Objective: To investigate whether microRNAs genes’ polymorphisms are associated with arthritis. Methods: The PubMed, Cochrane Library et al. were systematically searched to identify case–control studies, systematic reviews and meta-analyses. A meta-analysis was performed to calculate odds ratios (ORs), and confidence intervals (CIs) at 95% using fixed-effect model or random-effects model. Results: Twenty-two case–control studies involving 10489 participants fulfilled the inclusion criteria. MiR-146a rs2910164 (G/C) was not significantly associated with the risk of rheumatoid arthritis (RA) in any model. Significant associations were found between miR-146a rs2910164 (G/C) and the risk of psoriatic arthritis (PsA) in the heterozygous model and the dominant model. The heterozygous model showed a significant association between the miR-146a rs2910164 (G/C) polymorphism and ankylosing spondylitis (AS). And there was no significant association of miR-146a rs2910164 (G/C) with risk of juvenile rheumatoid arthritis (JRA) at any model. Additionally, there was a significant association of miR-499 rs3746444 (T/C) with risk of RA at two genetic models, and with a moderate heterogeneity. When subgroup analysis by ethnicity, significant associations were almost found between miR-499 rs3746444 (T/C) and the risk of RA in any model in Caucasian populations, and there is no heterogeneity. Conclusions: The association of miR-146a rs2910164 (G/C) with RA was not found. And there was a significant association between miR-146a rs2910164(G/C) and PsA or AS. MiR-499 rs3746444 (T/C) was associated with RA in Caucasian populations. These findings did not support the genetic association between miR-146a rs2910164 (G/C) and JRA susceptibility, as well as the association of miR-196a-2 rs11614913 (C/T), miR-146a rs2431697, miR-146a rs57095329, miR-149 rs22928323 with arthritis. Arthritis is a general term for acute or chronic inflammatory diseases of joint . Common The etiology of arthritis is unknown, but genetic factors are thought to be important in the pathogenesis and progress ,8. MicroThis meta-analysis design was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) prospectively.A systematic search of the PubMed, Cochrane Library, ISI Web of Science and Embase databases was conducted through May 2018 using the search terms ‘microRNA OR miRNA OR microRNAs’, ‘arthritis’ and ‘polymorphism or variant or mutation or polymorphisms or variants or mutations’, without any languages’ restrictions. The original research of published systematic reviews or meta-analyses were included for further relevant studies. Inclusion criteria of studies for the meta-analyses were published articles: (i) evaluation of the association between microRNAs genes polymorphisms and arthritis; (ii) genotype/allele distributions should be provided for estimating the odds ratios (ORs) and 95% confidence intervals (CIs) and (iii) a case–control design. Exclusion criteria: (i) abstracts, editorial, letters, case reports and other studies which were not focusing on humans; (ii) repeated or overlapping publications; (iii) studies with no detailed genotype distributions or allele data and (iv) family-based studies of pedigrees.The data from eligible studies were extracted independently by two researchers based on the inclusion and exclusion criteria. The following information was collected from each study: first author, publication year, country, ethnicity, control source, disease type, genotyping technology, numbers of cases and controls, genotype and allele distributions, Hardy–Weinberg equilibrium (HWE) in control subjects. Disagreements were resolved by consensus or a third researcher.http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp). According to the NOS, study qualities were evaluated based on the following three aspects: selection, comparability, exposure. The NOS uses a star grading system, with the minimum of zero point and the maximum of nine points. The studies graded with >7 stars were considered to be a high-quality study. Disagreements were resolved by consensus or a third researcher.Study qualities were judged independently by two researchers according to the Newcastle–Ottawa Scale (NOS)  were analyzed. The pooled effect of all subjects based on the disease type for each microRNA were compared. Meta-analysis was performed when more than one study was included in the study.The associations between microRNAs genes polymorphisms and arthritis was evaluated from the case–control studies using ORs and CIs at 95%. The pooled ORs and CIs were calculated, and their significance was determined by 2Istatistics. If P > 0.10 and 2I < 50%, the fixed-effects model (FEM) was applied to estimate pooled OR, else the random-effects model (REM) was used. HWE was assessed for each study by Chi-square test in control groups, and P-value <0.05 was considered a significant departure from HWE. In addition, stratified comparisons based on disease were made to further explore the potential heterogeneity according to female, different ethnicity (Asian and Caucasian), control source  and population-based (PB) population), quality score of studies.Heterogeneity among studies was assessed by Chi-squared based Q-test and P-value estimation and the Pcorr-value less than 0.05 was considered statistically significant. All statistical analyses were conducted using Stata version SE 11 .To investigate the potential origin of heterogeneity and validate the reliability of this meta-analysis, sensitivity analysis was performed to evaluate the effect of each study on the combined ORs by sequentially excluding individual studies. Potential publication bias was visually assessed by Begg’s funnel plot and statistically determined by Egger linear regression test. Step-down Bonferroni’s test  was usedThe literature search using databases yielded 492 potentially eligible records, and 40 full texts of these records were reviewed. Of 40 records, 24 records were case–control studies, 14 records were systematic reviews or meta-analyses, and 2 records were case–control studies which included a meta-analysis. After reading the full-text, 21 case–control studies met the inclusion criteria. In addition, one original research from published systematic reviews or meta-analyses was included for our meta-analysis. Supplementary Table S1 summarizes the case–control studies included in the systematic reviews or meta-analyses. The process of study selection was shown in We only performed quantitative data synthesis on studies conforming to HWE expectations. Therefore, our study carried out meta-analyses on the inclusion studies of miR-146A rs2910164 (G/C) and miR-499 rs3746444 (T/C), respectively. In addition, we conducted subgroup analyses of the inclusion of miR-146a rs2910164 (G/C), miR-499 rs3746444 (T/C) in accordance with the prior plan. When heterogeneity existed, the REM was applied to calculate the summary ORs in genetic model (Supplementry Table S2). The results of meta-analyses have been summarized in P=0.032) (P=0.021), and the dominant model . Corrected P-values for multiple testing remained significant in the heterozygous model and the dominant model. Although there was no statistical association between miR-146a rs2910164 (G/C) polymorphism and PsA in the homozygote model  and recessive model , a trend of decreased risk could be seen. Only the heterozygous model showed a significant association between the miR-146a rs2910164 (G/C) polymorphism and AS  and corrected P-values for multiple testing remained significant. However, there was no significant association between miR-146a rs2910164 (G/C) polymorphism and RA or JRA at any genetic model (After excluding a study  that didP=0.032) , the hetic model . AdditioP=0.019, Pcorr=0.038 . Based on the female, a significant association between miR-499 rs3746444 (T/C) polymorphism and RA was not found under all the genetic models , but not statistically associated with RA in the Asian population in any of the models. When stratified by control source or quality score, six studies reported the miR-499 rs3746444 (T/C) polymorphism and its association with RA in PB group or quality score >7 points group . Additionally, after a multiple testing miR-499 rs3746444 (T/C) polymorphism was significantly associated with RA in quality score >7 points group at homozygote model .After excluding two studies ,41 that rr=0.038 ; homozygc models . When suts group . There wP=0.416, homozygote model: P= 0.387, heterozygous model: P= 0.418, recessive model: P=0.558, dominant model: P= 0.348; miR-499 rs3746444 (T/C): allelic model: P=0.881, homozygote model: P=0.532, heterozygous model: P=0.898, recessive model: P=0.624, dominant model: P=0.853) further provided no evidence of significant publication bias.Publication bias was assessed by performing Begg’s funnel plot and Egger’s regression intercept test under all genetic models. Because there are few inclusion studies for other diseases, we actually only conducted publication bias tests on the included studies of the studies of RA. For miR-146a rs2910164 (G/C) and miR-499 rs3746444 (T/C), symmetrical funnel plots were obtained in all the genetic models . Moreover, the results of Egger’s test (miR-146a rs2910164 (G/C): allelic model: In order to determine the stability of our results, the sensitivity analyses were performed on miR-146a rs2910164 (G/C) and miR-499 rs3746444 (T/C) . First, the REM was compared with the FEM, and the statistically similar results were acquired under all genetic models. Second, we applied sensitivity analyses by sequentially excluding individual studies to evaluate the influence of individual study on the obtained conclusions. The analyses showed that the conclusions remained unchanged after exclusion of each study, which suggested that all the results were statistically robust.In this systematic review and meta-analysis, we reviewed the available case–control literature on genetic studies of miRNA SNPs in arthritis and conducted independent meta-analyses for the eligible research. The present study included 22 studies involving six SNPs of miRNA: miR-146a rs2910164 (G/C), miR-499 rs3746444 (T/C), miR-196a-2 rs11614913 (C/T), miR-146a rs2431697 (T/C), miR-146a rs57095329 (A/G), miR-149 rs22928323 (T/C), and four arthritis: RA, PsA, JRA, AS. We carried out a meta-analysis on the inclusion studies of miR-146a rs2910164 (G/C), miR-499 rs3746444 (T/C), respectively.Because there were many types of arthritis and the pathogenesis may not be the same, analyses based on disease were performed to investigate the relationships between genetic polymorphisms and different arthritis. Our results showed that miR-146a rs2910164 (G/C) was not significantly associated with susceptibility to RA, which was consistent with previous meta-analyses ,45–50. HPADI4 gene) [P-values and wider CIs. Further subgroup analyses showed there was significant association detected in four genetic models  among Caucasians, while no significant associations were found in all genetic models among Asians, which was similar to previous meta-analyses [Previous studies have shown that miR-499 can regulate the production of anti-cyclic citrullinated peptide antibodies by regulating the expression of its target gene (I4 gene) , therebyI4 gene) . In the I4 gene) . And theI4 gene) ,48,49,58I4 gene) . The reaanalyses ,46,48,58P-value estimation. In addition, this article not only updates the literature on the relationship between miR 146a rs2910164 (G/C) or miR 499 rs3746444 (T/C) polymorphisms and RA. In addition, this is the first meta-analysis to report the association between miR-146a rs2910164 (G/C) and PsA or AS or JRA. Therefore, this article can further enhance our understanding of the relationship between microRNAs gene polymorphism and arthritis.The present study has several limitations. First, the studies included in the present study were not always high quality, but with subgroup analysis based on quality scores, the results of high quality were almost always consistent with the results of ungrouped studies. Second, the present study divided the race into Caucasian and Asian populations, which may lead to selection bias. Third, we did not analyze factors such as environmental variables, gene×gene and gene×environment interactions due to lack of data. Finally, including studies of sample size in the meta-analysis were relatively small and, as such, our analysis may have been underpowered. However, compared with the previously published systematic reviews, we searched the databases more comprehensively and evaluated the quality of the literature. The diseases included were not limited to single disease such as RA. And to show the robustness of the conclusions, we performed multiple testing corrections technique for In this meta-analysis of case–control studies, the association of miR-146a rs2910164 (G/C) with RA was not found. And there was a significant association between miR-146a rs2910164(G/C) and PsA or AS. We also found that miR-499 rs3746444 (T/C) was associated with RA, especially in Caucasian populations. Additionally, our results did not support the genetic association between miR-146a rs2910164 (G/C) and JRA susceptibility.


