Objective: This meta-analysis and systematic review was performed with the aim of investigating the association between a disintegrin and metalloproteinase with thrombospondin motif (ADAMTS)4, AMDMTS5 polymorphisms and risk of musculoskeletal degenerative diseases.Methods: PubMed, EMBASE, ISI Web of Science, Wanfang and CNKI were searched from their inception until May 2018 to identify eligible studies. Data from individual studies were extracted using a standardized data collection sheet. The estimate of association between ADAMTS4, AMDMTS5 polymorphisms and risk of musculoskeletal degenerative diseases was expressed as odds ratio (OR) along with its related 95% confidence interval (95%CI) under an allelic model of inheritance. Meta-analysis was conducted using RevMan 5.3 software. Subgroup-analyses by ethnicity and type of diseases were performed.P=0.16). Rs2830585 in ADAMTS5 was significantly associated with musculoskeletal degenerative diseases in only Asians , but not in Caucasians. Since only two of the collected studies referred to ADAMTS4, we did not perform meta-analysis for these comparisons.Results: Eight studies including ten cohorts were included in this meta-analysis. The meta-analyses results based on seven studies showed that rs226794 in ADAMTS5 gene was not associated with risk of musculoskeletal degenerative diseases (A vs. G: OR 1.07; 95%CI 0.97–1.19; Conclusion: Taken together, rs226794 and rs2830585 in ADAMTS5 gene were not associated with musculoskeletal degenerative diseases in overall population, but there seemed to be an ethnicity-dependent effect of rs2830585 in the risk of musculoskeletal degenerative diseases. Insufficient evidence was found to support the association of other single nucleotide polymorphisms and musculoskeletal degenerative diseases. Musculoskeletal degenerative diseases are a diverse group of pathological conditions affecting bone, cartilage, joint and other connective tissues. They are typically characterized by severe chronic pain, stiffness, activity limitations and incapacity in patients’ later life ,2. The iOsteoarthritis (OA) and intervertebral disc degeneration are two most common musculoskeletal degenerative diseases that share comparative similarities. The surfaces of joints are overlaid by a layer of articular cartilage covering the subchondral bone. Progressive damage of articular cartilage as with subchondral bone is the pivotal hallmark of musculoskeletal degenerative diseases. Articular cartilage consists of plenty of extracellular matrix (ECM) components that include macromolecules, collagen fibrils and large proteoglycanaggrecans . Quite aA disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) in mammalian genomes contain a family of 19 secreted metalloproteinases ,11. All A fully understanding of the risk factors, etiology and mechanism is significant to prevent and treat a disease. But the precise etiopathogenesis underlying musculoskeletal degenerative diseases remains unclear. Risk factors like genetics, age and joint biomechanics seem to all together result in triggering the diseases ,25. MounThis meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline .Five online databases including PubMed, EMBASE, ISI Web of Science, Wanfang and CNKI were searched from their inception until May 2018 to identify eligible studies. Structured literature search strategy based on the combination of medical subject headings (MeSH) and free text terms was used to retrieve observational studies that analyzed the association between ADAMTSs and musculoskeletal degenerative disease, no language restriction was imposed on the literature search. The literature search was performed with the following terms:  and . A combination of related Chinese characters was used for literature search in Chinese academic databases: ‘ADAMTS’ and ‘Duo Tai Xing’. Reference sections of the acquired studies were manually searched for additional eligible studies.We followed the PICOS principle to establish the eligibility criteria for the current meta-analysis. Studies satisfying the following criteria were included for review: (1) patients to be included should be diagnosed as musculoskeletal degenerative diseases, such as OA and LDD; (2) published or unpublished studies on the relationship between ADAMTS4 or ADAMTS5 polymorphisms and musculoskeletal degenerative diseases susceptibility; (3) control subjects should be defined as healthy subjects without history of musculoskeletal degenerative diseases; (4) available odds ratio (OR) and 95%CI under allelic comparison of individual loci; (5) observational studies (case–control or cohort studies) on humans.Correspondingly, studies would be excluded if they met the following exclusion criteria: (1) animal studies, reviews, case reports, conference abstracts, as well as comments and editorials; (2) data that overlapped previous publications. If duplicated studies reporting overlapping data were identified, the most comprehensive one was included in the meta-analysis.P value for the associations. Once encountering discrepancy during this process, two investigators re-inspected the article together and reached an agreement through discussion.Two independent reviewers extracted detailed information according to a pre-specified data collection sheet, data extracted included: (1) surname of the first author; (2) year of publication; (3) variant locus; (4) country where the study was performed; (5) ethnicity of enrolled subjects; (6) diagnosis of cases; (7) sample size; (8) results of Hardy–Weinberg equilibrium (HWE) test; (9) major allele and minor allele distribution of case and control participants; (10) http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp). Higher score indicates higher methodological quality and the maximum score is 9 Stars. Two reviewers (J.H. and X.J.) independently assessed the methodological quality of included studies. The results of risk of bias assessment were compared afterwards. In case of discrepancies between two reviewers, the third reviewer (F.G.) was consulted.The Newcastle–Ottawa Scale (NOS) for the assessment of non-randomized studies was used to assess the methodological quality of case–control studies and cohort studies . Three bQ-statistical test and I2 test, where P>0.1 and I2 < 50% indicate acceptable heterogeneity [The strength of association between ADAMTS4, ADAMTS5 polymorphisms and musculoskeletal degenerative diseases susceptibility was assessed through pooling ORs and the corresponding 95%CI of individual studies. The between-study heterogeneity was assessed using the ogeneity . In our ogeneity ,31.The leave-one-out sensitivity analysis was performed by omitting each study in turn and re-evaluating the resulting effect on the overall effect. Egger’s regression test and Begg’s rank correlation test were used to estimate the publication bias  . Forest in silico analysis using HaploReg 4.1 database  [https://gtexportal.org/home/) [http://alggen.lsi.upc.es/cgi-bin/promo_v3/promo/promoinit.cgi?dirDB=TF_8.3) was used to identify putative transcription factor binding sites in rs2830585 and rs26932893 [In order to perform functional annotation of rs2830585 and rs26932893, we applied an reg.php) . The Geng/home/) . GTEx wa26932893 .Combining the search results of all databases, a total of 78 potentially relevant articles were retrieved with 19 from PubMed, 27 from EMBASE, 23 from ISI Web of Science, 5 from Wanfang and 4 from CNKI. No additional articles were obtained through the manual search. After removing 34 records of duplicates, 44 articles remained for further screen. Another 35 articles were eliminated after screening for eligibility with titles and abstracts. Only 1 article was removed after evaluating the full text because of unavailable data . FinallyAll included studies were based on a case–control design. Seven studies ,39–44 weI2 to detect the between-study heterogeneity. In this meta-analysis, the effect size of each included study was combined using random-effect model because there was an anticipated heterogeneity across study. The merged ORs suggested that for both rs2830585 and rs226794 polymorphisms, no pooled correlations with musculoskeletal degenerative diseases were identified under the allelic model when analyzing all of the relevant studies together. For rs2830585, four studies were pooled .= 79%). For rs226794, summarized data was based on seven studies , this finding was further strengthened by low heterogeneity between studies among Asian populations . We also performed subgroup analysis according to the diagnosis of patients (OA or LDD), studies focusing on different kinds of musculoskeletal degenerative diseases were combined in different subgroups. Based on the results of subgroup analysis, rs226794 was not associated with risk of OA or LDD, neither was rs2830585  and Egger’s test  also indicated no statistically significant publication bias.The leave-one-out sensitivity analysis was carried out to evaluate the stability of the overall effect for both rs2830585 and rs226794, and the results confirmed the non-significant association between rs2830585, rs226794 and musculoskeletal degenerative diseases (detailed data not shown). The funnel plots for rs2830585  and rs22Since only few studies reported detailed data about the association between rs1974415, rs2132824, rs151065, rs162509 and risk of musculoskeletal degenerative diseases, these results were not combined using a meta-analysis, providing a narrative description as an alternative. Detailed data about these polymorphisms and risk of musculoskeletal degenerative diseases were summarized in P<0.05).Chen et al.  investigP=0.001).Jiang et al.  looked aP=0.04068). The study led by Gu et al. [P=0.261). With regard to rs2830585, T allele carrier seemed to have a lower risk for the cervical OA  and overall OA vulnerability .In Rajasekaran et al.’s study , rs16250u et al.  looked aRodriguez et al.’s study  was condP=0.0166). Subjects with TT genotype also had significantly lower risk of LLD than subjects with CC genotype . Canbek et al.’s study [Since only two of the collected studies referred to ADAMTS4, we did not perform meta-analysis for these comparisons. Liu et al.  genotype’s study  investig’s study  conducteIn the GTEx database, no evidence was found to support the association between rs2830585, rs226794 and regulation of ADAMTS5 expression in any kind of human tissue (detailed data not shown). The effect of SNPs on expression from eQTL studies from HaploReg suggested that only rs2830585 was associated with altered expression of ADAMTS5 in human glioblastoma cell line U87MG, no promoter histone marks and enhancer histone marks were found in these variants A. AccordDespite extensively studied, the etiology and pathogenesis of musculoskeletal disorders have not been entirely understood. A large body of studies has indicated that genetic susceptibility in collaboration with environmental effects contributes to the etiopathogenesis of musculoskeletal degenerative diseases ,45,46. IADAMTS genes encode a series of secreted ADAMTS proteases which were known to regulate development, angiogenesis, coagulation, as well as homeostasis in the ECM . Currentin vivo and ex vivo experimental studies.ADAMTS4 and ADAMTS5 genes locate at chromosome 1q23 and 21q21.3, respectively, the corresponding proteases they encode share similar domain arrangement and comparable function . PrasadaP=0.0001). There seemed to be an ethnicity-dependent effect in the association between rs2830585 and risk of musculoskeletal degenerative diseases, but whether the variation in ethnicity leads to different results needs to be confirmed by further studies within different ethnic backgrounds.Rodriguez et al.  predicteIn order to confirm the negative findings of our present study, we performed functional predictions of rs226794 and rs2830585 using several online databases including GTEx, PROMO and HaploReg. We failed to find any evidence to support the hypotheses that rs226794 or rs2830585 could regulate the