Another mechanism thought to be involved in EE is related to adipose tissue. It may act as an endocrine tissue releasing inflammatory cytokines and leptin, which may further exacerbate the esophageal inflammatory process35.Obese individuals tend to experience more frequent and intense reflux symptoms compared to non-obese individuals37. This is consistent with our finding that the risk of EE is increased in diabetic patients. Interestingly, the esophageal dysfunction in diabetic patients is also associated with autonomic neuropathy involving the vagal nerve, especially when the patient is in hyperglycemic state or has diabetes for 5–10 years after onset39. Gastric emptying can be disrupted due to this process, which triggers EE39. This process is further worsened by the fact that reflux symptoms may be more frequent in diabetic patients with three major complications  and longer duration of DM41.In terms of metabolic diseases other than obesity, DM may cause esophageal dysfunction, which results in the amplitude reduction of esophageal contractions, less peristaltic waves, decreased LESP , and abnormal gastroesophageal reflux42, which finds a significantly higher systolic blood pressure (SBP) in EE compared to the controls, although the underlying pathophysiology is still unclear. The relationship between hypertension and esophageal reflux is further confirmed by Hu et al.43, which observes a significant improvement in the hypertension control after laparoscopic fundoplication during a 3.5 year follow-up period.In this study, we find that hypertension increases the risk of EE. This finding is first confirmed by Gudlaugsdottir et al.45. TG has also been correlated with high fat intake, causing delayed gastric emptying time48. Moreover, hypertriglyceridemia is a significant predictive factor of EE severity, possibly related to fatty liver and insulin resistance49. The chronic inflammation in EE due to gastric acid injury may cause abnormal lipid metabolism, increasing TG47. Yet, several studies do not find TG to be an independent risk factor of EE51.Our overall analysis finds dyslipidemia to be a risk factor for EE. However, most studies included in the analysis do not find dyslipidemia to be a risk factor. To evaluate this finding, we also separately analyzed several components of dyslipidemia, such as hypercholesterolemia, hypertriglyceridemia, high LDL-C, and low HDL-C. Our results suggest that hypertriglyceridemia is a risk factor of EE, but not dyslipidemia and its other components. Several studies have suggested triglyceride (TG) as an independent risk factor for EE related to humoral components that altered LESP and the frequency of transient relaxation45. NAFLD also increases the systemic oxidative stress and decreases the antioxidant capacity, which disrupts the gastric mucus layer and further causing esophageal mucosal damage and increasing the risk of EE45.NAFLD also reaches statistical significance as a risk factor for EE. A study reports that only NAFLD is associated with EE, but not obesityH. pylori infection show to be protective factors for EE. The gastric atrophy can be classified into closed-type (C-type) and open type (O-type) according to the endoscopic atrophic border. According to Kim et al.52, the ambulatory pH monitoring study indicates that the O-type is associated with a lesser number of reflux symptoms and EE than the C-type. The O-type is characterized by an increasing number of impaired acid secreting parietal gastric cells will hinder more the gastric acid production, which will lead to hypochlorhydria, lessen the esophageal acidity, and further contribute to the pathogenesis of EE53. In a similar manner, the H. pylori infection may present protective mechanism since H. pylori chronic inflammation can cause gastric atrophy and further decreases the acid secretory capacity of the gastric lining55. It is only observable in O-type cases, while missing in the C-type, which produces higher gastrin and acid secretion56. However, this finding should be interpreted carefully since uneradicated H. pylori still carries a high risk of gastric cancer through several complex mechanisms57. Therefore, even though H. pylori is protective towards EE in our study, its eradication should still be well-considered to prevent the incidence of gastric cancer in later life.Interestingly, both gastric atrophy and 58 and BE59 show similar results. A study by Qumseya et al.60 also finds a higher pooled prevalence of BE in low-risk Western populations compared to non-Western populations. One explanation for this distribution may be the difference in lifestyles. The typical Western diet is known to be high in fat, sodium, calories, and sugar, while it is low in fiber, fruits and vegetables. Concurrently, we have identified that White/Caucasian and individuals with obesity, type 2 diabetes mellitus, hypertension, dyslipidemia, and associated disease, such as NAFLD, are more significantly at risk of suffering from EE. Additionally, our meta-analysis shows a higher pooled prevalence of EE in Africa and the Middle East