Background and aims: Numerous studies examined the association between factors FV, FVII, FXII, and FXIII-A gene polymorphisms and ischemic stroke, but conclusive evidence is yet to be obtained. Thus, this meta-analysis aimed to investigate the novel association of FV rs1800595, FVII rs5742910, FXII rs1801020, and FXIII-A rs5982 and rs3024477 polymorphisms with ischemic stroke risk. Methods: A systematic review was performed on articles retrieved before June 2018. Relevant data were extracted from eligible studies and meta-analyzed using RevMan version 5.3. The strength of association between studied polymorphisms and ischemic stroke risk was calculated as odds ratios and 95% confidence intervals, by applying both fixed- and random-effect models. Results: A total of 25 studies involving 6100 ischemic stroke patients and 9249 healthy controls were incorporated in the final meta-analysis model. Specifically, rs1800595, rs5742910, rs1801020, rs5982, and rs3024477 consisted of 673, 3668, 922, 433, and 404 cases, as well as 995, 4331, 1285, 1321, and 1317 controls, respectively. The pooled analysis indicated that there was no significant association of FV rs1800595, FVII rs5742910, FXII rs1801020, FXIII-A rs5982, and FXIII-A rs3024477 polymorphisms with ischemic stroke risk, under any genetic models . Conclusions: The present meta-analysis concluded that FV rs1800595, FVII rs5742910, FXII rs1801020, and FXIII-A rs5982 and rs3024477 polymorphisms are not associated with ischemic stroke risk. Stroke is a life-threatening neurological disease. It is ranked as one of the top five leading causes of death and disability worldwide . EpidemiIschemic stroke is the most common form of stroke occurrence, accounting for about 87% of overall cases .FXII) gene was mapped to 5q33-qter, encompassing 13 introns and 14 exons. This gene is transcribed to a 2000-bp messenger RNA (mRNA) and translated to 596 amino acids to make up the corresponding protein [FXII rs1801020 (c.-4T>C or 46C>T) is correlated with FXII deficiency, with this polymorphism shown to affect gene expression and function. FXII rs1801020 CT and TT genotypes account for about 37% and 73% lower FXII levels than the wild-type CC genotype [FXII rs1801020 was reported to be associated with cerebral venous thrombosis [The factor XII  for the FV gene  is a HR2 haplotype that may cause FV type-I and type-II deficiencies and is linked to the development activated protein C (APC) resistance. For example, a previous study revealed that individuals who carried the FV rs1800595 variant tend to develop mild APC resistance, resulting in an increased risk of venous thrombosis [The rombosis .FXIII-A gene covers 160 kb of the 6p24–25 chromosomal region. It contains 15 exons and 14 introns which transcribes a 3.9-kb mRNA encoding for the FXIII-A subunit of the FXIII coagulation factor. A number of SNPs were identified in the FXIII-A gene, including c.103G>T , c.614A>T , and c.1694C>T . Previous studies focused on rs5985, with regard to its biochemical and clinical consequences [FXIII-A rs3024477 was mapped to the catalytic domain of the FXIII-A subunit, with the variant allele associated with a reduction of plasma FXIII level and reduced FXIII coagulation activity [The equences , but litactivity ,24. Beinactivity ,24. Moreactivity  reportedFV rs1800595, FVII rs5742910, FXII rs1801020, and FXIII-A rs5982 and rs3024477 polymorphisms are associated with stroke-related diseases such as cerebral venous thrombosis [FV rs1800595, FVII rs5742910, FXII rs1801020, and FXIII-A rs5982 and rs3024477 polymorphisms with ischemic stroke risk is yet to be clarified. Individual case-control studies that reported associations between FV, FVII, FXII, and FXIII-A gene polymorphisms and ischemic stroke yielded inconclusive results, and some of these may be under-powered. More importantly, no meta-analysis was undertaken to investigate these associations. Hence, this meta-analysis is the first to investigate the association of FV rs1800595, FVII rs5742910, FXII rs1801020, and FXIII-A rs5982 and rs3024477 polymorphisms with ischemic stroke risk.rombosis , cerebrarombosis , coronarrombosis , myocardrombosis , and hemrombosis . In partFACTOR V”, “FACTOR VII”, “FACTOR XII”, “FACTOR XIII”, “F5”, “F7”, “F12”, “F13”, “rs1800595”, “rs5742910”, “rs1801020”, “rs5982”, “rs3024477”, “ischemic stroke”, “brain infarction”, “brain ischemia”, “cerebrovascular accident”, “cerebrovascular disease”, and “polymorphism”, whereas the key terms of “Factor V Leiden”, “Arg506Gln”, “Arg353Gln”, and “Val34Leu” were excluded. Respective search terms were then translated to their respective Chinese characters. A detailed manual search was performed on unpublished materials, including research reports, theses, dissertations, and references cited in the relevant review articles, in order to obtain additional eligible studies. Literature searching was not restricted to any language and year of publication, and the final database searching was conducted in June 2018.We followed the Preferred Reporting Items for the Systematic Reviews and Meta-Analyses (PRISMA) guideline in reporting this study . RelevanThe titles, abstract, and full text of the retrieved articles were screened, following a set of inclusion and exclusion criteria. Case-control studies were considered for this meta-analysis, whereas prospective cohort and family-based studies were excluded. Eligible case-control studies that provided sufficient genotypic data  were included to calculate the effect size between cases and controls. If there was more than one study published by the same group of authors, only the study with the most updated data or the largest sample size was included in the final analysis. After screening all the relevant studies, data extraction was performed on those studies that met the inclusion and exclusion criteria.The characteristics of the eligible studies such as the first author’s name, year of publication, country of origin, ethnicity, study design, sample size, definition of ischemic stroke, mean or median age, percentage of male, genotyping methods, and frequencies of genotypes and alleles for cases and controls were retrieved by two independent investigators. The extracted data were assessed and compared to examine the completeness of data and to resolve any disagreement. Genotypic and allelic frequencies were carefully extracted from a multiracial study  and the 2 > 50%, Pheterogeneity < 0.10). The I2 values were categorized into 25% (low heterogeneity), 50% (moderate heterogeneity), and 75% (high heterogeneity). A fixed-effects model was applied if non-significant heterogeneity existed (I2 < 50% and Pheterogeneity > 0.10); otherwise, a random effect model was chosen. A potential source of heterogeneity was identified through stratification of Asian and Caucasian populations, with a minimum of three studies. Publication bias was examined by Begg–Mazumdar’s rank correlation test through funnel plot inspection. An asymmetrical funnel plot with the studies deviating from the 95% CI boundary line may be considered as publication bias. All statistical analyses were conducted using Review manager version 5.3 [p-values of less than 0.05 were regarded as statistically significant.Hardy–Weinberg equilibrium (HWE) was calculated from the genotypic data of each included study using a chi-square test. Different genetic models  and effect models  were used to determine the association between all studied polymorphisms and ischemic stroke risk . The strsion 5.3 . Two-sidFV (rs1800595), FVII (rs5742910), FXII (rs1801020), and FXIII-A  polymorphisms and ischemic stroke risk. The primary database search of FV (79 articles), FVII (122 articles), FXII (57 articles), and FXIII (64 articles) resulted in a total of 322 articles for the subsequent analysis. Sixty-eight duplicated publications were removed, while the remaining 254 articles were screened against the inclusion and exclusion criteria. A total of 38 articles were excluded due to insufficient information (n = 6), duplication (n = 5), and SNPs other than those of interest (n = 27). Eventually, a total of 25 studies, encompassing 6100 cases and 9249 controls, were incorporated in the final meta-analysis model , FVII rs5742910 , FXII rs1801020 , and FXIII rs5982  and rs3024477 .is model . In partp < 0.05) [All the included studies comprised both genders, except for two studies ,52 which < 0.05) ,52,53,54FXIII-A rs5982 (433 cases and 1321 controls), four studies of FXIII-A rs3024477 (404 cases and 1317 controls), six studies of FXII rs1801020 (922 cases/1285 controls), six studies of FV rs1800595  and seven studies of FVII rs5742910 (3668 cases and 4331 controls) were meta-analyzed. It is worth to take note that these 26 studies were derived from 25 eligible articles. Overall, 65% of the outcomes were based on fixed-effect models, except for FV rs1800595 , FXII rs1801020 (recessive model), FXIII-A rs5982 (over-dominant model), and FXIII-A rs3024477 . Researchers who are interested in the distribution of genotypes amongst cases and controls can request these data from the corresponding author.A total of three studies of FV rs1800595, FVII rs5742910, and FXIII rs3024477, and the over-dominant model of FXII rs1801020 exhibited protective effects against ischemic stroke , which was estimated from a single study of Pruissen et al. [FV rs5742910 was not associated with ischemic stroke risk in both Asian and Caucasian populations , FXII rs1801020 (recessive model), FXIII-A rs5982 (over-dominant model), and FXIII-A rs3024477 . However, heterogeneity was not able to be analyzed for the recessive model of FXIII-A rs3024477  and coronary heart disease (n = 231) reported that FXII levels were relatively similar between cases and controls [FXII plays a central role in the intrinsic coagulation pathway and kallikrein–kinin system, which initiates fibrinolysis, triggers complement activation, and forms platelet-thrombi . A case-controls . Likewiscontrols . Subsequcontrols .FVII rs5742910 heterozygous variant exhibited a reduction of 27.67% in their FVII antigen level as compared to the individuals with wild-type genotype [FVII promoter region reduces its promoter activity by 33%, and subsequently lowers its FVII procoagulant activity [FVII rs5742910 polymorphism is not associated with ischemic stroke risk, as indicated by the current meta-analysis. These results are in agreement with Corral et al. [FVII rs5742910 polymorphism and arterial thrombosis. In addition, Wu et al. [FVII rs5742910 polymorphism was not associated with neonatal stroke.In fact, FXII may activate FVII for the extrinsic coagulation pathway; thus, it may be linked to ischemic stroke risk. A previous study reported that individuals with genotype . Indeed,activity . On the l et al. , who faiu et al.  found nou et al.  also claFV rs1800595 polymorphism is located in exon 13 within the B-domain, which is associated with venous thrombosis [FV rs1800595 polymorphism may contribute to ischemic stroke by increasing levels of FVIII, but it is not involved in the APC pathway [FV rs1800595 polymorphism and ischemic stroke. Despite DNA sequences within the B-domain contributing to almost 