expression of ADAMTS5 in any kind of human tissues. The findings based on PROMO also suggested that predicted transcription factor binding sites remained unchanged in both polymorphisms. The HaploReg results further confirmed that no promoter or enhancer histone marks were associated with these variants. Taken together, reasonable confidence should be placed to the null findings of the association between ADAMTS5 polymorphisms and risk of degenerative musculoskeletal diseases.During the past two decades, there has been a far-reaching transformation in the ability to distinguish genes that contribute to various diseases, so as to the number of novel genetic polymorphisms in relation to musculoskeletal degenerative diseases are surging. Unfortunately, under most circumstances, researchers have less interest to further study these previously reported SNPs. In addition, these studies indeed suffered from large heterogeneity that was caused by diverse ethnic origin of the participants, sex and age variation, as well as the difference of diagnostic criteria and so forth. Both the aforementioned factors made it impossible to perform a formal meta-analysis of these studies. In this meta-analysis and systematic review, we summarized the available literature about SNPs in ADAMTS4 and ASAMTS5 genes, thus providing an analysis of the correlation between these genetic polymorphisms and musculoskeletal degenerative diseases vulnerability. There are several genetic models that could be used in meta-analysis of association studies, such as recessive model, allele model, dominant model and co-dominant model. Although all these aforementioned models are valid methods for analysis of an association study, any such study should have a pre-specified analysis plan because applying all tests will definitely increase the probability of a false-positive result. We only synthesize the two SNPs with allelic comparison in this systematic review, because the allele distributions in cases and controls could provide useful and direct summary statistics for the data. For rs2830585 and rs226794, the merged ORs and 95%CIs did not appear to be associated with musculoskeletal degenerative diseases. However, the result could not represent the overall population because six of the eight studies were performed across Asian population. Studies with larger samples conducted in various populations are required to obtain a clear understanding of these possible associations. Another limitation shouldn’t be ignored when interpreting the results was that there are several subtypes of OA and LDD. But a meta-analysis based on OA and LDD subtype could not be conducted because of the quantity limitation of currently available literature. Therefore, more well-designed clinical materials along with functional analyses are required to exactly elucidate the mechanisms of ADAMTS polymorphisms in the pathogenesis of musculoskeletal degenerative diseases.In summary, our study elaborated the association of ADAMTS4, ADAMTS5 polymorphisms and risk of musculoskeletal degenerative diseases. Based upon the findings of our present study, rs226794 and rs2830585 in ADAMTS5 gene were not associated with musculoskeletal degenerative diseases in overall population, but there seemed to be an ethnicity-dependent effect of rs2830585 in the risk of musculoskeletal degenerative diseases since rs2830585 conferred a significantly higher risk of musculoskeletal degenerative diseases in Asians. Insufficient evidence was found to support the association of other SNPs and musculoskeletal degenerative diseases. Considering the limitations of our meta-analysis, additional studies with larger sample-size among other ethnicities are encouraged to elucidate the real effect of these polymorphisms and musculoskeletal degenerative diseases.


The published data on the association between β2-adrenergic receptor gene polymorphisms and asthma susceptibility are inconclusive. To derive a more precise estimation of this association, a meta-analysis was performed.A literature search was conducted in PubMed, Web of Science, EMBASE, Wanfang, and the China National Knowledge Infrastructure (CNKI) databases to identify eligible studies. The pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used to calculate the strength of the association. A sensitivity analysis was performed to evaluate the influence of individual studies on the overall effect estimates, and funnel plots and Egger’s tests were used for indications of publication bias.2 = 25%, studies = 5, cases = 1190, controls = 1241). A significant risk association was found in the Arab population in the dominant model comparison  and the homozygote model comparison , and in the Hispanic-Latino population in the dominant model comparison . For the rs1042714 polymorphism, we found a significant association in the recessive model comparison , the homozygote genotype comparison  and the allelic genetic model  in the overall population. When stratified by age, a significant association was also found in children in the recessive model comparison  and the homozygote genotype comparison , but not in adult. For the rs1042711 polymorphism, no significant associations were found in the any genetic model.Seventy three studies with three single nucleotide polymorphisms (SNP)  were finally identified. For the rs1042713 polymorphism, no significant association with asthma risk was found in the overall population. However, a significant protective association was found in the Indian population in the dominant model comparison (OR = 0.72, 95% CI = 0.59–0.87, IThe meta-analysis suggests that the ADRB2 rs1042714 polymorphism has a protective association with asthma in the overall population and the pediatric subgroup. Asthma is a chronic respiratory inflammation disease characterized by airway hyperresponsiveness, reversible airway obstruction and airway wall remodeling . It is bADRB2 is encoded by an intronless gene on chromosome 5q31, which is abundantly expressed on many airway cells including smooth muscle cells , 8. ADRBConsidering the impact of the asthma risk potentially resulting from ADRB2 gene variations, a number of case-control studies have explored the association between the ADRB2 gene polymorphisms and asthma risk in different ethnicities –23. HoweThis systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement guidelines.Publications were obtained from the PubMed, EMBASE, Web of Science, the Chinese National Knowledge Infrastructure, and Wanfang databases . The keywords searched in our investigation were (asthma or asthmatic) and (β2-adrenergic receptor or ADRB2 or β2-AR or beta2-adrenoreceptor or β2-adrenoceptor) and (polymorphism or mutation or variant or rs1042713 or G46A or Gly16Arg or rs1042714 or G79C or Gln27Glu or rs1042711 or T-47C or Cys19Arg). The search was performed in duplicate by two independent reviewers (Songlin Zhao and Wei Zhang).The inclusion criteria of our study were as follows: (1) any human studies that estimated the prevalence of the β2-adrenergic receptor polymorphisms and asthma risk were included, which were published in English and Chinese. (2) They were case-control studies. (3) The genotype distributions or allele frequency of each study should be available for estimating an odds ratio with a 95% confidence interval. (4) When eligible papers had insufficient information, we contacted the authors for additional information via email. Studies were excluded from our meta-analysis if their authors did not provide us with the related data.The basic information extracted from each study was as follows: name of the first author, publication year, country, ethnicity, age of cases and controls, sample size, and genotype frequencies in cases and controls. The data were extracted independently and in duplicate by two reviewers (Songlin Zhao and Wei Zhang) who used a standardized data extraction form. Any disagreement was adjudicated by a third author (Xiuhong Nie).The Newcastle-Ottawa Scale (NOS) was used to assess the quality of the included studies. The items assessed included selection, comparability of case/controls, exposure/outcome, age and gender. The quality scores ranged from 0 to 9. We divided the NOS scores into three levels .A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2) was used to assess the quality of the systematic reviews . The AMSP < 0.05. The pooled ORs for the ADRB2 polymorphisms and asthma risk were calculated for the dominant genetic model, the recessive genetic model, the homozygote genetic model and the allele genetic model. The heterogeneity was assessed by using the Q-test and I2 test. A P-value> 0.10 of Q-test and I2 < 50% indicated a lack of heterogeneity among the studies; then, the fixed-effect model was used. Otherwise, the random effect model was used. Subgroup analyses were performed regarding ethnicity, case age and HWE P-value. The ethnicity subgroups were designed as Caucasian, Hispanic-Latinos, non-Hispanic Blacks, East-Asian, Indian and Arab. Age subgroups were designed as Adult and pediatric subgroups. HWE P-value subgroups were designed as P-value> 0.05 and P-value< 0.05 subgroups. Sensitivity analysis was conducted by sequentially excluding one study at a time to examine the effect of each study on the combined result. The funnel plot and Egger’s test was used to assess the potential publication bias. All the statistical analyses of this meta-analysis were performed using the STATA 11.0 software .A Hardy-Weinberg equilibrium (HWE) was assessed for each study by use of the Pearson’s chi-square test in control groups, and significance was set at Characteristics of the studies included in the meta-analysis.P-value of HWE for the rs1042713, rs1042714 and rs1042711 polymorphisms are respectively shown in Additional files The flow chart in Fig. 2 = 25%, studies = 5, cases = 1190, controls = 1241), and a significant risk association was found in the Arab population in the dominant model comparison  and the homozygote model comparison   .Among the 73 publications included in the meta-analysis, 71 studies investigated the association between the ADRB2 rs1042713 polymorphism and asthma risk      , and the allelic genetic model . No associations were found in the P < 0.05 subgroup  subgroup in our study and in that of Liang et al. [In this study, the associations between three ADRB2 gene SNPs  and the risk of asthma were conducted base on the data from 73 studies involving 13,493 asthmatic patients and 22,931 controls. This meta-analysis showed that the rs1042713 polymorphism was not a risk factor for overall asthma susceptibility, which was consistent with most of the previous meta-analyses , 27–29; g et al. . When reg et al. , 92, 95,Some studies reported that the genotype frequency and allele frequency of the rs1042713 polymorphism vary among different ethnic groups , 99. A sBecause the genotype frequency and allele frequency of the rs1042713 polymorphism vary among the different ethnic groups, we divided the ethnic groups according to the studies reported by Ortega et al. , 101, suFor the rs1042714 polymorphism in the current meta-analysis, benefitting from the inclusion of more case-control studies, a protective effect was found not only in the pediatric subgroup in the recessive model comparison and the homozygote genotype comparison but also in the overall population in the recessive model comparison, the homozygote genotype comparison and the allelic genetic model. This was consistent with previous reports by Liang et al.  and AmmaP-value for the rs1042714 polymorphism, significant associations were found in the subgroup with P > 0.05 in the dominant model comparison and the allelic genetic model but not in the P < 0.05 subgroup. These results need to be interpreted with caution. The reason the control group population was not in HWE may be selection for a particular phenotype or that the population was not sufficiently large or random.In the analysis stratified by HWE according to the For the rs1042711 polymorphism, no significant associations