compared to those in other regions. This finding is in contrast to a previous BE meta-analysis by Eusebi et al.59, which finds the prevalence of BE in African and Middle Eastern countries to be lower than that in American countries.To the best of our understanding, there has been no study that focuses on the meta-analysis of EE prevalence. We find that the prevalence of EE in America and Europe is higher than that in Asia. Recent meta-analyses on the prevalence of GERDWe acknowledge several limitations in our study. First, we find some considerable high heterogeneities in most of the analyzed factors, mainly between the studies, such as population characteristics, various EE diagnostic criteria, differences in UGI study indications, and comorbidities along with various diagnostic criteria and cut-off values for their diagnosis. Second, although the EE diagnosis in the included studies is based on endoscopic result and the associated diagnostic criteria, endoscopy is still relatively an operator dependent-investigation, which may affect the EE prevalence in each country. Third, the number of included studies in several factors is still less than 10 studies; hence, the results should be carefully interpreted. Fourth, the included studies are mostly conducted in Asia (84 studies) and America (15 studies). This may affect the prevalence and risk factors of EE, and their interpretations in our study. Accordingly, we encourage more researchers from regions other than Asia to conduct more studies regarding the prevalence and risk factors of EE. However, regardless of the limitations, our study carries some strengths. The numbers of our included studies and their participants are relatively sufficient to cover a wide range of geographical areas; therefore, we can analyze the worldwide EE prevalence.H. pylori infection and atrophic gastritis act as protective factors. The EE prevalence in each of America, Africa, and Europe are higher than that in Asia. Given these findings, an integrated care pathways of EE—including the decision regarding the timing of endoscopy based on the risk factors—is expected to be constructed, which then may help medical professionals to give proper and comprehensive managements for patients who are at a high risk of EE.As the conclusion, we find several risk and protective factors of EE classified in three groups of factors, including demographical factors, comorbidities, and medication history. In the demographical factors, the risk of EE is increased due to age ≥ 60 y.o., being White/Caucasian, being single or unmarried, and having GERD ≥ 5 years. Interestingly, both risk and protective factors of EE are found in the comorbidities. Obesity, DM, hypertension, dyslipidemia, hypertriglyceridemia, HH, and NAFLD act as risk factors, while 61. The protocol of this study has been previously registered to the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42023418716).This systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) latest statementA systematic computerized data searching of relevant studies was conducted in four electronic medical databases, including PubMed, Scopus, Cumulative Index to Nursing and Allied Health Literature (CINAHL) Plus database via EBSCOhost, and Web of Science, by two authors (A.P.W. and B.S.W.) from inception to June 2, 2022. The construction of keywords was performed based on Medical Subject Headings (MeSH) terms combined with their variance and other additional terms as following: “risk”, “predict”, “erosive esophagitis”, “gastroesophageal reflux disease”, and the variations of those terms. Boolean operators’ combinations were also applied in order to broaden and narrow the search results. The search was restricted to human participants only with no language and publication date restrictions.The relevant studies were included if they met several following inclusion criteria: (1) study design of observational study; (2) study participants consisted of adult patients aged 18 years or older who had undergone upper gastrointestinal (UGI) endoscopy, either to screen or to diagnose EE; and (3) the measured outcomes were odds ratios (ORs) of any possible risk factors related to EE and number of EE events. The exclusion criteria were as follows: (1) duplicate studies; (2) irrelevant titles and/or abstracts; (3) irretrievable full-texts; and (4) incorrect study design .All relevant studies were independently screened by seven of the co-authors. Any disagreements were resolved in a consensus involving all authors. The extracted data from the included studies were the author, year of publication, study location (country and region), study design, diagnostic guideline for EE, age, specific population characteristic, sample size, number of EE events, EE-related risk factors expressed in ORs, and the adjustment factors. We assessed the quality of the included studies using the Newcastle–Ottawa Scale (NOS) tool. For cohort and case–control studies, their quality was considered as good, moderate, or poor if their score was 7–9, 4–6, and 0–3, respectively. For cross-sectional