50% of the protein mass, these sequences are highly polymorphic and are poorly conserved across species [The rombosis , coronarrombosis , and iscrombosis . It is h pathway ,38,41,42 pathway . FVa ina species . A numbeFXIII-A rs5982 and rs3024477 polymorphisms were not associated with ischemic stroke risk. In contrast, variant alleles of FXIII-A rs5982 and rs3024477 are associated with the increased risk of nonfatal hemorrhagic stroke [FXIII-A rs5982 and rs3024477 polymorphisms are capable of reducing clot stability, but are not associated with ischemic stroke risk.FXIII-A, an 83-kDa pro-transglutaminase, belongs to the transglutaminase family, which is covalently cross-linked with two fibrin molecules to form a fibrin clot . In the c stroke . It is wNonetheless, there were a few limitations in the current meta-analysis. For instance, the number of included studies and their respective sample sizes, were relatively small. Heterogeneity is another unavoidable limitation in this meta-analysis, which ranged from moderate to high heterogeneity. Hence, the findings of the current meta-analysis should be interpreted with caution. The presence of heterogeneity may be due to the different numbers of study subjects, different genotyping methods, and deviation from HWE. To a lesser extent, different sources of controls, such as population-based and hospital-based controls, might cause study heterogeneity. It is well recognized that population-based controls represent the true exposure experience, but they may generate recall bias ,50,51,52FV rs1800595, FVII rs5742910, FXII rs1801020, and FXIII-A rs5982 and rs3024477 polymorphisms are not significantly associated with ischemic stroke risk.As evidenced by this meta-analysis, we conclude for the first time that


P = 0.07), SCL6A4 5HTTLPR , and CCK-1R 779T>C  genes failed to demonstrate susceptibility to FD. In a subgroup analysis, only minor allele (T) in GNB3 825C>T was associated with an increased susceptibility to the epigastric pain syndrome subtype . Our meta-analysis based on available studies using an additive model failed to show that GNB3, SCL6A4, and CCK-1R polymorphisms are associated with FD susceptibility.Functional dyspepsia (FD) is a common chronic gastrointestinal disorder with a complex, undefined mechanism. Clustering of patients with FD in families highlights the role of genetic factors in the pathogenesis of FD. We performed a systematic review and meta-analysis to clarify the associations between specific gene polymorphisms and FD susceptibility. PubMed, EMBASE, the Cochrane Library, and HuGE database were searched. An additive model was adopted to determine whether previous studied genes are associated with FD susceptibility. Carriers of minor allele in GNB3 825C>T (OR = 1.15, 95% CI 0.99-1.34,  Helicobacter pylori (H. pylori) infection, and delayed gastric emptying [Functional dyspepsia (FD) is a common gastrointestinal disorder affecting 20% of the global population . FD is aemptying . PatientEmerging studies demonstrate that susceptibility to FD is influenced by hereditary factors. Clustering of patients with FD in families highlights the role of genetic factors in the pathogenesis of FD , 8. FurtIn order to search for all relevant studies investigating association of gene polymorphisms and FD susceptibility, we conducted a systematic literature search with PubMed, EMBASE, the Cochrane Library, and HuGE database through April 2018 using the following keywords and subject terms: “functional dyspepsia” or “dyspepsia” and “polymorphism,” “mutation,” or “variant.” Detailed information of search strategy can be found in the supplementary file .The inclusion criteria for studies were as follows: (1) case-control studies or cohort studies assessing the association between any gene polymorphism and FD, (2) sufficient data available to obtain genotypic frequencies to calculate odds ratio (OR) and 95% confidence interval (CI), and (3) studies in adult population. Non-English manuscripts, review articles, conference abstracts, or studies with insufficient demographic data were excluded.Two investigators  independently extracted data. Data on the author, publication year, demographic characteristics, FD diagnostic criteria, genotyping method, and distribution of genotypes were collected. The quality of the studies was assessed by using the Newcastle-Ottawa Scale (NOS) based on three components: selection, comparability, and ascertainment of outcome . From a P value <0.05 was considered significant. All statistical analyses were conducted using Stata 13.0 and Review manager 5.3.The primary outcome was the OR of a specific gene polymorphism in patients with FD compared to the control population evaluated in three or more published studies. The presence of selection bias in control participants was evaluated by calculating the Hardy-Weinberg equilibrium (HWE), and genotypes frequencies of the control participants were compared using the chi-square test. ORs with 95% CI were calculated to assess the strength of the associations between gene polymorphisms and FD. When studies demonstrated significant heterogeneity, subgroup and sensitivity analyses were performed. Otherwise, a fixed effects model was used. Publication bias was evaluated by Begg's and Egger's tests. Two-sided The initial literature search yielded 1,362 citations, of which 912 remained after removing duplicates. After screening titles and abstracts of studies, 768 were not relevant to the study aim and one was performed in the pediatric population. Furthermore, 70 review articles, 22 case reports, and 16 animal studies were excluded.Finally, 35 case-control studies met the inclusion criteria for the systematic review. Thirteen studies evaluated the G-protein beta 3 subunit gene (GNB3) 825C>T in 1,390 FD and 3,058 control participants. Four studies evaluated the SCL6A4 serotonin transporter protein (5HTTLPR) in 326 FD and 1,285 control participants. Four studies evaluated the cholecystokinin receptor (CCK-1R) 779T>C in 521 FD and 677 control participants.α (TNF-α), interleukin-10 (IL-10), IL-17, IL-1b, regulated upon activation normal T cell expressed and secreted (RANTES), sodium channel Na (SCN10A), neuronal nitric oxide synthase (nNOS), transient receptor potential vanilloid 1 receptor (TRPV1), cytochrome P450 (CYP1A), alpha 2A adrenergic receptor (ADRA2A), glutathione-S-transferases (GSTP1), CD14, catechol-o-methyltransferase (COMT), fatty acid amide hydrolase (FAAH), macrophage migration inhibitory factor (MIF), toll-like receptor-2 (TLR2), cyclooxygenase-1 (COX-1), ghrelin, and p22PHOX) or two (5HT2A) studies for susceptibility to FD [Other gene polymorphisms associated with the pathophysiology of FD have been studied in one (serotonin-1A (5HT1A), 5HT3A, 5HT4A, tumor necrosis factor-ty to FD –31.Meta-analysis was performed for the following three genes  with three or more studies available meeting the study criteria for meta-analysis. Quality scores of the selected studies ranged from seven to nine indicating moderate to high quality. The study selection process is summarized in P = 0.07). Given the presence of substantial heterogeneity (I2 = 53%), the random effects model was utilized.The additive model was used to evaluate the association between GNB3 825C>T polymorphism and FD susceptibility , Table 2P = 0.003) and a trend towards increased susceptibility to the PDS subgroup . Further subgroup analyses demonstrated that studies with N > 200  demonstrated increased susceptibility to FD but not in studies with sample size <200 . Finally, no increased susceptibility was observed when the studies were stratified by studies from Asian  or Western  population.Subgroup analyses were further conducted by FD subtypes. Minor allele (T) was associated with increased susceptibility to the EPS subgroup . Three studies were available for subgroup analysis evaluating susceptibility to FD subtypes. No association was observed in minor allele (S) and susceptibility to either FD subgroups: EPS  or PDS .SCL6A4 5HTTLPR polymorphism as a predictor of FD susceptibility was examined , Table 2P = 0.09)   [34–36, α, and 5HT3A were not associated with FD in a single study, respectively [H. pylori infection [In terms of individual studies, nNOS, CD14, MIF, and TRPV1 gene polymorphisms demonstrated increased susceptibility to FD , 42. Ghrectively , 36, 40.ectively , 40. Fornfection . COX-1 wnfection .In the present meta-analysis, we used additive genetic model to assess and measure the associations of the most extensively studied gene polymorphisms and susceptibility to FD. Carriers of the minor allele in genes GNB3 825C>T, SCL6A4 5HTTLPR, and CCK-1R 779T>C in FD failed to demonstrate susceptibility to FD. In the subgroup analysis, only minor allele (T) of GNB3 825C>T was associated with increased susceptibility to the EPS subtype.P = 0.003) and a trend towards susceptibility in PDS  subtypes. Therefore, our result suggests that GNB3-mediated signal transduction is more closely linked to pain sensory rather than motility abnormalities. However, the observation of an increased susceptibility to FD in studies with sample size >200 but not in studies with sample size <200 suggested that heterogeneity present smaller studies may have impacted the effect estimate. Furthermore, the effect size of minor allele (T) on FD susceptibility in EPS subgroup was modest and should be interpreted with caution.Guanine nucleotide-binding proteins (G-proteins) play an integral role in the function of stimulus-response coupling of membrane receptors that are linked to intracellular effector system . Hormone5-HT is the primary neurotransmitter involved in the regulation of psychological processes . 5-HT plImpaired gastric emptying is one of the major pathophysiologic mechanisms in FD. CCK-1, secreted by the neuroendocrine cells of the duodenal mucosa, has a physiologic function of delaying gastric emptying and inducing satiety. Furthermore, CCK-1 receptor belongs to the family of GPCRs and has been shown to be associated with symptoms of dyspepsia , and hypα, IL-17, IL-10, IL-1b, and RANTES), and mediation of gastric accommodation or relaxation (NOS) were hypothesized to be associated to FD susceptibility [H. pylori is a potential confounder of FD. Previous studies have demonstrated that homozygous GNB3 825C>T may be associated with dyspeptic symptom among H. pylori-negative subjects [H. pylori status in majority of the studies precluded a subgroup analysis to examine the association of genetic polymorphisms on FD susceptibility independent of H. pylori infection.Several other candidate genes have been explored for FD susceptibility. Genes that play important roles in the regulation of enteric primary afferents and brain-gut interaction , induction of inflammatory response  of GNB3 825C>T was associated with an increased susceptibility to EPS subtype. The potential role of utilizing gene polymorphisms to decide diagnostic strategy and therapeutic interventions in FD is appealing, but robust evidence is lacking. Additional studies with larger sample size and detailed characterization of the patients are needed to clarify the role of genetic polymorphisms in FD.