with the risk of asthma were found in any comparison model. More research is needed because only seven case-controls were included in this study. There might not be sufficient statistical evidence to clarify the association between the rs1042711 polymorphism and the risk of asthma.There could be several potential limitations to this meta-analysis. The first problem relates to the limitations of the literature. All available literature should be included in the meta-analysis, but we only included literature published in English and Chinese, thus neglecting studies published in other languages. Second, even though the existing literature had acceptable quality, detailed information was not provided such as asthma definition varied among different articles and this may be a confounding factor. Using a self- or physician-diagnosis of asthma can be confounded by individuals who do not have asthma such as older subjects with a smoking history who could have COPD. These physician-diagnosed cohorts many times do not have an objective diagnostic basis of asthma based on methacholine BHR or beta agonist responsiveness which could result in confounded and undetected associations. In addition, the participation rates for cases and controls were not reported in the majorities of included studies; thus, our meta-analysis was unable to explore the selection bias. Moreover, with limited information about maternal constitutional and environmental risk factors for asthma (such as smoking history), we could not evaluate the gene-gene and gene-environmental interactions. The different definitions of asthma and the environmental factors in individual studies were obvious sources of clinical heterogeneity and may produce bias. Therefore, moderate-to-high heterogeneities were found in some genetic models for the Gly16Arg polymorphism. Stratification by ethnicity may help to improve homogeneity among studies, but it may also influence statistical power. In addition, some meta-analysis studies claimed to divide the cohorts by ethnicity but it seems like the cohorts were actually being divided by continent for the most part, it will induce the contradictory findings. Third, the Gly16Arg and Gln27Glu polymorphisms tagging for rare variants modulated therapeutic responses and contributed to asthma risk ; howeverIn conclusion, the present meta-analysis indicates that the rs1042714 polymorphism is an important genetic protective factor to decrease the risk of developing asthma, especially in children. The rs1042713 polymorphism may be involved in the risk of asthma in the Arab and Hispanic-Latino populations and a protective factor in the Indian population. However, more well-designed and high-quality studies with larger sample sizes should be conducted to support this finding in various ethnic groups.Additional file 1: Table S1. Characteristics of the studies included in the meta-analysis. (XLSX 14 kb)Additional file 2: Table S2. Genotype and allele distribution in the meta-analysis for the rs1042713 polymorphism. (XLSX 17 kb)Additional file 3: Table S3. Genotype and allele distribution in the meta-analysis for the rs1042714 polymorphism. (XLSX 15 kb)Additional file 4: Table S4. Genotype and allele distribution in the meta-analysis for the rs1042711 polymorphism. (XLSX 9 kb)Additional file 5: Figure S1. Forest plots of the association between the ADRB2 rs1042713 polymorphism and risk of asthma in recessive model comparison. GG vs. GA + AA genotype. Each study is shown by an OR estimate with the corresponding 95% CIs. The horizontal lines denote the 95% CIs and the squares represent the point OR estimate of each study. The size of the square is proportional to its inverse-variance weight in the meta-analysis. The diamond represents the pooled meta-analysis effect size estimate. The stratified meta-analysis was performed regarding the ethnicity. (TIF 19900 kb)Additional file 6: Figure S2. Forest plots of the association between the ADRB2 rs1042713 polymorphism and risk of asthma in homozygote genotype comparison. GG vs. AA genotype. Each study is shown by an OR estimate with the corresponding 95% CIs. The horizontal lines denote the 95% CIs and the squares represent the point OR estimate of each study. The size of the square is proportional to its inverse-variance weight in the meta-analysis. The diamond represents the pooled meta-analysis effect size estimate. The stratified meta-analysis was performed regarding the ethnicity. (TIF 19918 kb)Additional file 7: Figure S3. Forest plots of the association between the ADRB2 rs1042713 polymorphism and risk of asthma in the allele comparison. G vs. A allele. Each study is shown by an OR estimate with the corresponding 95% CIs. The horizontal lines denote the 95% CIs and the squares represent the point OR estimate of each study. The size of the square is proportional to its inverse-variance weight in the meta-analysis. The diamond represents the pooled meta-analysis effect size estimate. The stratified meta-analysis was performed regarding the ethnicity. (TIF 19763 kb)Additional file 8: Figure S4. Forest plots of the association between the ADRB2 rs1042714 polymorphism and risk of asthma in the allele comparison. G vs. C allele. Each study is shown by an OR estimate with the corresponding 95% CIs. The horizontal lines denote the 95% CIs and the squares represent the point OR estimate of each study. The size of the square is proportional to its inverse-variance weight in the meta-analysis. The diamond represents the pooled meta-analysis effect size estimate. The stratified meta-analysis was performed regarding the ethnicity. (TIF 23295 kb)Additional file 9: Figure S5. Forest plots of the association between the ADRB2 rs1042714 polymorphism and risk of asthma in dominant model comparison. GG + CG vs. CC genotype. Each study is shown by an OR estimate with the corresponding 95% CIs. The horizontal lines denote the 95% CIs and the squares represent the point OR estimate of each study. The size of the square is proportional to its inverse-variance weight in the meta-analysis. The diamond represents the pooled meta-analysis effect size estimate. The stratified meta-analysis was performed regarding the age. (TIF 24131 kb)


Despites numbers of case-control studies working on this area, the actual relationship of HIF-1α gene generic variant rs11549465 C>T imposing on cancer susceptibility remains unveiled. To get a better understanding of such relationship, this meta-analysis was carried out by incorporating all eligible case-control studies. Qualified articles were acquired from PubMed, CNKI, EMBASE, PMC, and Wanfang database update to April 2019. Odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were employed to estimate the relationship of interest. Heterogeneity tests, sensitivity analyses and publication bias assessments were also carried out to ensure the strength of our conclusion. A total of 46 articles with 49 studies including 12920 cases and 13363 controls were included. The results indicated that HIF-1α rs11549465 C>T was significantly related to the increased risk of overall cancer under four genetic models . Furthermore, enhanced cancer risk was detected after stratification by cancer type, ethnicity, the source of controls and HWE. These results suggest that HIF-1α rs11549465 C>T polymorphism may predispose to cancer susceptibility.HIF-1 Cancer ranks itself the leading causes of death around the world. In 2019, 1,762,450 new cancer cases and 606,880 cancer deaths are projected to occur in the United States. It has become a universal public health issue α plays a vital role in activating various genes that is significantly involved with cell adhesion, erythropoiesis, angiogenesis and glucose transportation in the process of cancer development and progress Hypoxia possesses a vital role in the maintenance of tumor microenvironments. Hypoxic tumor microenvironment triggers extensive cellular responses, such as angiogenesis, proliferation and invasion HIF-1α has been a research hot spot and numerous SNPs in HIF-1α were identified, whose polymorphism known as 1772 C>T , having been the most widely investigation polymorphism. rs11549465 C>T is a nonsynonymous SNP. Compared to the wild type, this polymorphic variant can tremendously enhance transcriptional activity in both normoxic and hypoxic environment in in-vitro studies HIF-1α rs11549465 C>T is linked to increased tumor microvessel density which makes contribution to the cancer progression. HIF-1α rs11549465 C>T polymorphism was previously investigated in various types of cancer. Nevertheless, the conclusions obtained from previous epidemiological studies are inconsistent and contradictory. Thus, the relationship between HIF-1α rs11549465 C>T polymorphism and cancer risk requires further exploration. Herein, we performed this more comprehensive meta-analysis on selected case-control studies in the aim of giving a more thorough demonstration of the association of HIF-1α rs11549465 C>T polymorphism with cancer risk.Mounting evidence provided that featuring a high tumor grade, HIF-1α is over-stated in numbers of human cancers, indicating that HIF-1α functions as an independent element of cancer prognosis hypoxia-inducible factor-1 or HIF-1α or rs11549465 or 1772 C>T; 2) SNPs or polymorphisms or polymorphism or variants; 3) cancer or carcinoma or neoplasm or tumor. To acquire all qualified publications, we also reviewed the references of the selected studies.We systematically searched EMBASE, PubMed, PMC, Wanfang and CNKI to retrieve relatively pertinent publications based on case-control studies . No language restriction is made for this analysis. The search terminology involved were as listed: 1) Impertinent and irrelevant studies were excluded on primary stage. Elimination criteria were: if 1) the study population was not mapped out; 2) it is not case-control study; 3) lack of information in allele frequency. Other than that, editorials, reviews and meta-analysis were ruled out. Only case-control studies with detailed number of different genotypes for estimating odds ratios (ORs) with 95% confidence intervals (CIs) were taken into the final analysis.Two authors (Hu-Nian Li and Ting He) were arranged to extract information of all the articles respectively. Items listed below were extracted from every single study: 1) authors name; 2) publication year; 3) ethnicity of the study subject; 4) cancer type; 5) allelic frequency; 6) quality score. Studies with scores ≤9 were of low quality, whereas those with scores >9 were of high quality HIF-1α rs11549465 C>T polymorphism and cancer risk by calculating ORs with the corresponding 95% CIs. Moreover, we conducted the stratification analysis by ethnicity, cancer type, source of control, and HWE in controls. We also used Chi square-base Q-test to gauge the presence of heterogeneity. The fixed-effect model was used to compute the pooled OR, given the studies were confirmed to be homogeneous (P>0.10 for the Q test). Or the random-effect model should be used instead. Sensitivity analysis was undertaken on the base of re-calculation of the ORs and 95% CIs by excluding each study individually. In order to detect the presence of publication bias, Begg's funnel plot and Egger's linear regression were adopted simultaneously. We also performed the trial sequential analysis (TSA) to avoid the random errors caused by repeated significance testing and dispersed data P value <0.05 as a baseline significant finding.We first performed Hardy-Weinberg equilibrium (HWE) for the controls utilizing the goodness-of-fit test. Homozygous model, heterozygous model, recessive model, dominant model, and allele model were employed to determine the relationship between Figure 1. We first collected 196 articles of the interest by a comprehensive search in the above-mentioned databases. After a basic check-up on articles relevance and abstracts conciseness, 156 articles were ruled out, which left us a total of 40 articles for full text assessment. To expand its sample size to ensure