studies, a score of 9–10 was considered as very good, 7–8 as good, 5–6 as satisfactory, and 0–4 as unsatisfactory. The quality assessment was conducted collaboratively through a group discussion by all authors, and the final decision was also taken based on the agreement of all authors.2 statistic as follows: 0% was considered negligible heterogeneity, < 25% as low heterogeneity, 25–75% as moderate heterogeneity, and > 75% as high heterogeneity62. Since there was a considerable variability and diversity among studies and the characteristics of the study participants, we primarily applied the random-effect model (REM) for risk factors and prevalence analyses. P-value < 0.05 was considered statistically significant. The publication bias was visually assessed using funnel plot and quantitatively assessed using Egger’s test. Sensitivity analysis was carried out using the leave-one-out method.Meta-analyses were performed for the outcome of pooled ORs in each EE-related risk factor using RevMan ver. 5.4 . We also performed meta-analysis of pooled EE prevalence in each study using STATA ver. 16.0  as the secondary outcome. The heterogeneity among studies was assessed using chi-square test (Cochran’s Q statistic). Then, we quantified the level of heterogeneity with the Higgins’ ISupplementary Information 1.Supplementary Figures.Supplementary Tables.


Maternal diabetes might be related to a high risk of allergic disease in offspring. However, it remains unknown if maternal gestational diabetes mellitus (GDM) is also associated with a high incidence of childhood asthma in offspring. A systematic review and meta-analysis was performed to investigate the above association.Relevant observational studies were obtained by search of electronic databases including Medline, Embase, Cochrane Library, and Web of Science. A randomized-effects model was selected to pool the data by incorporating the influence of potential heterogeneity. The Newcastle-Ottawa Scale was used for study quality evaluation. Subgroup analyses were performed to evaluate the potential influences of study characteristics on the outcome.2 = 30%). Subgroup analyses showed that the association was not significantly affected by study design, validation methods for GDM, or diagnostic strategy for asthma . The association between maternal GDM and asthma in offspring was more remarkable after adjusting maternal body mass index in early pregnancy , but significantly weakened after adjusting hypertensive disorders during pregnancy .Ten datasets from seven moderate to high quality cohort studies, involving 523,047 mother-child pairs were included in the meta-analysis. Overall, maternal GDM was associated with a higher risk of childhood asthma in offspring (risk ratio [RR]: 1.22, 95% confidence interval [CI]: 1.07 to 1.39, p = 0.003; IMaternal GDM may be associated with an increased incidence of childhood asthma in offspring. Asthma is a chronic and allergic disease which usually starts in childhood. Children with asthma experience respiratory symptoms such as wheezing, coughing, shortness of breath, chest tightness, as well as variable airflow limitation , 2. AccuWe followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) , 15 and The PICOS criteria were used for study inclusion.(1) P (Participants): Pregnant women;(2) I (Intervention/exposure): With GDM during pregnancy;(3) C (Control/comparator): No GDM during pregnancy;(4) O (Outcome): Incidence of asthma in offspring;(5) S (Study design): Observational studies, including cross-sectional studies, case-control studies, or cohort studies;The diagnostic strategies for GDM and asthma were consistent with the methods applied in the original articles. Only studies published as full-length articles were included. Grey literatures, such as abstracts and unpublished data were excluded because these studies were typically not peer-reviewed, and inclusion of these studies may affect the reliability of the meta-analysis results. Reviews, editorials, meta-analyses, preclinical studies, studies that did not evaluate GDM during pregnancy, or studies that did not report the incidence of asthma in offspring were excluded. For studies with overlapped patients, the one with the largest sample size was included for the subsequent meta-analysis.We identified relevant studies by a systematic search of Medline, Embase, Cochrane Library, and Web of Science electronic databases using the following search strategy:  AND (“diabetes” OR “diabetic” OR “hyperglycemia”)) AND  AND (“child” OR “children” OR “adolescent” OR “pediatric” OR “pediatric” OR “infant” OR “neonate” OR “newborn” OR “toddler”). The search was from the inception of the databases to the date of last search . Only clinical studies published in English were selected. According the aim of the meta-analysis, only original studies were included. However, we also performed a manual check-up for the reference lists of the related original and review articles for potential identification of non-included original studies.The Newcastle–Ottawa Scale (NOS)  was used2 statistic was also