WHO identifies pregnant women to be at increased risk for severe outcomes from influenza virus infections and recommends that they be prioritized for influenza vaccination. The evidence supporting this, however, is inconsistent. Ecologic studies in particular suggest more severe outcomes from influenza infection during pregnancy than studies based on individual patient data. Individual studies however may be underpowered and, as reported in a previous systematic review, confounding factors could not be adjusted for. We therefore conducted an individual participant data meta-analysis to assess the risk for severe outcomes of influenza infection in pregnant women while adjusting for other prognostic factors.We contacted authors of studies included in a recently published systematic review. We pooled the individual participant data of women of reproductive age and laboratory confirmation of influenza virus infection. We used a generalized linear mixed model and reported odds ratios (OR) and 95% confidence intervals (CI).A total of 33 datasets with data on 186,656 individuals were available, including 36,498 eligible women of reproductive age and known pregnancy status. In the multivariable model, pregnancy was associated with a 7 times higher risk of hospital admission , among patients receiving medical care as in- or outpatients, pregnancy was associated with a lower risk of admission to intensive care units , and was not significantly associated with death .Our study found a higher risk of influenza associated hospitalization among pregnant women as compared to non-pregnant women. We did not find a higher mortality rate or higher likelihood of ICU admission among pregnant women who sought medical care. However, this study did not address whether a true community based cohort of pregnant women is at higher risk of influenza associated complications. Pregnancy is considered to be an important risk factor for severe influenza-associated illness –3. DurinTwo systematic reviews conducted by three of the co-authors , however, questioned whether pregnancy confers an increased risk for severe influenza illness: beyond increasing the need for hospitalization, pregnancy was not associated with more severe influenza associated outcomes in studies where exposure to influenza and outcomes are measured in individuals, including admission to an intensive care unit (ICU), and death , 5. ThesTo explore the potential influence of confounding, we obtained individual participant-level data (IPD) from studies of reproductive age women with confirmed pregnancy status who had laboratory confirmed influenza virus infection, and conducted a multivariable, IPD meta-analysis to assess the odds of severe influenza outcomes  among pregnant women compared to non-pregnant women, adjusting for demographic, comorbid, and clinical covariates.The eligibility criteria, co-variates of interest and analyses plan were defined a priori.We requested de-identified IPD from corresponding authors of studies included in our prior systematic reviews, at varying levels of observation, including community, hospital, and ICU , 5. StudEligible study designs included cohort as well as case control studies published in English, French, Spanish, and German, and must have reported IPD on pregnancy as a risk factor for influenza-associated mortality (primary outcome) and/or influenza associated hospitalization and/or ICU admission (secondary outcomes). Previous systematic reviews included pneumonia as an outcome, however, given its inconsistent definition and rare reporting, we decided a priori to exclude pneumonia as an outcome of interest , 5. WomeAll datasets were compared with the published results and checked for missing or potentially invalid data. Discrepancies were discussed with the study authors. Study quality was assessed independently and in duplicate using the Newcastle-Ottawa Scale  as previFor the primary analyses, we only considered covariates with less than 20% missing data across all studies (‘core variables’). We chose the 20% threshold to balance between excluding potentially relevant risk factors from the multivariable model with excessive missing data, but simultaneously preserving sample size at both the participant and study level. These ‘core variables’ were: age, antiviral usage, diabetes mellitus, cardio-respiratory diseases, immunocompromised status, and influenza vaccination status as defined in the original studies. Vaccination status was only included for ICU admission in a sensitivity analysis due to more than 20% missing data. We conducted a one-stage IPD meta-analysis. First, we run univariate analyses using a generalized linear mixed model (GLMM) with the participant level as a fixed effect and the study level as a random effect. We calculated odds ratios (OR) and associated 95% confidence intervals (CI). For the multivariable analyses, all core variables were included. Furthermore, we conducted post-hoc subgroup analyses separating study populations enrolled in the community and in hospitalized patients, respectively. In a secondary analysis, we added the following covariates with > 20% missing data that had been excluded from the primary analysis but were of potential relevance one by one to the primary model: obesity, smoking status, chronic respiratory diseases alone instead of the composite of cardiac-respiratory co-morbidities, as well as vaccination status for ICU admission. We also considered this as a sensitivity analysis for pregnancy as a risk factor by testing the robustness of our findings when adding additional potential confounders. We did not plan to conduct a subgroup analysis based on influenza season as we anticipated, based on the original systematic review, that there would be sparse data for seasons other than the 2009 H1N1 pandemic. We used PASW Statistics 18 and SAS/STAT 9.4 for analysis. Given the low event rate, we are using the term ‘risk’ throughout the text when discussing ORs to improve readability. Age was treated as a continuous variable and odds were reported per 5-year increase in age.There was no patient/public involvement.n = 1106) than in studies that had not been shared (n = 1685). Otherwise, the study characteristics were similar between included and excluded studies: The median Newcastle-Ottawa score was 6 (interquartile range 6–7) in each group. Similarly, 11/33 (33.3%) of included studies were from low- and middle-income countries as compared to 33/110 (30.0%) in excluded studies, and a cohort study design was the most common design (31 of 33 (93.9%) in included studies compared to 103/110 (93.6%) in excluded studies). Nucleic acid amplification testing was used for the case definition in all studies with data provided for this analysis, with the exception of two studies which used any positive influenza test for case confirmation  [A total of 33 –42 data culture) . Studies31 of 33 3.9% in iWe had IPD of 43,837 (23.5%) women of reproductive age (15–45 years of age). Pregnancy status was unavailable for 7339 (16.7%), leaving us with a total of 36,498 eligible participants. Nine studies with a total of 27,993 (76.7%) patients were conducted in a community setting, 20 studies with a total of 8013 (22.0%) enrolled patients that were admitted to the hospital, and 4 studies with 492 (1.3%) patients included patients in an ICU setting, only. Influenza vaccination status was missing in 11.9 and 6.6% of participants with influenza-associated mortality and hospital admission outcomes, respectively, and it was missing in 48.3% of participants with ICU admission as an outcome. Missing data in the other core variables ranged from 7.1 to 19.1% of participants depending on outcome of interest. Among variables for secondary outcomes, obesity status was missing in 36.3 to 54.5%, smoking status in 16.6 to 86.9%, and chronic respiratory comorbidity in 7.4 to 21.1%.The 4379 pregnant women 12.0%) were significantly younger (mean 26.7 years) compared to non-pregnant women   1.00, 95% CI 0.75–1.34) , nor in hospital-based studies .Of the additional variables considered in the secondary analysis, obesity was independently associated with an increased risk of influenza-associated mortality  along with smoking . The lack of association between pregnancy and influenza-associated mortality persisted when additional covariates were added in the sensitivity analysis, with the exception when smoking status was added to the model resulting in a higher risk for death in pregnant women  (Table Nine of 33 studies (27%) reported on influenza-associated hospital admission with outcome data available for 27,699 participants. Four of the studies were conducted in Europe, two in Australia, and one each in Brazil, China, and Mexico. Pregnant women were at a significantly increased risk for hospitalization compared to non-pregnant women in the univariate analysis  , followed by studies from North America , and Asia . Pregnancy was associated with a reduced risk for ICU admission in the univariate analysis . Older age by 5-year increase , cardio-respiratory co-morbidities , diabetes , immunosuppression  and antiviral usage  were associated with an increased risk of ICU admission (Table Data for influenza-associated ICU admission was reported in 26 out of 33 (79%) studies with outcome data available for 9166 participants. The majority of studies were conducted in Europe , participants known at baseline to be not admitted to a hospital  or participants with no information on hospital admission status but information on ICU admission status . In our post-hoc subgroup analyses, the association seemed to be driven by studies conducted in hospitalized patients , while there was no significant association with ICU admission in community-based studies .In the multivariable model, pregnancy remained significantly associated with a decreased risk of ICU admission . The point estimates for the other variables were similar; however, immunosuppression was no longer significantly associated  with ICU