statistical representativeness, we identified another 6 articles from retrieve studies, quantity adding up to 46 articles in total Table .The study workflow was graphically displayed in Table 2 and Figure 2. The results concluded that the rs11549465 C>T polymorphism was significantly related to the increased risk of overall cancer under homozygous model , recessive model ; dominant model , and allele model . We failed to detect any distinguished relationship between rs11549465 C>T and renal cell carcinoma (RCC), endometrial cancer, colorectal cancer, lung cancer, breast cancer, hepatocellular cancer (HCC) under all the five genetic models. However, we observed that the rs11549465 C>T polymorphism could confer to increased risk in subgroups of prostate cancer , cervical cancer , oral cancer , pancreatic cancer  and other cancers .The quantitative results of the meta-analysis were displayed in When it comes to the stratification analysis by the ethnicity, significant increased risk was detected in Asians, Caucasians and mixed population. In terms of source of controls, either population-based controls or hospital-based controls were associated with the increase risk of cancer. Further subgroup analysis by HWE in controls revealed that no significant correlation was observed in subgroup of HWE≤0.05. As regard to the quality of publications, significant increased risk was detected in high-quality and low-quality publications.Q test (P<0.001) implied an existence of heterogeneity under all the genetic models. Thus, we adopted a random-effect model to produce ORs and 95% CIs. In addition, the sequential sensitivity analysis was performed to give an evaluation of the impact of a sole study on the pooled estimation. Given the attempt of omitting in each study incurred no statistical fluctuation of the pooled ORs, we have reason to believe that the meta-analysis's data is of great reliability .The Figure 4, no evidence of asymmetry was found. Egger's test's statistics also gives no evidence of publication bias among the studies.From the shape of the Begg's funnel plot shown in Figure 5).The TSA showed that the cumulative z-curve did not cross both the traditional threshold and the TSA threshold, yet the accumulated information was sufficient, indicating that no further evidence was needed to verify the conclusion  could induce proline-to-serine amino acid substitutions. However, the exact role of rs11549465 C>T polymorphism in cancer risk obtained from different studies remain inconclusive.The HIF-1α rs11549465 C>T and cancer risk. However, association analysis between rs11549465 C>T and RCC risk in panels of 20 cases and 44 non-neoplastic controls did not reveal allelic frequency differences. An investigation conducted by Konac et al. HIF-1α may contribute to risk of endometrial and cervical cancers. In a meta-analysis performed by Zhao et al. HIF-1α rs11549465 C>T polymorphism was reported to be related to increased cancer risk. In 2015, Li et al. HIF-1α rs11549465 C>T polymorphism predispose to higher overall cancer risk. To better illustrate the relationship of interest, we hereby conducted this updated meta-analysis by using all the qualified publications with a total of 12920 cases and 13363 controls. The results revealed that HIF-1α rs11549465 C>T polymorphism contributes to increased overall cancer risk. In a sense, this meta-analysis has succeeded in giving a clearer clue of the relationship between HIF-1α rs11549465 C>T polymorphism and cancer risk.In 2001, Clifford et al. In the current meta-analysis, we undertaken many measurements to increase the credibility of our conclusion. First and foremost, we included as many as qualified studies to expand the analyzed sample size, by incorporating studies not only pressed in English but also in Chinese. Second, we adopted the sensitivity analysis and the publication bias. However, several limitations could not be settled down. First, between-study heterogeneity exists, which might weaken the persuasiveness of the conclusion. Second, the relationship strength was only assessed by use of unadjusted estimates. Lacking original data, such as environment factor, adjustment analysis was absent. Third, most of the included studies were conducted among Asians and Caucasians. The lack of other ethnicities, such as Africans, compromised the generalization of the conclusion.HIF-1α rs11549465 C>T polymorphism was significantly related to an increase in cancer risk. Our work no doubt will encourage more dedication into further elucidation of the etiology of cancer predisposition. However, with limited sample size of subgroup analysis, we must admit that this analysis is imperfect and thus in the future more case-control studies should be conducted with a larger size of samples.In a word, our finding has come to a fruition that


Background: Epidemiological evidences regarding the association between physical activity and the risk of lung cancer are still controversial.Objectives: We aimed to investigate the relationship between physical activity and risk of lung cancer in men and women, as well as other high-risk populations such as cigarette smokers.Methods: We conducted a meta-analysis of cohort studies to evaluate the association between physical activity and risk of lung cancer. Relevant studies were identified by searching PubMed and Web of Knowledge through August 2018. Study-specific relative risk (RR) with 95% confidence interval (CI) were pooled using random effect model when significant heterogeneity was detected.Results:Twenty cohort studies with a total of 2,965,811 participants and 31,807 lung cancer cases were included. There was an inverse association between the physical activity and risk of lung cancer. Compared with the low level of physical activity, the pooled RR was 0.83 , with significant heterogeneity . The corresponding pooled RRs were 0.90  for women and 0.81  for men. Smokers with a high level of physical activity were associated with a 10% lower risk for lung cancer , while the association was not significant among non-smokers . Subgroups analysis stratified by whether the studies adjusted for smoking intensity and durations yielded the same magnitude of RR. However, the RR for subgroups without adjustment for dietary factors was 0.74 , which was significantly lower than that with dietary factors adjusted .Conclusions:Increased physical activity might be associated with lower risk of lung cancer. Such inverse association was identified among smokers rather than non-smokers. Large interventional studies are expected to further verify these findings. The global burden of lung cancer has been increasing over the past years. It is the most frequently diagnosed cancer and the leading cause of cancer death, accounting for 11.6%  of the total new cancer cases and 18.4%  of the total cancer deaths in 2018 , hazard ratio or risk ratio of highest level vs. lowest level as risk estimates with the corresponding 95% confidence intervals (CIs) or standard errors. We used the RR as the measure of the association between physical activity and risk of lung cancer. If multiple estimates were provided, priority was given to the multivariable adjusted risk estimates. Instances in which data were insufficient or missing, we attempted to contact the authors of the articles to request the relevant data. Two authors (Yang Liu and Yue Li) independently performed the literature search and study selection. Discrepancies were resolved by discussion with other reviewer (Xiao-Xi Fan).Two researchers (Xiao-Xi Fan and Yun-Peng Bai) independently used a standardized reporting form to abstract the following data from each study: the first author's name, the year of publication, the country in which the study was performed, the duration of follow-up, number of study population, the number of lung cancer events, the assessment of physical activity, the study outcome, the categories of exposure with the corresponding RRs and 95% CIs, the covariates adjusted in multivariable models.To assess study quality, a 9-point system on the basis of the Newcastle-Ottawa Scale was used in which a study was judged on 3 broad categories for cohort studies as follows: the selection of study groups, comparability of groups, and ascertainment of either the exposure or outcome of interest .I2 statistics and results were defined as heterogeneous for a P-value < 0.10 or an I2 > 50% . Two-sided A flow diagram for the search is presented in Figure Descriptive data for the 20 included cohort studies were summarized in Table The quality scores ranged from 5 to 9 with a median score of 8. Three studies were evaluated with a score of <7, and others with a score of ≥7. Thus, the majority of the studies included in the meta-analysis were assessed as high-quality studies  across the included studies. Publication bias were tested by Egger's test (P = 0.414), Begg's test (P = 0.023) and arcsine-Thompson test (P = 0.151). The funnel plot was shown in Figure As shown in Figure  P = 0.02 and arcsSubgroup analyses for the association between physical activity and risk of lung cancer was shown in Table In sensitivity analyses, we recalculated the pooled RRs by sequentially excluding one study. The pooled RRs ranged from 0.82  to 0.86 . The trend was generally similar with the overall analysis  . This poIn current meta-analysis, there were significantly heterogeneous results across subgroups stratified by whether the included studies adjusted for the dietary factors. Although both of the subgroups showed significant results, the strength of the association differed. The dietary factors such as total energy intake may mutually interact with physical activity and be associated with lung cancer as either a confounder or an intermediate factor, which may subsequently lead to the heterogeneous results across subgroups. Moreover, heterogeneity may also exist across the subgroups stratified by smoking status. A significant inverse associations between physical activity and lung cancer risk were observed among smokers, but not among never smokers. One of the largest study  with pooIt is suggested that physical activity increases pulmonary function, which may reduce the duration of exposure to carcinogenic agents in the lung . SeveralOur study also has some limitations. First, because of the nature of the observational design, residual confounding may distort the observed association and we were not able to address problems with confounding inherent in the original studies. For example, dietary factors such as total energy intake may affect physical activity and be associated with risk of lung cancer. The lack of data on chronic lung disease may probably bias the results. However, most studies included in this meta-analysis adjusted for some of the major potential confounders, such as age, sex, smoking status, body mass index. To overcome this limitation, large randomized trials would be necessary to definitively verify the observed association. Second, there was a significant heterogeneity in current meta-analysis. There are several potential explanations for the observed between-study heterogeneity, such as different type of physical activity, different measurement of physical activity, various size of cohort and length of follow-up from study to study. Since all these together may result in statistical heterogeneity, the results of current study should be interpreted with caution. Despite these limitations, the major strength of this meta-analysis was the large sample size which provided sufficient statistical power to detect a significant association, as well as across various subgroups.YaL and X-XF contributed to the conception or design of the work. X-XF and YaL contributed to the acquisition, analysis, or interpretation of data for the work. YaL drafted the manuscript. YuL and Y-PB critically revised the manuscript. All authors gave final approval and agree to be accountable for all aspects of work ensuring integrity and accuracy.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.