estimated [2 > 50%. We used a randomized-effects model for data synthesis because this model has incorporated the potential between-study heterogeneity and could provide a more generalized result [Risk ratios (RRs) and 95% confidence intervals (CIs) were selected as the general outcome variable for the relationship between maternal GDM and the incidence of asthma in offspring. For studies that reported odds ratio (OR), data were converted to relative risks (RRs) for the meta-analysis as previously reported  (RR = ORstimated . Heterogd result . Sensitid result . We usedThe database search process is summarized in Fig. As shown in Table 2 = 30%; Fig. Since two studies reported outcomes in women with dietary-treated GDM and pharmacologically treated GDM , 23, andFigure In this meta-analysis, we pooled the results of ten datasets from seven cohort studies and showed that maternal GDM may be associated with a higher risk of childhood asthma in offspring. The results were not significantly changed in sensitivity analysis by excluding one dataset at a time, suggesting the robustness of the finding. In addition, consistent results were obtained in subgroup analyses according to study design, validation methods for GDM, and diagnostic strategy for asthma. Moreover, the association between maternal GDM and the risk of childhood asthma in offspring was more remarkable in studies after adjustment of maternal BMI at early pregnancy, suggesting the association is independent of maternal obesity at pregnancy. Finally, the association was weakened in studies after adjustment of maternal gestational hypertensive disorders, suggesting the association between maternal GDM and the risk of childhood asthma in offspring may partly be confounded by the concurrent maternal gestational hypertensive disorders. Taken together, results of the meta-analysis suggest that maternal GDM may be a risk factor of childhood asthma in offspring.To the best of our knowledge, few meta-analyses have been performed to investigate the potential influence of maternal GDM on the incidence of childhood asthma in offspring. As far as we know, only one previous meta-analysis evaluated the relationship between maternal diabetes in pregnancy and risk of allergic disease in offspring . This meResults of our meta-analysis further validated the hypothesis of the relationship between hyperglycemia in pregnancy and the risk of childhood asthma in offspring, by showing that maternal GDM may also be associated with childhood asthma. The methodological advantages of the meta-analysis may include the following. Frist, we extensively searched for relevant studies in four commonly used electronic databases, and seven up-to-date cohort studies were retrieved. In addition, only cohort studies were included, which could therefore provide a longitudinal association maternal GDM and childhood asthma in offspring. Moreover, multivariate analyses were used to estimate the association maternal GDM and childhood asthma in offspring in all the included studies, and potential confounding factors such as maternal age, smoking, and social economic factors etc. were adjusted. The results may therefore suggest a potentially independent association between maternal GDM and childhood asthma. At last, to further strengthen the robustness of the findings, multiple sensitivity and subgroup analyses also showed consistent results. Taken together, this meta-analysis confirmed that maternal GDM may be a risk factor of childhood asthma in offspring.Subgroup analysis showed that the association between maternal GDM and childhood asthma was even stronger in studies after adjustment of maternal BMI in early pregnancy, suggesting the potential association was not confounded by maternal obesity in pregnancy. This is important because pre-pregnancy maternal obesity has been suggested as a possible risk factor for childhood asthma in offspring . InteresThis meta-analysis has indicated that GDM could potentially increase the risk of asthma in offspring. Consequently, interventions aimed at preventing GDM may also contribute to the prevention of asthma in the offspring. Various strategies, including lifestyle modifications, dietary supplementation, and pharmacological and non-pharmacological approaches, have been examined as potential means of preventing GDM. Among these interventions, adopting a healthy diet alone, combining a healthy diet with physical activity, supplementing with vitamin B complex, and implementing probiotic treatment have demonstrated promising outcomes in reducing GDM in high-risk women. However, further replication studies are necessary to validate these findings. The initial step in addressing this matter would involve identifying efficacious strategies for preventing GDM, with a particular focus on women who are predisposed to developing GDM. Subsequently, it would be imperative to assess the effectiveness of these measures in mitigating adverse outcomes in offspring, such as asthma.Currently, the mechanisms underlying the association between GDM and childhood asthma in offspring remain