admission. In the primary analysis, the comparison group for ICU admission was –depending on data availability- participants who at baseline were admitted to a hospital but not to the ICU . When obesity was included in the model, pregnancy was no longer significantly associated  (Table In our IPD meta-analysis, pregnancy was associated with a seven times higher risk of hospitalization but, among patients seeking medical care as in-or outpatients, was not found to be independently associated with influenza-associated mortality, after adjusting for other potential risk factors in multivariable analysis. These findings are consistent with previous systematic reviews/meta-analyses , 5. HoweOne explanation for our findings is that pregnant women may be more likely to seek care and be preferentially admitted to a hospital because of concerns that they are at higher risk for complications, particularly in the high resource settings where most of the included studies were conducted. The fact that pregnant women were not found to be at increased risk for death or ICU admission despite a higher hospital admission rate would support such an explanation. Similarly, pregnant women being considered to be at higher risk may explain the observation that pregnant women were more likely to be treated with antivirals and were more likely vaccinated. While our multivariable analysis accounted for comorbidities, vaccination status, and antiviral treatment, potential selection bias could not be controlled for. Most of our data were from hospitalized cohorts, a group in which non-severely ill pregnant women may have been overrepresented -if there was a lower threshold to test for influenza and admit women with influenza if pregnant. While precautionary influenza hospitalizations may be preventable with influenza vaccination, this is currently not supported by the available evidence. Furthermore, our data did not provide consistent support for pregnancy being an independent risk factor for severe influenza disease across outcomes. The direction of the association was not consistent among the three outcomes: in the primary analysis, there was a significantly increased risk for hospitalization, a significantly decreased risk for ICU admission, and no significant risk for mortality. These findings are in keeping with previously published systematic reviews , 5 and sAs already outlined in a previous systematic review, the majority of ecological studies suggest more severe outcomes in pregnant women, while a meta-analysis of individual-patient studies did not . The finStrengths of this review were the extensive quantity of data included along with the breadth of studies and risk factors examined. The IPD allowed us to evaluate pregnancy as an independent risk factor while adjusting for several patient characteristics including comorbidities. The main limitation of our meta-analysis was the potential for selection bias in source studies, where pregnant women enrolled in the studies might have been less ill than non-pregnant women and no studies where women living in the community were followed until hospitalization and afterwards to assess for severe outcomes. Missing data among participants for some covariates was yet another limitation. Furthermore, risk factors may have been defined differently across studies, e.g. the diagnosis of obesity would optimally be based on the body mass index prior to being pregnant. In addition, differences in patient populations resulted in clinical heterogeneity which resulted in statistical heterogeneity as shown in our aggregate data systematic review . FurtherOur study found a higher risk of influenza associated hospitalization among pregnant women as compared to non-pregnant women. We did not find a higher mortality rate or higher likelihood of ICU admission among pregnant women who sought medical care as in- or outpatients. However, this study did not address whether a true community based cohort of pregnant women is at higher risk of influenza associated complications. To address this question, a cohort study of pregnant and non-pregnant women with a study population representative of the community who are infected with influenza would need to be conducted.


Cardiovascular disease (CVD) is the leading cause of death worldwide. Some studies have suggested anassociation between serum uric acid levels and cardiovascular mortality; however, the results have not been summarized in a meta-analysis.A comprehensive search of all related studies until April 2018was performed in MEDLINE/PubMed and Scopus databases DerSimonianand Laird random-effects models were used to combine hazard ratios (HRs) with 95% confidence intervals (CIs). Dose-response analysis was also carried out.2 = 79%). Sub-group analysis showed this relationshipwasstronger in women compared to men. Moreover, there was a significant non-linear association between uric acid levels and the risk of CVD mortality .Thirty-two studies containing forty-four arms with 1,134,073 participants reported association between uric acid and risk of CVD mortality were included in our analysis. Pooled results showed a significant positive association between uric acid levels and risk of CVD mortality (HR 1.45, 95% CI 1.33–1.58, IOur analysis indicates a positive dose-response association between SUA and CVD mortality risk. Cardiovascular diseases (CVD) are the first leading cause of death worldwide . This miTo gain a greater understanding of the prognostic value of SUA for future clinical decision making, we conducted a meta-analysis of prospective cohort studies with dose– response analysis to determine the relationship between SUA and CVD mortality.https://www.ncbi.nlm.nih.gov/pubmed/) and Scopus (https://www.scopus.com/search/) databases up to April 2019 without any time restriction. Following keyword was followed for systematic search: in PubMed/MEDLINE: (((“Uric Acid”[Mesh] OR uric acid [Title/Abstract]) OR serum uric acid [Title/Abstract]) AND  OR “cardiovascular mortality”[Title/Abstract]) OR “CVD mortality”[Title/Abstract]) OR CVD-mortality [Title/Abstract])) AND  OR follow-up [Title/Abstract]) OR cohort [Title/Abstract]), in Scopus: ((TITLE-ABS-KEY (prospective) OR TITLE-ABS-KEY  OR TITLE-ABS-KEY (follow-up) OR TITLE-ABS-KEY (cohort))) AND ((TITLE-ABS-KEY (uric AND acid) OR TITLE-ABS-KEY (serum AND uric AND acid))) AND  OR TITLE-ABS-KEY  OR TITLE-ABS-KEY  OR TITLE-ABS-KEY  OR TITLE-ABS-KEY )).This meta-analysis conducted by following the Meta-analysis of Observational Studies in Epidemiology study guidelines (MOOSE) . A comprNon-English articles, reviews papers, editorials, non CVD mortality, non-human studies, in vitro research, case reports, and letters without sufficient data were excluded. Studies that met the following inclusion criteria were included in this meta-analysis:1) Cohort study design with CVD mortality outcome.2) Hazard ratio (HR) and the corresponding 95% confidence interval (CI) of CVD mortality were reported based on uric acid levels.The first author, publication year, country, study design, number of participants, mean age, gender, years of follow-up, hazard ratios and 95% CIs of CVD mortality information extracted from included studies.P < 0.10 and I2 < %50 were considered as heterogeneity detection among included studies. In order to find source of heterogeneity, subgroup analysis was conducted based on gender, whereas meta-regression analysis was conducted based on follow-up years, age of participants and HR of CVD mortality. Non-linear association was examined by modeling concentration level using restricted cubic splines [The STATA 14.0 statistical software  was used for statistical analyses. Combined results of hazard ratio of CVD mortality conducted by Random-effects model . P < 0.1A flow chart of included studies is shown in Fig. Table p = 0.86) or duration of follow-up(p = 0.44).In 44 arms, pooled results from the random effects model showed a positive association between SUA and risk of CVD mortality in highest versus lowest category of SUA    Fig. .Fig. 4Dp = 0.04 and Egger’s test). Using the ‘Trim and fill’ method to adjust for publication bias and random effects model showed 62 arms with pooled results HR = 1.19 (CI:1.09–1.30).Figure The present meta-analysis of cohort studies revealed that there is a strong relationship between SUA levels and risk of CVD mortality. Moreover, the pooled HR from the random-effects dose-response model indicated that this positive association is stable when SUA is greater than 6 mg/dL. Although the exact mechanism of the relationship between SUA and CVD mortality risk has not yet been elucidated, previous studies have suggested some possible explanations..An experimental study has reported that using an inhibitor of uricase can elevate blood pressure in rats by activating the renin-angiotensin system and inhibition of nitric oxide synthase . MoreoveIt has been suggested that UA can significantly slow down coronary flow by promoting the calcification of coronary arteries , 46. In The main strength of this meta-analysis was the application of cohort studies containing over one million participants, and subsequent dose-response analysis. This study has some possible limitation. The heterogeneity in the study populations is the main limitation of this study. Moreover, the duration of follow-up in our included studies differed. Further, there is an insufficient number of randomized clinical trials to confirm the effects of decreasing SUA levels on CVD deaths; however, our results suggest higher levels of SUA is an independent risk factor associated with CVD mortality. Furthermore, although we searched the literature extensively, we did not explore grey or unpublished literature to limit the possibility of publication bias.In conclusion, our analysis indicates a positive dose-response association between SUA and CVD mortality risk; however, further clinical trials are needed to confirm these findings and to determine the possible cause-effect relationship.