Prodynorphin (PDYN) gene polymorphisms have been linked with opioid dependence (OD) with conflicting outcomes, the aim of this study is to synthesize the existing evidence of the association between PDYN polymorphisms and OD susceptibility.Four databases including PubMed, EMBASE, Web of Science, and Wanfang were retrieved for relevant studies before August, 2018. All identified studies were evaluated using predetermined inclusion and exclusion criteria. Summary odds ratio (OR) and 95% confidence interval (95%CI) were calculated to appraise the association. Statistical analysis was performed using RevMan 5.3 software.rs910080, rs1997794, rs1022563, and rs2235749 polymorphisms of PDYN gene, there were six, four, five, and four studies eventually included, respectively. The findings indicated that rs910080 polymorphism was significantly correlated with OD among Asian population under allelic model  and dominant model . However, rs1022563, rs1997794 and rs2235749 polymorphisms did not appear to associate with OD susceptibility.A total of seven case-control studies with 3129 cases and 3289 controls were recruited in the meta-analysis. For rs1022563 polymorphism and OD among Asian population. As the included studies were not adequate to guarantee a robust and convincing conclusion, future studies with larger sample size among more ethnicities are recommended.There existed a significant association between  Opioid dependence (OD), mainly characterized by persistent drug-taking and drug-seeking behavior, is a chronic brain disorder that has seriously negative social and health consequences . A rangeActually, early in 1990s, the isolation of genes that encoded opioid peptide precursors had opened an era of molecular and genetic investigations of OD . Family-PDYN gene is mapped to chromosome 20p13 ) AND  case participants with confirmed diagnosis of OD; (3) studies with sufficient genotype counts to estimate odds ratio (OR) as well as 95% confidence interval (95%CI). Accordingly, case-case studies, reviews, conference abstracts, as well as animal studies were excluded.Publications that were included in the present study had to satisfy the following criteria: (1) case-control studies looking into the association of The quality of eligible studies was evaluated separately by two investigators (CW and MM) according to Newcastle-Ottawa Scale (NOS). A ‘star system’ was used to judge the quality of each study on the basis of selection, comparability, as well as exposure. The NOS ranges from zero to nine stars. Studies with five or more stars indicated a high quality.The following data were extracted independently by two investigators (CW and MM) from each qualified article: author, year of publication, country, ethnicity and gender of participants, sample size, and genotype distribution. Once encountering discrepancies, two authors re-checked the original articles until an agreement was achieved.2 test were utilized. P < 0.1 and I2 > 50% suggested the heterogeneity was not significant, and the fixed-effect model could be applied, otherwise the random-effects model should be employed. Subgroup-analysis by ethnicity was performed to test if there was an ethnicity-specific effect. For multiple testing corrections, the Benjamini-Hochberg method was applied to control false discovery rate (FDR) [Hardy-Weinberg Equilibrium (HWE)  of contrte (FDR) . Forest An initial search of four databanks yielded 151 records, of which 44 from Web of Science, 78 from EMBASE, 21 from PubMed, and 8 from Wanfang. Forty-seven records were deleted because of duplication. Ninety-three irrelevant citations were removed from the remaining 104 records after title and abstract screening. Another 4 ineligible articles were erased after comprehensive assessment according to inclusion and exclusion criteria. Ultimately, 7 articles –18 were rs910080 polymorphism, Hashemi et al.’s study [rs1022563 polymorphism, three studies [rs2235749 polymorphism, three studies [The general characteristics of included studies were displayed in Table ’s study  was not  studies –18 were  studies , 16, 17 PDYN gene polymorphisms  and OD vulnerability were summarized in Table The correlations of rs910080 was available on six studies [rs910080 polymorphism and OD susceptibility under five genetic models. Subgroup analysis stratified by ethnicity suggested a significant association between rs910080 polymorphism and OD across Asian population in allelic model  and dominant models . While no correlation was detected under other models.Data synthesis for  studies –17 with rs1997794, four studies [rs1997794 polymorphism did not significantly associate with OD in five genetic models. Subgroup analysis stratified by ethnicity also yielded a null association.As for  studies , 15, 18 rs1022563, five studies with six cohorts containing 2378 cases and 2400 controls satisfied the eventual data combination. Because of huge heterogeneity, random-effect model was utilized. Rs1022563 polymorphism appeared to have no significant correlation with OD in five genetic models. Subgroup analysis by ethnicity as well indicated a non-significant association.In respect of rs2235749, four studies [rs2235749 polymorphism and OD susceptibility.When it came to  studies , 16, 17 After studies that deviated from HWE were excluded, the corresponding OR did not reverse. Consequently, they were not removed from our meta-analysis. Sensitivity analysis confirmed the stability of the outcomes, where exclusion of individual dataset did not significantly change the overall effects. Furthermore, visual inspection of funnel plots did not identify substantial asymmetry for all the four loci under any genetic model.PDYN gene has received more and more attention [OD affects the lives of millions of people worldwide and imposes a heavy burden on society . Hence, ttention .PDYN gene polymorphisms and OD vulnerability, while it is quite regrettable that no convincing evidence is available. This inconsistency could be interpreted by several factors, including severity of diagnosis, limited sample size, inadequate power, ethnic heterogeneity, population stratification, as well as large phenotype range. The present study, with pooled data from Asian , Caucasian (European American), and African (African American) populations, indicated that rs910080 polymorphism was significantly correlated with OD among Asian population. However, rs1022563, rs1997794 and rs2235749 polymorphisms did not appear to associate with OD susceptibility.Several studies across different populations have been performed on the association of PDYN gene codes ligand of opioid receptor. Functional variant in PDYN gene hampers the downstream signaling pathway and affects the overall biological networks, thus implicating in the pathophysiology of OD. Dynorphins are a cluster of posttranslational products of PDYN gene. They bind to all three types of opiate receptors, but exhibit considerable affinity to kappa opioid receptor [PDYN gene have been reported to inhibit neurotransmission and take part in mood regulation, stress responses [PDYN was rich in brain areas that were associated with drug-taking and drug-withdrawal. Wang et al. [PDYN and kappa opioid receptor mRNA level in the brains of rat models. Solecki et al. [PDYN mRNA in the nucleus accumbens shell and core of rats. All this evidence suggested that PDYN gene played a crucial role in the occurrence and development of OD.receptor . Productesponses , reward esponses , and motesponses  reportedg et al.  found thi et al.  observedHeterogeneity is a crucial issue when elucidating the outcomes of a meta-analysis. We attempted to minimize this issue by developing strict criteria for study inclusion, information extraction, as well as data analysis. Considerable heterogeneity between studies still existed despite subgroup analysis was stratified. Several potential reasons might give rise to the presence of heterogeneity. For demographics, age of individual study ranges greatly. For gender, although majority studies are mixed genders, some are focusing on only men or women. For genetic background, included studies are multi-national and many ethnic groups were represented within them. For environmental factor, participants from both developing countries and developed countries were incorporated into the present study.PDYN gene polymorphisms and OD predisposition, several limitations could not be neglected. First, the present outcomes were based on unadjusted estimates. Because raw data for confounding factors like age [PDYN gene. However, finding susceptibility polymorphisms and genes was a difficult task owing to the intricate mode of inheritance and multiple polymorphisms in various genes contributing to increased disease risk. OD, without exception, is a multifactor disorder determined by the synthetic effects and interactions of a series of polymorphisms, genes, and environmental factors. These interactions might conceal or enlarge the function of the included polymorphisms. Lastly, only seven articles from four databanks were searched for this study, potentially relevant studies published in other databanks might be missed.Although the current study has collected available data on the association between like age , gender like age , socioeclike age  of the prs910080 polymorphism was significantly correlated with OD among Asian population. However, rs1022563, rs1997794 and rs2235749 polymorphisms did not appear to associate with OD susceptibility. Due to limitations demonstrated above, the associations between PDYN gene polymorphisms and the risk of OD could not be entirely concluded. As the included studies were not adequate to guarantee a robust and convincing conclusion, studies with larger sample size among more populations are recommended.Taken together, the current study indicated the