to be elucidated. A recent preclinical study in a murine model of diet-induced GDM showed that female offspring exposed to GDM displayed increased methacholine reactivity, elevated proinflammatory cytokines in lung lavage, and an elevated abundance of matrix metalloproteinases in their airway, which all subsequently expose them to an increased risk of inflammatory lung conditions, such as asthma . HoweverThis study also has limitations. First, studies available for the meta-analysis are limited, and more prospective cohort studies are needed to validate the finding. At current stage, we are unable to determine if the number of participants included in this meta-analysis is sufficient. Our meta-analysis is based on cohort studies aiming to evaluate if GDM is a risk factor of childhood asthma in offspring, and no intervention was involved. According, trial sequential analysis is not suitable for this meta-analysis because it is usually used for meta-analysis evaluating intervention effect to weigh type I and II errors and to estimate when the effect is large enough to be unaffected by further studies . In addiTo sum up, results of the meta-analysis indicate that maternal GDM may be associated with an increased incidence of childhood asthma in offspring. Studies are needed to validate these findings and elucidate the underlying mechanisms. Moreover, studies are needed to determine if optimizing the glycemic control of women with GDM could reduce the incidence of asthma in their offspring.


Background: Leukocyte telomere length and hepatic disorders have been linked in various research studies, although their causative association has not been clarified. This study investigated the causal relationship between the length of telomeres on peripheral blood leukocytes and certain liver disorders.Methods: Mendelian randomization (MR) analysis was used to examine the relationship between leukocyte telomere length and risk of liver disease using the publicly accessible worldwide gene-wide association study (GWAS) database. The weighted mode, weighted median, and inverse variance weighted (IVW) methods were employed as supplements to the IVW approach, which is the main analytical method.Results: Leukocytes with longer telomeres may have a lower risk of developing cirrhosis  and a higher chance of developing benign liver tumors . There was no direct link between telomere length and fatty liver, hepatic fibrosis, or liver cancer. Our findings in the replication analysis agreed with those of the previous studies.Conclusion: Further research is needed to examine the mechanisms underlying the probable causal association between the length of leukocyte telomeres and cirrhosis and benign liver cancer. Telomeres are DNA–protein complexes present at the ends of eukaryotic linear chromosomes that protect the genome from loss of genetic material, maintain chromosomal integrity, and regulate the cell division cycle. However, owing to the cell’s replication mechanism, the cell does not entirely reproduce the chromosome, and each division loses 50–100 nucleotides, causing telomeres to gradually shorten, which is known as a physiological marker of cellular and biological aging . PreviouOne of the key organs in the body that metabolizes primarily in individuals is the liver. Liver damage leads to the manifestation of some common clinical disorders, such as fatty liver, cirrhosis, liver fiber, malignant tumors, and other liver diseases. Although there have been significant advancements in the treatment of liver illnesses, our top objective continues to be the investigation of potential therapies. Telomere length and liver disease are causally related, according to recent studies. According to a cross-sectional study, leukocyte telomere length is independently linked to a high risk of fatty liver, and individuals with shorter telomeres may have more liver fibrosis . LeukocyProbably, variables, including the sample source, variety of research individuals, and selection bias, led to the conflicting outcomes of the current study. The Mendelian randomization (MR) technique effectively dealt with the confounding effects of race, sample size, and reverse causality that were present in earlier observational and cross-sectional investigations. Similar to randomized controlled trials, MR examines the association between phenotype and disease using genetic variations as exposures. According to Mendelian’s second law of inheritance, alleles are distributed randomly during gamete formation. While avoiding bias in reverse causal linkages and errors brought on by confounding factors, it explores the causality between phenotype and disease using the diversity of genes as an instrumental variable . This prUsing the most recent gene-wide association study (GWAS) pooled data, the current study conducted the largest two-sample MR analysis to evaluate the causal connection between telomeres and liver disease. Three hypotheses have to be satisfied using the MR analysis : 1) expohttps://gwas.mrcieu.ac.uk/) database, the largest GWAS database of telomere length