Cyclin D2/D3 (CCND2/3) are core components of the machinery that drives cell cycle progression and therefore, are associated with tumorigenesis. Currently, there are contradictory evidences on the function of CCND2/3 in tumorigenesis. Thus, we conducted a comprehensive meta‐analysis to derive a precise predictive value of CCND2/3 in various tumors. We searched PubMed, EMBASE, Web of Science for eligible studies up to October 8, 2018. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) of OS or DFS/PFS/RFS were calculated using Forest plot analysis to demonstrate their associations. A total of 14 studies were ultimately included in this meta‐analysis. Our results indicated CCND2/3 played an oncogenic role in all of the cancer patients . In tumor subgroup, CCND2 was associated with shorter OS in patients with gastric cancer , whereas it might be a tumor suppressor in NSCLC . In addition, CCND3 was correlated to reduced OS in breast cancer patients  and shorter DFS/PFS/RFS in bladder cancer patients . Taken together, CCND2/3 could be the promising biomarkers for predicting the prognosis of patients with malignant neoplasms. Cyclin–CDK complexes promote a plethora of cellular proteins entry into G1 phase. It also coordinates the sequential completion of DNA replication and in turn determines cell division, thereby ensuring that the cell cycle progresses in an ordered manner., and D3,Cyclin D1 (CCND1) is an established oncogene. The involvement of CCND1 amplification and overexpression is associated with tumor differentiation, increased metastasis, and poor survival.Several meta‐analysis articles have explored the prognostic role of CCND1 in breast cancer,22.1http://kmplot.com/analysis/).http://gepia.cancer-pku.cn/).https://www.proteinatlas.org/).The prognostic data of CCND2/3 were from KM‐plotter  and (“Cyclin D2” or “Cyclin D3”) and .2.3All eligible articles were selected according to the following inclusion criteria: (a) Human subjects, English publications; (b) Independent case‐control or cohort studies; (c) Possessing at least one of D‐type cyclins (D2 or D3); (d) Availability of hazard ratios (HRs) for prognostic outcomes data of both cases and controls. The exclusion criteria were as follows: (a) No case‐control study; (b) Duplicate or unavailable data; (c) Studies not related to Cyclin D2 or Cyclin D3.2.4Two blind investigators assessed the quality of all included studies according to the Newcastle‐Ottawa Scale (NOS) system, which is one of the most useful scale to evaluate the quality of non‐randomized studies in meta‐analysis.2.5P‐values. Data were extracted from Kaplan–Meier curves to extrapolate HRs with 95% CIs using previously described methods, if it could not be directly obtained from each article.All data from eligible studies were extracted independently. Ambiguous data were reviewed in detail between authors to reach a consensus. All the extracted data were recorded in a unified format and the collected items were as follows: first author' name, publication year, patients' median or mean age, nationality, dominant ethnicity, the number of patients, investigating method, follow‐up time, cutoff value, and hazard ratios (HRs) for prognostic outcomes  along with their 95% CI and 2.62 statistic was utilized to quantify the effect of heterogeneity in each eligible study. If the heterogeneity is acceptable (I2 < 50% suggested no obvious heterogeneity), the fixed effect model will be adopted; otherwise, a random‐effects model was used instead. In addition, subgroup analysis was adopted to reduce the effects of heterogeneity. Begg's funnel plots and Egger's linear regression test were used to detect the publication bias between all included studies. Sensitive analysis was tested to determine the stability and reliability of the results in this meta‐analysis. All P‐values were calculated using a two‐sided test, and P < 0.05 was considered statistically significant. STATA 12.0 software  was utilized to dispose all above statistical analyses.The Forest plot analysis was used to assess the association between CCND2/3 and various cancers. A vertical invalid line  was considered as a graphic center. A prism is used to describe the effects and confidence intervals of multiple research. In this study, when the prism intersects the invalid line, suggesting CCND2/3 has no significant prediction for cancer prognosis. When the prism falls to the right of the invalid line, suggesting CCND2/3 predicts high risk of cancers. When the prism falls to the left of the invalid line, suggesting CCND2/3 predicts low risk of cancers. Higgins I33.1P < 0.05). CCND3 might be associated with the prognosis in patients with cervical squamous cell cancer or liver hepatocellular cancer or sarcoma or thymoma or thyroid carcinoma or uterine corpus endometrial carcinoma . Discrepant mRNA levels of CCND2/3 were observed in normal or tumor tissue in various cancers  . In ethnicity subgroup, high expression of CCND2 was related to unfavorable OS in Asians    Figure A. In et) Figure B. When s) Figure C. Due to3.4P = 0.001)  in NSCLC patients, while no significant association was found in other tumor types  , which indicated there was no significant association between OS and CCND3 expression. , while no significant association was found in other cancers      of patients with various cancers were explored systemically. Our results indicated CCND2/3 played an oncogenic role in all cancer patients. We found high expression of CCDN2 was associated with reduced OS in gastric cancer patients, whereas it was related with favorable outcome in NSCLC patients. In addition, CCND3 overexpression was an adverse predictor of OS in breast cancer. Meanwhile, CCND3‐positive expression was correlated with shorter DFS/RFS/PFS in bladder cancer. These results indicated CCND2/3 could be promising biomarkers and novel therapeutic targets for various cancers. When stratified by ethnicity, only Asians revealed significant association between CCDN2 expression and OS level. As for CCND3, significant association between CCND3 expression and DFS/RFS/PFS level was only observed in Caucasians. Thus, CCND2/3 expression in the patients above might be useful for prognosis prediction. Sensitivity analyses and publication bias were performed to make sure that all included studies were robust and stable.Cyclin D2 is a direct target gene of proto‐oncogene Myc and links growth signaling with the nuclear export of p27, contributing to the progression of the cell cycle through the G(0)‐G(1) transition.There are many strengths to the study. Sensitivity and publication bias analysis were conducted to ensure robustness of the study. In addition, this is the first systematic review to address the prognostic role of CCND2/3 in multiple human malignant neoplasms. To a certain extent, limitations should also be addressed. First, it was difficult to establish a standard expression cutoff point due to varied cutoff points in the selected studies. This could lead to bias in the effectiveness of CCND2/3 as a prognostic factor in cancer patients. Second, the retrospective nature of the majority of the studies could hinder a clear impact on group baseline features. Third, the number of included studies in the stratified analyses was not enough, leading to the limited statistical power to explore the real relationship. Last but not least, cancer is a kind of multifactorial disease, related to complex interactions between genetic and environment factors. It is so complicated that the investigation of gene expression cannot predict the prognosis of cancers accurately. Considering these limitations, our results should be interpreted rigorously, and more attention should be paid to the function of CCND2/3 in various carcinomas in large multicentric studies.5In summary, this meta‐analysis suggested that CCND2 played an oncogenic role in gastric cancer, whereas it could also be a tumor suppressor in NSCLC. In addition, CCND3 was an adverse prognostic factor in breast cancer and bladder cancer. These results indicated CCND2/3 could be promising biomarkers and novel therapeutic targets for patients with malignant neoplasms, and the biological functions of CCND2/3 are of great research value of the subject.The authors declare that they have no competing interests. Click here for additional data file. Click here for additional data file.


The aim of the present study was to determine whether the interleukin-6 (IL-6) -572G/C polymorphism correlates with prostate cancer.According to inclusion and exclusion criteria, the association of the IL-6 -572G/C polymorphism with prostate cancer was searched in databases and analyzed using comprehensive meta-analysis software. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the associations.We considered a total of six case-control studies including 2237 patients and 1754 controls and the meta-analysis results showed significant association between the IL-6 -572G/C polymorphism and prostate cancer risk. In stratified analyses by ethnicity, significant associations were found among Asian populations. However, no significant association was found in Caucasian populations.Our findings demonstrated that the -572G/C polymorphism of the IL-6 gene may be a risk factor for the development of prostate cancer in Asians. Prostate cancer is a common cause of cancer-related death and is one of the most commonly diagnosed malignancies in menInterleukin-6(IL-6) is a pleiotropic cytokine that not only exhibits immunological effect but also functions in haematopoiesis, bone metabolism, and tissue regenerationSeveral studies have been performed to figure out whether there is an association between prostate cancer and the IL-6 −572G/C polymorphism, but the results are equivocal. Meta-analysis combines the results from relevant studies, explores the heterogeneity and identifies subgroups associated with the factor of interest.Therefore, we performed this meta-analysis to clarify the association of this variant with prostate cancer.PubMed, Embase, Web of Science, Google Scholar, China Biological Medicine Database (CBMD), and the China National Knowledge Infrastructure (CNKI) databases were searched for papers linking the IL6 −572G/C polymorphism prior to March 2017, using the keyword: “interleukin 6/IL6”,“−572G/C”,,“prostate cancer”,“polymorphism”. The search was not limited to English language articles. Furthermore, the reference lists of retrieved articles were manually screened to obtain relevant papers.Studies included in this meta-analysis meet the following inclusion criteria: I) case-control design; II) evaluation of the correlation of IL-6 −572G/C polymorphism with prostate cancer risk; and III) adequate data to calculate the odds ratio (OR) and its corresponding 95% confidence interval (CI). Of studies published, the same case series, we selected the most recent papers. In addition, studies without effective information were excluded after the efforts to extract data from the included paper.The following information was extracted: a) authors, b) year of publication, c) country, d) ethnicity of the study subjects, e) sample size, f) allele and genotype distribution, and g) evidence of Hardy-Weinberg equilibrium (HWE) in the control population.Meta-analysis was performed using a comprehensive meta-analysis software program .The pooled OR and 95% CI were used to investigate the association between the risk of prostate cancer and IL-6 −572G/C polymorphism. In the present meta-analysis, we adopted the following genetic models:a homozygote comparison(CC vs GG), a heterozygote comparison(CG vs GG), a dominant model(CC+CG vs GG) and a recessive model (CC vs CG+GG)The search strategy retrieved 21 relevant papers. Based on the inclusion criteria, 6 case-control studies met inclusive criteria 11–16, and 15 studies were excluded. The flow chart for the study selection is shown in The combined data showed that the IL-6 −572G/C polymorphism is associated with increased prostate cancer risk in various genetic models indicated in When patients were stratified according to HWE, a significant association was found in the studies consistent with HWE. Sensitivity analysis was performed via assess the influence of each individual paper on the pooled OR via deleting one single study each time.There is no single article that influenced the pooled ORs, suggesting that the results are stable.The funnel plot was performed to assess the publication bias. There was no evidence of publication bias visually from the funnel plot , which sProstate cancer is the second most common cancer diagnosed in men, and the fourth most common cancer diagnosed worldwide. Although genetic variants appear to play an important role in prostate cancer risk, the precise mechanism is likely to be complexFrom the combined meta-analysis results, the data suggest sthat −572G/C polymorphism was associated with the risk of prostate cancer. For the difference in the environment in which they lived in, we perform a ethnicity-specific subgroup analysis, and significant association was found in Asians, but not in Caucasians. Deviation of allelic distributions from HWE may contribute to between-study heterogeneity, the sub-group analysis via limiting this meta-analysis to those papers that are consistent with HWE revealed that our data was robust. No evidence showed publication bias in this meta-analysis.The meta-analysis suggested that the GG genotype of IL-6 −572G/C polymorphism might be related to the increased risk of prostate cancer in Asians. Nevertheless, the mechanism of how this polymorphism relates to prostate cancer risk remains unclear. Previous study suggested that the GG and GC genotypes of the −572G/C polymorphism are associated with higher IL-6 serum levels than in the CC genotypeAlthough our study provides a better understanding of the IL-6 −572G/C polymorphism and susceptibility to prostate cancer, it has limitations. Firstly, only two studies involving Caucasian patients met inclusion criteria. This may not provide enough statistical power to detect the possible effects of the −572G/C polymorphism in Caucasian patients. Secondly, original individual data could not be extracted from each study and our results were based on unadjusted estimates, the introduction of heterogeneity is therefore unavoidable and may affect our results. Thirdly, the possibility of gene-gene interactions and environmental factors were also not considered in our study.In summary, the present meta-analysis indicated that the IL-6 −572G/C polymorphism might increase the prostate cancer risk in the Asian population.