COL9A3 gene encodes the α3 (IX) chain of type IX collagen that is part of the interior structure of the disc. Mutations in COL9A3 gene sequence, leading to an Arg103Trp substitution in its 3 chain , respectively, have been found to be connected with IDD occurrence in several studies. However, those studies have showed conflict results. Thus, a meta-analysis has been performed to assess the associations between the COL9A3 trp3 polymorphism and IDD.Intervertebral disk degeneration COL9A3 trp3 polymorphism and IDD.Data were gathered from the following four electronic databases: PubMed, Web of Science (WOS), Embase and Cochrane library up to January 01, 2018. The pooled odds ratio (polled ORs) and 95% confidence interval (CI) were calculated to evaluate the strength of relationship between the COL9A3 trp3 polymorphism was not associated with IDD . Furthermore, the Egger’s test and the Begg funnel plot did not show any evidence of publication bias.Eleven eligible studies with 1631 cases of IDD and 1366 controls were included in this meta-analysis. The results indicated that the COL9A3 trp3 polymorphism might not be associated with IDD. Nor did we find any relationship in subgroup analyses stratified by gender and ethnicity. Future researches with larger samples are required to verify this outcome.Our results suggest that the  Low back pain (LBP), a common musculoskeletal disorder, involves the muscle, nerve, and bone tissues of back –3. It haCOL9A3) gene polymorphism with IDD risk has been studied much frequently. COL9A3 gene, located in the chromosome 20q13.3, encodes the α3 (IX) chain of type IX collagen which is part of the interior structure of the disc, nucleus pulposus [COL9A3 gene leading to an Arg103Trp substitution in its 3 chain , in other words, this change in collagen IX by substitution of glutamine by tryptophan, which is relative rare in collagen, can contribute to a disorder in the collagen properties of intervertebral disc. The increasing proportion of tryptophan in collagen can result in alterations in collagen triple helix, as well as interfering the interaction between collagens IX and II or disturbing the process of lysyl oxidase, which catalyzes cross-link formation, finally leading to disc disease [For the last several years, many genes have been discovered to be associated with IDD, some of which are collagen genes, such as Collagen I, IX and XI genes –14. Amonpulposus . MutatioCOL9A3 trp3 polymorphism up to now. Therefore, we performed a meta-analysis to evaluate the connection between them. In this study, we aim to identify the association of genetic mutations with IDD, which is likely to be of significant importance and might help identify ‘high-risk’ individuals of IDD or guide the clinical treatment of some specific individuals.However, recent studies have obtained conflicting results. Some of them, such as Toktas et al.  and PaasCOL9A3 Trp3 polymorphism with IDD, we searched electronic databases including PubMed, Web of Science (WOS), Embase and Cochrane library up to January 01, 2018. The search strategy to screen out all possible articles involved the use of the following terms:  AND (“Gene polymorphism”) AND ; (“Trp3” OR “rs61734651” OR “20q13.33” OR “arg103”) AND (“Gene polymorphism”) AND ;  AND (“Trp3” OR “rs61734651” OR “20q13.33” OR “arg103”) AND . In order to increase the sensitivity of the searching strategy, both MeSH terms and free words were applied.In order to identify all articles that studied the association of COL9A3 trp3 polymorphism and the risk of IDD; (2) Human subjects; (3) Case-control study; and (4) Available genotype data were provided to calculate the odds ratios (ORs) and 95% confidence interval (CI).Studies included in this meta-analysis should satisfy the following inclusion criteria: (1) Evaluation of the association between Correspondingly, the exclusion criteria were defined as: (1) Comments, reviews or animal studies; (2) Duplicate reports with previous publications; (3) the study only described data of case population; (4) Studies without available genotype frequencies.All retrieved articles were evaluated and discussed to achieve accordance by two junior investigators depending on the inclusion and exclusion strategies independently. If a conflict  still existed, a senior author was invited to extract the specific data independently using blind method. Then comparing the results with the two junior investigators to solve the problem and finally come to a consistency.The following characteristics of each study were collected: (1) name of the first author; (2) year of publication; (3) country of enrollment; (4) ethnicity of the study population; (5) age and gender of individuals included; (6) diagnostic criteria for IDD cases; (7) genotyping methods; (8) source of controls; (9) matching items; (10) number of subjects under IDD cases and controls; (11) Relation with IDD; Data were extracted carefully from all eligible publications independently by two investigators. For conflict resolution, an agreement was reached by discussion.The two investigators assessed the qualities of all the included studies separately using the Clark scores system, which contains 10 items , 25. ScoCOL9A3 trp3 polymorphism and IDD risk was assessed by combining ORs with 95%CI. The estimations of pooled ORs were determined by the weighted average OR from each study. Significance was identified by a P-value less than 0.05 in Z-test. The pooled ORs and 95%CI were calculated for trp3 positive (the mutation type) versus trp3 negative (the wild type). Because seven studies [I2 statistics. Fixed-effect model was used to estimate the ORs and 95%CI when heterogeneity was low (I2 < 50%), while the random effects was adopted when heterogeneity was high (I2 > 50%) [P-values were two-sided. Publication bias was checked using the Begg funnel plot [P < 0.05 was considered statistically significant).The PRISMA checklists and their guidelines were cautiously followed during the whole process of the study . The ass studies , 27–29 i studies , 22, 30 2 > 50%) . Sensitinel plot  and the nel plot  .Significant heterogeneity was found among the studies of trp3 in the overall meta-analysis. So the random effects model was applied to evaluate the connection between trp3 polymorphism and IDD risk. The result of the evaluation showed that there was no association of trp3 polymorphism with IDD risk .Subgroup meta-analysis of the studies based on gender  showed no significant heterogeneity. Thus, the fixed effects model was used to assess the relationship between trp3 polymorphism and IDD risk. The result of the evaluation indicated that trp3 polymorphism was not associated with IDD risk in both gender .Subgroup analysis was conducted according to different ethnicity  and was observed significant heterogeneity. So the random effects model was used to test the association between trp3 polymorphism and IDD risk. The result of the calculations indicated that trp3 polymorphism had no associations to IDD risk in any ethnicity .The Begg funnel plot  [COL9A3 trp3 polymorphism with IDD risk both in male or female subgroup. To our limited knowledge, ethnicity may contribute to different genetic characteristics of IDD. Hence, we also performed a subgroup analysis by ethnicity and the outcomes indicated no association of COL9A3 trp3 polymorphism with IDD risk in any of ethnicity subgroup. Based on the analyses above, we speculated that COL9A3 trp3 might be a minor factor in genetic etiology of IDD risk due to the small amount of COL9A3 inside the intervertebral discs [The pooled ORs (trp3 positive versus trp3 negative) and 95%CI did not show a significant association of  female) . So we pal discs . All of I2 values had significantly decreased after excluding Paassita et al. [I2 values had significantly decreased after excluding a study of Paassita et al. [No significant heterogeneity was observed in subgroup analysis of gender, whereas there existed heterogeneities in the overall comparisons and subgroup analysis of continent for trp3 and IDD risk. To search the source of heterogeneity, we observed that a et al.  or Kelema et al.  in overaa et al.  in subgrMoreover, no significant change of results was identified by sensitivity analyses, which indicating the reliability of results. These suggested the reliability of the results. Publication bias was also tested in this study. On the basis that a meta-analysis collects various data from numerous studies, the effect of publication bias among the articles included in the study can influence the meta-analytic results. Neither the Egger’s test nor the Begg funnel plot showed significant publication bias for this analysis. Although the results are reliable, more studies are required to be conducted in order to confirm the outcome of this meta-analysis.COL9A3 trp3 polymorphism and the risk of IDD. We suggest that such a method of incorporating the outcomes of related studies may help us to understand the effect of polymorphism on disease development better. Secondly, we also have taken the gender and ethnicity of subjects into account. This study included researches of Asia , Europe  and America (USA), containing different kinds of ethnicities and enrolling both male and female. So the results are much more comprehensive. Moreover, several strategies and strict principle were applied to evaluate the methodological quality of the studies and most of the studies included in this meta-analysis possessed moderate or high qualities.Our meta-analysis has several strengths. Firstly, to our best knowledge, this is the first meta-analysis focusing on the connection between COL9A3 trp3 polymorphism is a little bit small. Secondly, the heterogeneity was a little bit high when overall and sub group of ethnicity analyses were conducted, contributing to a cautious acceptance of the results. What’s more, some studies were removed from our research for lacking detailed data, which may contribute to selection bias. Limited to data, we only analyze trp3 positive versus trp3 negative to estimate the ORs and 95%CI rather than five models . This may also influence the reliability of outcomes. Finally, although most of articles in this meta-analysis made a good match of age, gender or other items which might influence the results, some articles did not take certain items into account or even did not mention the match points. These confounding factors might affect the results.The present meta-analysis also has a few limitations that should be taken into account. Firstly, the number of filtered studies for COL9A3 trp3 polymorphism did not seem to be connected to risk of IDD in any gender, continent or ethnicity of people. Future researches with larger sample sizes are required to verify this outcome.Basing on the epidemiological evidence, our meta-analysis suggested that