genetic variation related to telomeres to date. The database consists of a sizable population-based cohort that the UK Biobank (RRID: SCR_012815) put together from 2006 to 2010, with participants between the ages of 40 and 69. These individuals were thoroughly profiled through questionnaires, physical examinations, plasma biomarkers, genome-wide analyses, and other studies. In their analysis of 489,092 peripheral blood leukocyte DNA samples obtained from UKB, p < 5 × 10−8), and the threshold was set at R2 < 0.001 and a base pair window size of 10,000 kb to prevent the influence of linkage disequilibrium (LD). When screened single-nucleotide polymorphisms (SNPs) were not discovered in the outcome, they were disregarded. Finally, when matching SNPs in exposure to the result, we removed echo SNPs with intermediate allele frequencies. Based on the aforementioned inclusion and exclusion criteria, the final SNPs discovered were used as instrumental factors. In addition, to validate our conclusions, we extracted SNPs significantly associated with telomere length from a GWAS meta-analysis of 78,592 participants of European ancestry as our replication stage  database . The FinBy mimicking random assignment in an RCT research study, we used a two-way MR analysis technique to evaluate the causal impact of exposure on outcome. The fundamental approach to MR analysis methods is the IVW (inverse variance weighted) random effects method. The IVW technique is fitted using regression without an intercept term and the inverse of the ending variance (quadratic of SE) as a weight. To verify the reliability of the IVW approach, we also used the weighted mode, the MR-Egger method, the weighted median method, and the MR-PRESSO approach to examine pleiotropy and probable outliers .p-value of the intercept term is substantial, horizontal multiplicity is unavoidable , p = 1.57E-04], and not causally associated with fatty liver (p = 0.653), liver fibrosis (p = 0.077), or liver cancer (p = 0.833), according to the current study (p = 0.033). When hepatocellular cancer in the replication stage was the outcome, there was significant heterogeneity (p = 0.002) and pleiotropy (p = 0.034). The possible SNPs that may alter causation were eliminated using the leave-one-out approach and the MR-PRESSO program; however, the secondary MR analysis did not modify our result (The chosen screening conditions evaluated 118 SNPs for the outcome of liver fibrosis and hepatocellular carcinoma and 117 SNPs for the outcome of fatty liver, cirrhosis, and benign liver tumors. Similar to the original analysis, the replication analysis evaluated 13 SNPs for liver fibrosis, benign liver tumors, and hepatocellular carcinoma and 14 SNPs for fatty liver and cirrhosis. The F-values of these screened instrumental variables were all larger than 10, and there was no bias toward subpar instrumental variables . The cornt study . In the nt study . In addint study –5. With r result .To the best of our knowledge, the current study is the first to examine the causal connection between telomere length and liver illness using MR analysis. In this study, we discovered that, independently of fatty liver, liver fibrosis, and liver cancer, long telomeres may be able to lower the risk of cirrhosis and increase the chance of benign liver tumors. This is comparable to several previous investigations . The stuA case–control analysis of 134 cirrhotic patients by In contrast to our findings, which did not reveal a correlation between telomere length and fatty liver, liver fibrosis, or liver cancer, other research has shown that leukocyte telomere length may be linked to fatty liver, liver fibrosis, and liver cancer . ConfounOur research offers various advantages. First, our work is based on a large-scale GWAS database with large sample size and an F-statistic value of more than 10 for a selected instrumental variable. Second, we ruled out confounding variables and reverse causality. Finally, to check the stability of our findings, we performed sensitivity analyses such as heterogeneity, pleiotropy, and the leave-one-out approach. At the same time, our research has certain limitations. First, the great majority of the people chosen for this study were of European descent; therefore, our findings cannot be generalized to all races. Second, the instrumental variable telomere length used in this investigation was acquired from blood rather than hepatocyte telomere length. Third, we cannot be certain that all SNPs chosen meet the three fundamental assumptions of the MR analysis. Fourth, although our results suggest an association between leukocyte telomere length and liver disease, because of limitations, additional studies are warranted in the future to corroborate our findings.In summary, this study raises the possibility of a causal link between the length of leukocyte telomeres and cirrhosis and benign liver tumors. To corroborate our findings and elucidate the pathophysiological relationships between leukocyte telomere length and liver disease, additional research on other populations is required.