Background: Anti-bacterial drugs are thought to be associated with several malignancies.Objective: We conducted a systematic review and meta-analysis to assess the association between antibacterial drug exposure and the risk of digestive system neoplasms.Methods: Relevant publications reporting a relationship between antibiotic use and the risk of cancer were identified in PubMed, EMBASE, and Cochrane Central Register through June 2018. The random-effects model was selected to pool the risk ratios (RRs) and determine 95% confidence intervals (95% CIs). We performed subgroup analyses by tumor organ site, individual antibacterial drug class, and drug dose accumulation.Results: A total of 17 eligible studies  involving 77,284 cancer patients were included in our analyses. Anti-bacterial drug exposure slightly increased the risk of overall digestive system cancer , stomach and small intestine , anorectocolonic , and hepatobiliary and pancreatic cancers . For different anti-bacterial drugs classes, nitroimidazoles  and quinolones  showed a modest association with the risk of cancers incidence. The risks of digestive system cancers increased with the rise of drug dose accumulation: low , intermediate , and high .Conclusions: Anti-bacterial drug exposure was associated with the risks of digestive system cancer occurrence in our analysis. Digestive system cancers, such as esophageal, stomach and small intestine, anorectocolonic, hepatobiliary, and pancreatic cancers, are a global threat to human health and a leading cause of cancer death –3. The iWith the concern of the global, widespread use of anti-bacterial agents, the effects on drug-induced cancer create uncertainty. We conducted a systematic review and meta-analysis to assess the association between the risk of digestive neoplasms and anti-bacterial drug exposure.We performed the systematic review based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines . The proA search of the relevant publications (in English) up to June 2018 was conducted in PubMed, EMBASE, and the Cochrane central register. Case-control, cohort studies, and randomized control trials (RCT) were identified by searching with the following Medical Subject Heading (Mesh) terms and text words: “neoplasms,” “tumors,” “tumor,” “cancer,” “cancers,” “malignant neoplasms,” “neoplasm,” and “anti-bacterial agents,” “anti-bacterial compounds,” “anti-infective agents,” “anti-mycobacterial agents,” and “risk.” Additional literature was searched by scanning the reference lists of included studies. Abstracts and titles were reviewed in the primary search independently by both investigators . Potentially relevant articles were evaluated in detail, and disagreements between investigators were resolved by consensus. Studies were included if they met the following criteria: (1) Study reported the association between antibiotic exposure and the digestive system cancer risk; (2) Study provided four-fold table data or effect sizes, such as risk ratio (RR), relative risk (RR), and odds ratio (OR); (3) Study used prospective or retrospective, cohort or (nested) case-control designs. When multiple articles originated from the same population, we would combine these articles into one study, and used the most applicable data, or data with the longest follow-up duration.Two investigators extracted all data independently . Data was double checked for accuracy after finishing the individual work, and arguments were resolved by discussion. Information needed for the meta-analysis that was absent from any of the selected studies was obtained by contacting the authors via email. The following data were extracted from each included study: journal name, first author name, publication year, country or region, study type (case–control studies/cohort studies/nested case–control studies/RCTs), follow-up period, total patients, number of anti-bacterial drugs exposed to (which could include 0), detailed prescription of anti-bacterial drug use, RRs, ORs, or SIRs, and the corresponding 95% confidence intervals (CIs).The two investigators  used the Newcastle-Ottawa Scale (NOS) to assess the quality of cohort or nested case-control studies independently , and a sI2 statistic value  . A significant degree of heterogeneity between studies was defined using the ic value , 17, and2 > 50%) , 19. Giv2 > 50%) , 21.We performed subgroup analyses according to different digestive system organ sites involving the esophagus, stomach and small intestine, anorectocolonic, hepatobiliary system, and pancreas , 10. RisA total of 4,392 articles were initially identified from the search in the selected databases and 78 articles were retrieved and further reviewed after the screening of titles and abstracts. We ultimately identified 17 eligible studies including 13 observational studies , 23–31 –35 Figu. The chap = 0.68) and funnel plot .Thirteen observational studies were of significant high quality (scores ranged from 7 to 9) and four RCTs were assessed as moderate or high quality , 3. Eggenel plot  did not An increased risk of total digestive system cancers was associated with whole anti-bacterial drug exposure . Slightly elevated cancer risks related to anti-bacterial drugs were also demonstrated in subgroups of stomach and small intestinal , anorectocolonic , hepatobiliary, and pancreatic cancers . However, esophageal cancer  showed no relationship to anti-bacterial drug use , Table 2Anti-bacterial drug exposure and gastric cancer event risk was evaluated in a combination of 11 studies, no obvious association was observed between gastric cancer and exposure to each individual anti-bacterial drug . The RR Analysis of the subgroups of low, intermediate, and high anti-bacterial drug dose accumulation revealed that the digestive system cancer risks increased with the rise of medical prescriptions. The RRs (95% CIs) for the low, intermediate, and high groups were: 1.08 , 1.15 , and 1.22 , respectively. The dose accumulation effect on the risk of cancer was replicated in analyses among groups of cephalosporins, macrolides, penicillins, and quinolones .We conducted the meta-analysis by combining 13 observational studies with four RCTs, a total of 77,284 digestive system cancer cases from a large population of 18,205,771 individuals were included in our analyses. Statistically significant associations between anti-bacterial drug exposure and the risk of digestive cancers occurrence were observed, especially in the subgroups of anorectocolonic, hepatobiliary, and pancreatic cancers. Although only modest associations were observed, a significant connection between higher drug dose accumulation and higher cancer risk further substantiated the correlations.In our study, populations with exposures to nitroimidazoles and quinolones had a higher cancer risk than any other individual anti-bacterial drug class, these two anti-bacterial drug classes were commonly used to treat gastrointestinal infections or anaerobic bacterial infections , 37. PreA variety of studies support the theory that Helicobacter pylori (Hp) plays an important role in gastric cancer incidence and development , 48. EarThere has been no evidence to suggest that anti-bacterial drugs have a direct carcinogenic effect on cancer development in previous investigations . We obseAnother possible explanation for the observed association is that anti-bacterial drug exposure induces changes in the composition of gut microbiota , 57. TheTo our knowledge, only one meta-analysis has evaluated the relationships between anti-bacterial drug exposure and cancer incidence risk. This study concluded that anti-bacterial drug ever-use is related to a slightly elevated breast cancer risk . A numbeOur study had several limitations. First, most of our included studies were observational, therefore, comprehensive information on residual confounding factors and the underlying diseases of patients was not available. If we ignore the dose accumulation response effect, the slightly increased risk of digestive cancer in our study may be partially explained by confounding factors and infections requiring anti-bacterial drug treatment. However, included studies were adjusted for some confounders such as sex, age, partial medical history including the use of acetylsalicylic acids, non-steroidal anti-inflammatory drugs and acetylsalicylic acids. Second, although we conducted subgroup analyses based on follow-up period, the follow-up time duration did not reflect the actual exposure dose of anti-bacterial drugs. Third, most of included studies were retrospective, although we have try our best to contact authors via email. The dose of anti-bacterial drug use was not obtained. Fourth, the included patients may receive multiple antibiotics at the same time. All of the data was retrieved from patient demographics database. We can only conducted subgroups analysis in different antibacterial drugs. Finally, lack of information on anti-bacterial drug treatment indications or pathogens is another notable limitation. If we combine anti-bacterial drug exposure and infectious pathogens, additional values in evaluating the relationship between anti-bacterial drug exposure and digestive system cancer incidence may exist.In conclusion, anti-bacterial drug exposure slightly increased the risk of total digestive system cancer development, and the risks were elevated with the rise of anti-bacterial drug dose accumulation. Nitroimidazoles (mainly metroimidazole) and quinolones showed a closer relationship to cancer, especially in anorectocolonic tumors and hepatobiliary and pancreatic malignancies. Anti-bacterial drug exposure may be a treatment indicator rather than a direct carcinogen. Changes in intestinal microbiota or immune defense deregulation induced by anti-bacterial drugs may be the indirect cause of increased cancer risks. More comprehensive information about treatment indications or underlying diseases would be valuable information to combine with our analyses.CB: study concept and design, acquisition of data, analysis and interpretation of data, statistical analysis, drafting of the manuscript, critical revision of the manuscript, and approved final submission. KW: study concept and design, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript, approved final submission, and study supervision. YD: acquisition of data, analysis and interpretation of data, statistical analysis, drafting of the manuscript, and technical or material support. JK: study concept and design, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript, and approved final submission.