To assess the association of genes in the high-density lipoprotein metabolic pathway (HDLMP) with polypoidal choroidal vasculopathy (PCV) and the genetic difference in the HDLMP between PCV and age-related macular degeneration (AMD).  We performed a literature search in EMBASE, PubMed, and Web of Science for genetic studies on 7 single nucleotide polymorphisms (SNPs) from 5 genes in the HDLMP including cholesteryl ester transfer protein (CETP), hepatic lipase (LIPC), lipoprotein lipase (LPL), ATP-binding cassette transporter A1 (ABCA1), and ATP-binding cassette transporter G1 (ABCG1) in PCV. All studies were published before September 30, 2017, without language restriction. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) of each polymorphism were estimated. We also compared the association profiles between PCV and AMD and performed a sensitivity analysis. P < 0.01), CETP rs2303790 , and ABCG1 rs57137919  were significantly associated with PCV, and ABCG1 rs57137919  has different effects in PCV and AMD. The other 4 polymorphisms in LIPC/LPL/ABCA1 had no significant association with PCV (P > 0.05). The sensitivity analysis validated the significance of our analysis.  Our result is based on 43 articles. After excluding duplicates and articles without complete information, 7 studies were applicable to meta-analysis. 7 polymorphisms were meta-analyzed: CETP rs2303790/rs3764261, LIPC rs10468017/rs493258, LPL rs12678919, ABCA1 rs1883025, and ABCG1 rs57137919. We found that in Asian population, CETP rs3764261  and ABCG1 (rs57137919) were the major susceptibility genes for PCV in Asian population and ABCG1 (rs57137919) showed allelic diversity between PCV and AMD. Since the size for PCV and AMD was small, we need to study these genes genotyping in larger samples. Polypoidal choroidal vasculopathy (PCV) is a choroidal vascular disease of first described in the early 1980s as polypoidal subretinal vascular lesions associated with serous or hemorrhagic detachment of the retinal pigment epithelium (RPE) . From a Many studies have indicated lipid deposition in Bruch's membrane and soft drusen, and the amount of lipid was lower in the peripheral area than in the macula of human eyes . A numbeThus far, some studies have studied the impact of lipid metabolism-related and systemic lipoprotein genes in PCV. Here, in order to give the comprehensive analysis of effects and solve the controversies, we conduct meta-analysis and report a systematic review by summing up all published articles of genetic associations in the HDLMP of PCV. This study (1) conducted an investigation of which genetic variants of the HDLMP are meaningfully associated with PCV and their effect sizes and (2) analyzed whether there were differences between genetic risks of the HDLMP in PCV and AMD.We searched EMBASE, PubMed, and Web of Science using the following MeSH terms and free words:  and (cholesteryl ester transfer protein or CETP or hepatic lipase or LIPC or lipoprotein lipase or LPL or ATP-binding cassette transporter A1 or ABCA1 or ATP-binding cassette transporter G1 or ABCG1). All searched articles were published before September 30, 2017, without language restriction. We also screened the reference lists of all eligible studies, reviews, and meta-analyses to ensure that any relevant studies were not omitted. We also searched all reported genome-wide association studies of PCV including the supplementary materials to maximize the usable data. The detail of search strategy is revealed in We included those studies that satisfied the following criteria in the meta-analysis: (1) case-control studies, cohort studies, or population-based studies that evaluated the association of gene variants of CETP/LIPC/LPL/ABCA1/ABCG1 with PCV or its subtypes and (2) allele or genotype counts and/or frequencies being presented or able to be calculated from the data in the study. Case reports, conference reports, reviews, animal studies, and reports with insufficient information were excluded .Two reviewers (Y. M. z. and Y. J. y.) independently reviewed and extracted data from studies on the association between CETP/LIPC/LPL/ABCA1/ABCG1 SNPs and PCV. If there were any differences between them, another two reviewers would help to resolve it (Z. C. x. and H. R. a.) after thorough discussion. The following information was extracted from each article: the name of first author, publication year, ethnicity of the study population, study design, genotyping method, sample size, demographics, allele and genotype distribution , and theI2 value to quantify the proportion of the variability in effect estimates, which is due to heterogeneity rather than sampling error. The I2 value was shown as of no (0–25%), low (25–50%), moderate (50–75%), or high heterogeneity (75–100%) [I2 test was to assess heterogeneity among studies. The potential publication bias was assessed visually in a funnel plot of log (OR) against its standard error, and the degree of asymmetry was evaluated using Begg's test and Egger's test . We undertook the sensitivity analysis to examine the influence by removing the unreliable study [P value of less than 0.05 was considered statistically significant.We conducted meta-analysis for each polymorphism which had been reported in ≥2 studies or cohorts. The association was evaluated by different genetic models, including allelic, heterozygous, and homozygous models. For each study, the odds ratio (OR) with 95% confidence interval (95% CI) was calculated to evaluate the strength of association between the each SNP and PCV risk. Moreover, we used the 75–100%) . The I2le study . The sofAs shown in Totally 17 SNPs had been studied in PCV in the literature . HoweverP < 0.01, I2 = 0%). In the subgroup analysis by ethnicity, still significant association was detected in Chinese . Also, CETP rs2303790 [P < 0.01, I2 = 0). As for ABCG1 rs57137919, the frequency of the A allele was significantly higher in PCV patients than in controls, conferring a 1.168-fold increased risk . Through quality assessment and sensitivity analysis, we found the heterogeneity derived from the data of Shantou population [P < 0.01, I2 = 0%). Regarding the other 4 SNPs, LIPC rs10468017/rs493258, LPL rs12678919, and ABCA1 rs1883025, the pooled ORs were not statistically significant in PCV in the allelic (P > 0.05). As for ABCA1 rs1883025 , quality assessment and sensitivity analysis showed that the study of Zhang et al. was of higher risk of causing bias than the other cohorts [P=0.257, I2 = 0%).CETP rs3764261 is the most widely investigated SNP in PCV, with a number of 1355 cases and 1493 controls studied for the meta-analysis , 35, 36.s2303790 , 38 and  cohorts . TherefoP=0.017, I2 = 0%) [P > 0.05). As for CETP rs3764261 , quality assessment and sensitivity analysis showed that the study of Liu et al. was of higher risk of causing bias than the other cohorts [P=0.025, I2 = 0%) [We identified 6 studies in which both PCV and AMD were assessed for associations with a total of 7 SNPs in 5 genes  . Only 1 2 = 0%) , 37. The cohorts . Therefo2 = 0%) .P > 0.05)  Tables  and S2.In the systematic review and meta-analysis, we have summarized the association profiles of genes in the HDLMP in PCV and assessed the genetic difference in the HDLMP between PCV and AMD for the first time . We found significant association between reported CETP rs2303790/rs3764261, ABCG1 rs57137919, and PCV. Also, we identified ABCG1 rs57137919 showing significant differences between PCV and AMD. In contrast, LIPC rs10468017/rs493258, LPL rs12678919, and ABCA1 rs1883025 were not statistically significant in PCV and reported SNPs in 4 genes in the HDLMP  showed no significant differences between PCV and AMD.CETP can make oxidized lipids transfer from the outer segments of the photoreceptors or other membranes to HDL-like lipoprotein particles. The particles are internalized by RPE and excreted back into the circulation via ABCG1 transporters through Bruch's membrane . ABCG1 wP=0, I2 = 0%) for the T allele. Apart from CETP rs3764261, we also found that CETP rs2303790 was associated with PCV in Asian population [P < 0.01, I2 = 0). Therefore, CETP rs3764261/rs2303790 provided an increased risk for PCV in Asian population. Through the analysis of the studies in which both PCV and AMD were assessed for associations with CETP, we found CETP rs2303790 showed no significant difference between PCV and AMD. However, as for CETP rs3764261, two studies dedicated that CETP rs3764261 was significantly associated with an increased risk for PCV, but no association was found with AMD [In the studies  , but one2 = 0%) . However2 = 0%) , 57. TheP=0.029, I2 = 61.5%). Interestingly, we found the result had the heterogeneity. Through quality assessment and sensitivity analysis, we found the heterogeneity derived from the data of Shantou population. After reading the related articles, we found all the studies used TaqMan genotyping assays, as well as the same inclusion criteria and exclusion criteria. Therefore, we speculate that there may be racial differences between Shantou population and others, but we need further studies to prove the view and find the causes of heterogeneity. Also, we found the significant difference between PCV and AMD in ABCG1 rs57137919 . In one of the studies, Li et al. studied the relevance of ABCG1 rs57137919 to PCV and AMD in Hong Kong, Shantou, and Osaka study subjects, and the results showed that the association of ABCG1 rs57137919 with PCV was significant in the Hong Kong cohort, but not in the Shantou or the Osaka cohort. Also, they indicated that the association of ABCG1 rs57137919 with AMD was not significant in the Hong Kong, Shantou, and Osaka cohorts. In another study, Liu et al. provided putative evidence of a role of ABCG1 rs57137919 in the vascularized complication of PCV. Because there were only two studies about relevance of ABCG1 rs57137919 to PCV and AMD, we need further replication studies in other ethnic populations to confirm the role of ABCG1 in PCV and AMD.From the studies , 37, forP=0.73E−04), but not with AMD , and suggested the need to find biological clues about the different underlying HDL pathways by separating PCV from AMD so as to explore the pathogenesis of PCV and AMD [From our meta-analysis, we found other 4 SNPs  were not statistically significant in PCV and AMD. Besides, the associations of eleven SNPs in CETP/LIPC/ABCA1/ABCG1 were reported in only 1 study , 36–38 . Among t and AMD .P=0.0094), but not AMD . Also, this study found hyperlipidemia is a risk factor for PCV [P=0.026) and AMD  in Chinese and Japanese subjects, which pointed out ABCG1 as a new susceptibility gene for PCV and AMD [P=3.07E−07), was in high LD with the currently studied SNP rs3764261 in Europeans, and similar association patterns were shown in AMD at CETP rs183130 . Also, they found that the most significant association signals recognized in Europeans were at rs5817082, rs1864163, and rs17231506 in CETP, but only rs17232506 showed significant association with PCV and AMD [Another recent study reported that LIPC rs1532085 conferred an increased risk for PCV  and ABCG1 (rs57137919) are the major susceptibility genes for PCV in the Asian population, and ABCG1 (rs57137919) has different effects in PCV and AMD in the Asian population. However, due to the small pooled sample size for PCV and AMD, further studies of these genes in larger samples are warranted to confirm the association of gene variations in the HDLMP with PCV in other populations such as Caucasian and Australian. Moreover, further studies should focus on the genotype-phenotype correlations and the relevance of genotype to therapy in PCV, which may provide us the clues about the pathogenesis of PCV.