Glycemic variability (GV) has been associated with vascular complications in patients with diabetes. However, the relationship between GV and risk of atrial fibrillation (AF) remains not fully determined. We therefore conducted a systematic review and meta-analysis to evaluate the above association.Medline, Embase, Web of Science, Wanfang, and China National Knowledge Infrastructure were searched for longitudinal follow-up studies comparing the incidence of AF between patients with higher versus lower GV. A random-effects model incorporating the potential heterogeneity was used to pool the results.2 = 20%). Subgroup analyses suggested consistent association between GV and AF in prospective  and retrospective studies , in diabetic  and non-diabetic subjects , in studies with short-term  and long-term GV , and in studies with different quality scores .Nine cohort studies with 6,877,661 participants were included, and 36,784 (0.53%) participants developed AF during follow-up. Pooled results showed that a high GV was associated with an increased risk of AF (risk ratio [RR]: 1.20, 95% confidence interval [CI]: 1.11 to 1.30, p < 0.001, IA high GV may predict an increased risk of AF in adult population. Atrial fibrillation (AF) is one of the most common arrhythmia, particularly in older population , 2. AlthAccumulating evidence from clinical observations suggests that diabetes may be a risk factor of AF , 7. In dThe meta-analysis was performed in accordance with the MOOSE   and Cochvia systematic search of electronic databases including Medline, Embase, Web of Science, Wanfang, and China National Knowledge Infrastructure (CNKI) from inception to September 19, 2022. A combined search strategy was used, which included: (1) “glycemic” OR “glyceamic” OR “glucose” OR “hemoglobin A1c” OR “A1C”‘; (2) “variability” OR “variation” OR “fluctuation”; and (3) “atrial fibrillation” OR “AF”. The search was limited to clinical studies published in English. The reference lists of related original and review articles were also analyzed using a manual approach.Studies were identified post-hoc analyses of clinical trials, or nested case-control studies; (2) included adult population who were evaluated for GV at baseline; (3) incidence of AF during follow-up was observed and recorded; and (4) the incidence of AF between patients with higher versus lower GV was compared and reported as risk ratio (RR) and corresponding 95% confidence interval [CI], or these data could be calculated or estimated. Measuring methods and definition of GV were consistent with the criteria applied among the included studies. Reviews, editorials, preclinical studies, cross-sectional studies, studies that did not evaluate GV, studies that did not report the incidence of AF, or other studies that were irrelevant to the aim of the meta-analysis were excluded.The inclusion criteria for the studies were: (1) observational studies that are designed to follow up over time, such as cohort studies, Literature search, data extraction, and quality assessment of the included studies were independently performed by two authors according to the predefined criteria. Discrepancies were resolved by consensus or discussion with the corresponding author. The extracted data included: (1) general information of the study ; (2) study design characteristics; (3) patient characteristics ; (4) exposure characteristics ; (5) follow-up and outcome ; and (6) potential confounding factors that were adjusted or matched when the association between GV and the incidence of AF was estimated. The quality of each study was evaluated using the Newcastle-Ottawa Scale  which ra2 statistic was also estimated . Sensitivity analysis by excluding one study at a time did not significantly affect the results (data not shown). Subgroup analyses showed consistent association between a high GV and increased incidence of AF in prospective  and retrospective studies (RR: 1.18, 95% CI: 1.08 to 1.29, p = 0.002; p for subgroup difference = 0.44; Pooled results of the nine cohort studies showed that overall, a high GV was associated with a higher risk of AF in adults population (RR: 1.20, 95% CI: 1.11 to 1.30, p < 0.001; The funnel plots for the meta-analysis of the association between GV and risk of AF are shown in In this systematic review and meta-analysis, by pooling the results of nine