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The relationship between obstructive sleep apnea hypopnea syndrome (OSAHS) and a variety of disease from obesity, type 2 diabetes mellitus and cardiovascular disease has been investigated previously. Reduced adiponectin levels are also associated with increased risk of these disease. However, whether serum/plasma adiponectin levels in OSAHS patients are lower than their counterparts remain controversial. Therefore, this study evaluated the association between serum/plasma adiponectin levels and OSAHS.2 test. Subgroup analysis and meta-regression analysis were employed to detect the sources of the heterogeneity. RevMan 5.3 and Stata 12.0 software were used in this meta-analysis for data synthesis.We performed a comprehensive literature search to locate eligible articles published on electronic databases including PubMed, EMBASE, Cochrane Library, WANFANG (Chinese database), VIP (Chinese Database) and Chinese National Knowledge Infrastructure (CNKI). The methodological quality of included studies was evaluated using the Newcastle-Ottawa scale (NOS). Pooled standard mean difference (SMD) with 95% confidence interval (CI) was calculated as effect size. Heterogeneity test was performed by Cochrane Q test and Ip < 0.001]. Subgroup analysis indicated that the heterogeneity would decreased when subgroup analysis was stratified by race. In addition, meta-regression analysis also suggested that the adiponectin levels were only significantly correlated with race. The removal of any independent study did not affect the pooled SMD in the sensitivity analysis.A total of 20 eligible studies with 28 databases involving 1356 participants were included in this meta-analysis. Results revealed that serum/plasma adiponectin levels in OSAHS patients were significantly lower than that in controls [SMD = − 0.71, 95% CI = − 0.92 to − 0.49, The serum/plasma adiponectin levels were significantly lower in OSAHS patients than that in control subjects, suggesting a possible role of adiponectin in OSAHS pathogenesis, deserves further studies as a potential marker of OSAHS. Obstructive sleep apnea hypopnea syndrome (OSAHS), the most frequent sleep-related breathing disorder, is characterized by repetitive events of partial or complete collapse of upper airway during sleep. Clinically, it is characterized by snoring, witnessed apneic episodes, marked sleep fragmentation and daytime sleepiness, which would lead to metabolic disturbance, impaired quality of life, high morbidity as well as high mortality . ApproxiAdiponectin (Acrp30) is one of the common adipocytokines largely secreted by adipocytes and has insulin-sensitizing, anti-inflammatory and anti-atherosclerosis properties . ReducedThus, we sought to perform a meta-analysis using all available relevant studies to assess the association between adiponectin levels and OSAHS. Given that most of the previous findings were confounded by obesity, sex and age, we only included studies that found no statistically significant difference between OSAHS patients and controls in terms of age, gender and body mass index (BMI) to address these possible confounding factors.This meta-analysis is being reported in accordance with Preferred Reporting items for Systematic Reviews and Meta-analysis (PRISMA) statement .We performed a comprehensive literature search to locate eligible articles published on electronic databases including PubMed, EMBASE, Cochrane Library, WANFANG (Chinese database), VIP (Chinese Database) and Chinese National Knowledge Infrastructure (CNKI). Keywords and search strategy were as follows: “obstructive sleep apnea hypopnea syndrome” or “OSAHS” or “obstructive sleep apnea” or “OSA” or “obstructive sleep apnea syndrome” or “OSAS” or “obstructive sleep hypopnea” or “sleep apnea” combined with “adiponectin” or “ADPN” or “APN”. The electronic databases were searched from inception through January 2018. Besides, the references cited in these articles were reviewed to identify additional publications. We only recruited data from fully published articles written in English and Chinese.Two reviewers first independently reviewed the titles and abstracts to identify relevant articles. A second screening was based on full-text articles to further see whether they were eligible for inclusion. Any disagreement was resolved by discussion.The study design was a case-control study that must have reported values in mean and standard deviation or median with range of adiponectin levels;The study must have included at least two separate groups with one being a groupconsisting of individuals with OSAHS and the other consisting of individuals without OSAHS;3)OSAHS was defined as apnea hypopnea index (AHI) ≥ 5;4)All OSAHS patients were diagnosed for the first time, without receiving any form of treatment;5)No statistically significant difference was found between OSAHS patients and controls in terms of age, gender and BMI;6)All participants were adults (age > 18 years).The studies that satisfied the following criteria were included:Conference abstracts, reviews articles and case reports;Original papers that did not contain precise data about serum/plasma levels of adiponectin in patients or controls;Studies were not performed in humans;Duplicate publication of articles.The exclusion criteria were:The following information was recorded from each included study: first author’s name, publication year, population country, total simple size, serum/plasma adiponectin levels in patients or controls, age, gender, BMI and assay approaches for adiponectin levels.The methodological quality of included studies was evaluated using the Newcastle-Ottawa scale (NOS) by two investigators independently. Discord was resolved by a third reviewer. The quality scale consists of three parts: selection, comparability and exposure assessment. The quality score ranges from 0 to 9. In our meta-analysis, we considered a study which is equal to or higher than 6 stars as a high-quality study.2 test. Generally, if P < 0.05 (Q-test) or I2 > 50%, the heterogeneity was thought to exist and then the random-effect models would be used. Otherwise, fixed-effect models would be applied. An I2 of 25 to 49% was considered to represent a low level of heterogeneity, 50 to 74% a moderate level, and 75 to 100% a high level. Subgroup analysis was performed to assess the impact of race, adiponectin source, assay approaches, average age, BMI and AHI. Sensitivity analysis was conducted to evaluate the stability of pooled results. Potential publication bias was assessed by using the funnel plots, Begg’s rank correlation method and the Egger’s linear regression method. The statistical analysis was performed with Revman 5.3 and Stata12.0 software. P < 0.05 were considered statistically significant.Due to the inconsistency of measurement units and assay approaches, standardized mean difference (SMD) with 95% confidence intervals (CI) was chosen as effect size. Heterogeneity test was performed by Cochrane Q test and IA total of 397 relevant articles were preliminarily identified. After removing duplicates and screening by titles and abstracts, 312 articles were excluded. The remaining 85 articles were projected to be assessed according to the inclusion and exclusion criteria after reading the full-text. Then another 65 articles were excluded due to different reasons. Finally, a total of 20 studies with 28 datasets met inclusion criteria and were pooled for this meta-analysis –30. A flN = 878] and controls [N = 478]) were included in our meta-analysis. The information of the first author’s name, publication year, population country, total simple size, assay approaches and NOS score of each study were showed in Table A total of 20 studies involving 1356 participants  . The fixed-effect model drew a similar result which pooled SMD was − 0.66 .Sensitivity analysis were performed to assess the stability of the results Fig. . The remP = 0.06) and Egger’s tests (P = 0.09) did not give sufficient evidence that the present study had publication bias.The funnel plot was not completely symmetrical, suggesting that the present study has some slight publication bias Fig. . Howeverp = 0.002), but not significantly correlated with publication year (P = 0.56), adiponectin source(P = 0.09), assay approaches(P = 0.77), average age (P = 0.27), BMI (P = 0.12) and AHI (P = 0.28).In meta-regression analysis, the outcome variable was the SMD of adiponectin level and the covariates included publication year, race, adiponectin source, assay approaches, average age, BMI and AHI. We can find that the adiponectin levels were significantly correlated with race (The current meta-analysis sought to summarize all available studies on the serum/plasma adiponectin levels among OSAHS patients and control subjects. We found that patients with OSAHS had significantly lower serum/plasma adiponectin levels compared with control subjects, indicating that adiponectin may play a role in the development of OSAHS. However, previous studies have found uncertain results for the association between adiponectin levels and OSAHS. Zhang et al. , Ebru et2 would result in a decrease of I2 in both white and non-white groups. In addition, meta-regression analysis also suggested that the adiponectin levels were only significantly related with race. We can speculate race may be the potential source of heterogeneity in this present meta-analysis. Therefore, the relationship between serum/plasma adiponectin levels and OSAHS from different races requires further investigation and especially the exact composition of the non-white group.Moderate heterogeneity was observed among these studies. Therefore, subgroup analysis and meta-regression analysis were performed to detect the potential source of heterogeneity. In subgroup analysis, only stratification by race ITo our knowledge, this is the first meta-analysis conducted to assess the relationship between serum/plasma adiponectin levels in OSAHS patients and in control subjects. Most of clinical research studies have focused primarily on older obese males with apnea because OSAHS is more common in males and in overweight/obese populations , 32. HowIn conclusion, the serum/plasma adiponectin levels were significantly lower in OSAHS patients than that in control subjects, suggesting a potential role of adiponectin in OSAHS pathogenesis, deserves further studies as a potential marker of OSAHS.