No associations were determined for CML, AML, or MM for either polymorphism. This meta-analysis demonstrated that the A1298C polymorphism was associated with an increased risk of developing ALL, whereas the C677T polymorphism was associated with a decreased risk (protective factor) in the Latino population.Our objective was to determine the association between the methylenetetrahydrofolate reductase polymorphisms (C677T and A1298C) and the risk of developing acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), and multiple myelomas (MM) in Latinos. PubMed, SCOPUS, EBSCO, LILACS, and other Latin-specific databases were searched for case-control studies that investigated the association between these polymorphisms and hematologic malignancies until November 2017. Genotype distributions were extracted and either fixed-effects or random-effects models were used to calculate the pooled crude odds ratios (ORs) for the heterozygous, homozygous, dominant, recessive, and allelic genetic models. No publication bias was detected by the Begg-Mazumdar’s test and Egger’s test. From 290 publications, we identified 15 studies on the C677T polymorphism and 13 studies on the A1298C polymorphism. We observed a significant decrease in risk for the C677T polymorphism (OR range=0.54-0.75,  Characterized as an uncontrolled growth of cells, cancer is a multi-stage and multi-factorial process  with environmental factors, such as diet, lifestyle habits , and a gmthfr gene is located on chromosome 1 and is a key enzyme for reducing 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate . PubMed, Wiley, SCOPUS, EBSCO, LILACS, BIBLAT, CABI, DOAJ, GALE, IMBIOMED, LATININDEX, MEDIGRAPHIC, PERIODICA, and REDALYC databases were searched for studies that investigated the association between the MTHFR polymorphisms and cancer in Latin Americans. The following keywords/terms and any of their derivations were used: “Latino or Hispanic” as well as other terms associated with Latin American countries, “MTHFR or methylenetetrahydrofolate”, “polymorphism or SNP”, and “cancer or carcinogenesis” (Table S2). Latin American countries were identified according to the United Nations Educational, Scientific and Cultural Organization and the Community of Latin American and Caribbean States (CELAC) definitions , Latinos, and MTHFR. For inclusion, the studies must had met the following criteria: 1) case-controls studies; 2) examined at least one of the MTHFR polymorphisms (C677T or A1298C); 3) focused on human subjects that were Latinos or of Latino-descendants; 4) patients with a diagnosis that was confirmed by either pathological or histological examination; and 5) contained information about genotype frequencies. Studies were excluded if: 1) not a case-control study; 2) information was used in a previous publication; 3) failed to describe cancer conformation; 4) failed to report the complete genotype distribution or unable to determine it from the reported data; 5) failed to use local controls; or 6) were a meta-analysis, review, or editorial article.Table S3, Figure S1). For analysis, the quality scores ranged from 0 to 9. Studies that scored ≥6 were considered of high quality. The following data was collected from each study: first author’s name, year of publication, geographical location, type of cancer, technique used to detect the polymorphism, source of controls, and the genotype distribution for cases and controls.Two authors independently assessed the quality of the studies using the Newcastle-Ottawa Quality Assessment Scale . The fol2-test for the controls and a p-value <0.05 was considered in agreement. Crude odds ratios (ORs) and 95% confidence intervals (95%CI) were used to assess the strength of the association between the MTHFR polymorphism and the risk of cancer. The pooled crude ORs were calculated for allelic (2 vs. 1), dominant (12 + 22 vs. 11), recessive (22 vs. 12 + 11), heterozygous (12 vs. 11), and homozygous (22 vs. 11) genetic models, where 1 corresponded to the wild-type and 2, the mutant form. Heterogeneity was determined using the Ψ2-based Q-test and its degree was assessed by the inconsistency index (I2). Depending on the results of heterogeneity tests, either the random effects model (Ψ2-based Q-test p<0.10 and I2>50%)  were considered statistically significant.For each study, the Hardy-Weinberg Equilibrium (HWE) was determined by the Ψ I2>50%)  or fixed I2>50%)  was sele I2>50%) , and Egget al., 2008; A total of 521 publications were retrieved from searching multiple databases and reviewing the publications bibliographies ; howeverFour types of hematologic malignancies were assessed in this meta-analysis. The most representative hematologic malignancy was ALL with 7 studies .All models presented significant heterogeneity, analyzed using the random effects model, except for the heterozygous model in which the fixed effects model was used. The C677T polymorphism showed a decreased risk for developing cancer in only the heterozygous genetic model .For each genetic model, the stability of the results was determined by re-calculating the pooled ORs after removal of one study. For the heterozygous genetic model, removal of either Figure S8). Moreover, no correlation was determined by the Begg-Mazumdar’s test or bias by Egger’s Test for each model .Publication bias was assessed by examining the funnel plot for each genetic model. Funnel plots demonstrated no significant asymmetry and the shape of the funnel plot suggested no evidence of publication bias (p=0.01) and recessive  genetic models (p=0.05). All forest plots are available as supplementary material .All models presented with significant heterogeneity and were analyzed using the random effects model, except for the Recessive model in which the Fixed Effects model was used. The A1298C polymorphism showed an increased risk of developing hematologic malignancies for the homozygous . However, for the dominant genetic model, removal of the HWE-inconsistence study . Moreover, this was confirmed by the Begg-Mazumdar’s test and Egger’s Test .When publication bias was assessed, no significant asymmetry was determined by examining the funnel plots  study due to the high level of bias and the lack of local controls. For each model, the C677T polymorphism was associated with a significant decrease in risk of developing ALL , whereas the A1298 polymorphism was associated with an increased risk of developing ALL . This suggests that the MTHFR polymorphisms have a dual function among ALL cases.When hematologic malignancies were separated by type of cancer, neither of the polymorphisms had an effect on AML, CML, or MM . For ALLet al. and Xie et al., included eleven of the studies used here that were categorized as mixed, which also included studies from USA  is low compared to other regions of the world . We initial hoped that including alternative databases — LILACS, BIBLAT, LATININDEX, PERIODICA, and REDALYC to name a few — would increase the coverage; however, there remained a significant underrepresentation of Latin America. Moreover, the ability to search and export the citations was problematic. This highlights the problems for research and dissemination of information that occurs among Latin American countries and suggests that studies that were presented at national conferences or regional scientific meetings could have been missed.Our study has a few limitations. First, only three countries are represented in this meta-analysis, which suggests that parts of the Latin American community are underrepresented. Second, we calculated the crude ORs from genotype distributions and they are unadjusted estimations. Adjusting the OR for an age category (adults versus children) could influence the OR, possibly affecting the significances of our results. However, we were focusing on risk and not the age of onset. Moreover, we did not adjust the ORs for the distribution of males and females. Lastly, dietary folic acid consumption was shown to affect the risk associated with cancer development. Here, minimal studies stratified by diet and we were unable to correct for this.Here, we report the risk of hematologic malignancies associated with the two main polymorphisms of the MTHFR gene in Latin Americans. There was a significant association with ALL and not with CML, AML, or MM. The A1298C polymorphism was associated with an increased risk of developing ALL, whereas the C677T polymorphism was associated with a decreased risk, being a protective factor.