cohort studies, we found that subjects with a high GV at baseline was associated with a higher risk of AF as compared to those with a low GV. The stability of the finding was confirmed by similar results of sensitivity analyses by excluding one study at a time. Moreover, subsequent predefined subgroup analyses showed that the association between a high GV and the increased risk of AF was consistent in prospective and retrospective cohort studies, in diabetic and non-diabetic subjects, in studies with short-term and long-term GV, and in studies with different quality scores. Taken together, these results indicate that a high GV at baseline may be a risk factor of AF in adult population. Although large-scale prospective studies are needed to validate these findings, results of the meta-analysis suggest that measuring GV may be useful to predict the risk of AF.To the best of our knowledge, this study may be the first systematic review and meta-analysis which investigated the potential relationship between GV and the incidence of AF. We extensively searched for relevant studies in five electronic databases, and nine up-to-date cohort studies were retrieved, with about half of them published within the recent 3 years. Besides, only cohort studies were included, which could therefore provide a longitudinal association between GV and AF. Moreover, multivariate analyses were used to estimate the association between GV and AF among all the included studies, and potential confounding factors such as age, sex, and comorbidities etc. were adjusted, which therefore could indicate an independent relationship between GV and AF. Finally, consistent results were obtained in multiple sensitivity and subgroup analyses, which further confirmed the robustness of the finding. Taken together, this meta-analysis confirmed that a high GV may be a risk factor of AF in adult population, which expanded the previous observations that a high GV is associated with an increased risk of adverse cardiovascular events, such as CAD, stroke, and cardiovascular deaths.via inducing oxidative stress, cardiomyocyte apoptosis, and atrial fibrosis. In addition, a previous clinical study in patients with newly diagnosed and well-controlled type 2 diabetes showed that a high GV may be associated with reduced cardiac autonomic modulation (via affecting the autonomic function. Finally, emerging evidence from preclinical studies suggested that a high glucose fluctuation may adversely affect the structural and electrical remodeling of the atrium, which may also be the underlying mechanisms for the association between GV and AF (The mechanisms underlying the association between GV and AF remain to be fully understood. An early experimental study in streptozotocin-induced diabetic rats confirmed that glucose fluctuation in uncontrolled diabetes was associated with a high inducibility of AF . Meanwhidulation . Interesdulation , suggestV and AF , 39. StuOur study has several limitations. First, the number of the included studies was limited, and some of them were of retrospective design. Therefore, results of the meta-analysis should be validated in large-scale prospective studies. Second, the parameters and definitions of patients with high GV varied among the included studies, which may be a main source of heterogeneity of the meta-analysis. However, as mentioned previously, no consensus has been reached regarding the optimal parameter and corresponding cutoff value for defining subjects with high GV. Additionally, AF is usually classified according to its temporal pattern as paroxysmal, persistent, or permanent . StudiesIn conclusion, results of the meta-analysis indicate that a high GV may be a risk factor of AF in adults. Although the results should be validated in prospective studies and the mechanisms should be further determined, results of the meta-analysis suggest that measuring GV may be useful to predict the risk of AF in adult population.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.WL and GZ designed the study. WL and YW performed database search, literature review, study quality evaluation, data collection, and statistical analyses. WL, YW, and GZ interpreted the results. WL drafted the manuscript. YW and GZ critically revised the manuscript. All authors contributed to the article and approved the submitted version.