Parkinson’s disease (PD) is a common heterogeneous neurodegenerative disorder in elder population. Parkinson’s disease dementia (PDD) is one of the most common non-motor manifestations in PD patients. No comprehensive review has been conducted to assess risk factors for PDD.A systemic search for studies on PDD risk factors was performed. Cohort and case–control studies that clearly defined PDD and presented relevant data were included. The data were analyzed to generate a pooled effect size and 95 % confidence interval (CI). Publication bias was assessed using the Egger’s test and the Begg’s test.A systematic search was conducted and yielded 5195 articles. After screening, 25 studies were included in the current analysis. Development of PDD was positively associated with age , male , higher Unified Parkinson’s Disease Rating Scale (UPDRS) part III scores , hallucination , REM sleep behavior disorder (RBD) , smoking (ever vs. never)  and hypertension . An inverse association was found between education  and PDD. Other reported factors, including age of onset, disease duration of PD, Hoehn and Yahr stage and diabetes mellitus were not significantly associated with PDD.Advanced age, male, higher UPDRS III scores, hallucination, RBD, smoking and hypertension increase the risk of PDD, whereas higher education is a protective factor for PDD.The online version of this article (doi:10.1186/s40035-016-0058-0) contains supplementary material, which is available to authorized users. Parkinson’s disease (PD), a heterogeneous neurodegenerative disorder in elder population, is characterized by cardinal motor symptoms including bradykinesia, rigidity, tremor and postural instability . RecentlSeveral demographic, motor and non-motor features have been identified as predictors for PDD. Advanced age is the most common risk factor for dementia and for later diagnosis of PDD in PD patients . More adWe conducted the search according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA 2009) guideline. We searched MEDLINE and EMBASE database for studies reporting predictors for later diagnosis of PDD. No language restrictions were used. The keywords we selected were: “Parkinson Disease” AND “Dementia” AND “Risk” OR “Predict” OR “Age” OR “Age of Onset” OR “Education” OR “Family history” OR “Hallucination” OR “Sleep Disorders” OR “Constipation” OR “Olfactory Disorders” OR “Color Vision” OR “Depression” OR “Anxiety” OR “Mood Disorders” OR “Erectile Dysfunction” OR “Urinary Dysfunction” OR “Hypertension” OR “Coronary Artery Disease” OR “Head Injury” OR “Diabetes Mellitus” OR “Smoking” OR “Alcohols” OR “Coffee” OR “Pesticides”. We also hand searched the reference lists of relevant reviews and articles with required data for missed references. The final search was carried out on December 1, 2015.We included articles that met the predefined criteria: 1) cohort or case–control studies assessed at least one risk factor preceding a later diagnosis of PDD; 2) compared PDD patients with PD patients who did not develop dementia; 3) clearly stated diagnostic criteria for PD and PDD, and carried out by an experienced clinician; 4) reported odds ratio (OR), relative risk (RR) or equivalent values representing risks of developing dementia or case–control studies with cases defined as diagnosed PDD; and 5) reported data that could be easily obtained via questionnaires.Reviews, editorials, case reports, commentaries, letters that reported no new data, meta-analysis, handouts, and abstracts were excluded from the study. We excluded studies that: 1) reported on treatment or management of PDD; 2) reported a diseases other than PDD or PD; 3) studied only young onset PD; 4) did not use a PD non-demented group as comparable group to PDD group or did not provide adequate data on the comparable group; 5) were twin studies; 6) reported one predictor repeatedly in one study population ; 7) reported on predictors that were not easily available in most clinical settings (i.e. questionnaires designed for a certain population or country); 8) reported only uncommon genetic risk factors; 9) reported measures other than OR, RR or equivalent values, or from which an OR could not be calculated. Two authors (X.Y. and J.Y.) independently evaluated the eligibility of all studies, and if there was disagreement between authors, the articles were further evaluated by a third author (H.S.) and discussed in detail until an agreement has been reached.Study characteristics, PDD diagnostic criteria, a risk estimate of the main study finding, and secondary findings were extracted using a unified form. We did not include studies that reported dementia before or within one year to the onset of PD, since these cases did not fulfill the diagnostic criteria for PDD and were more likely cases of dementia with Lewy bodies (DLB). If studies did not report OR, RR or equivalent measures, raw data were screened to determine whether ORs could be calculated. When the studies reported both the crude OR/RRs and the adjusted OR/RRs, the adjusted figures were extracted. We calculated a quality score to assess the quality of the studies according to the Newcastle-Ottawa Scale (NOS). Length of time that any predictor precedes the diagnosis of PDD was not analyzed in the study due to inconsistent reporting.2 statistic [p < 0.05), we used randomized effects model to combine results. We assessed publication bias using the Egger’s test and the Begg’s test, and constructed funnel plot in order to visualize any possible asymmetry [P values less than 0.05 were considered statistically significant. All analyses were performed using Stata version 12.0 .We combined the reported risks first separately for case–control and cohort studies, and second for all studies together, in cases where two or more studies reported on the same factor. The data were analyzed to generate a pooled effect size and 95 % confidence interval (CI). We examined the heterogeneity across studies using the Itatistic , 17. Whesymmetry . Two-taiThe electronic search yielded 5195 articles, all of which were reviewed by titles and abstracts. Full text of 278 articles were reviewed, of which 23 articles met the inclusion criteria. We also hand searched the references of the articles, 2 of which were included into the analysis. Finally, a total of 25 articles were included in the meta-analysis. Full details of the studies included were provided , gender   and hypertension , to be significantly associated with later diagnosis of PDD  part III  increased the risk of PDD, but higher Hoehn and Yahr stage  was not associated with the development PDD. Studies analyzing the association between PD motor subtypes and PDD were not included in the present meta-analysis because of limited data. Two common non-motor symptoms of PD patients, hallucination  and RBD , were both strong predictors of PDD. Single studies also reported positive association between PDD and family history of dementia (first-degree relatives), urinary dysfunction, impaired color vision or orthostatic blood pressure drop and no significant association between family history of PD (first-degree relatives), exposure to pesticides, occupational exposure to chemicals and PDD , 15, 20.The funnel plot for each included factors were individually examined visually. The shape was presented essentially symmetrical in age, AOO, gender, smoking, disease duration, education, UPDRS III, hallucination, RBD, hypertension, diabetes mellitus and Hoehn and Yahr stage, which was proved by Begg’s and Egger’s test.This study identified 12 individual predictors that have potential value in screening for PDD. The identified risk factors include demographic characteristics, lifestyle factors, non-motor features of PD, and widely accepted scales evaluating PD. Some of the factors may present pathogenic importance while others could represent the relationship between symptoms and cognitive decline. Together, these factors tend to be markers preceding diagnosis of PDD in PD patients. Of the identified factors, 7 factors were significant predictors for subsequent diagnosis of PDD, the understanding of which may contribute to higher quality of care and improve quality of life in PD patients.Age, AOO and disease duration were all common risk factors for PDD. However, since these three factors are interdependent, their individual effect on PDD is under debate. One study comparing early and late onset PD patients suggested that late onset PD group presents with more severe impaired sensory abilities, sleep disorders and dementia . AnotherWe also found male to be a risk factor for PDD. However, some studies suggested that there might be no relationship between gender and PDD if potential confounding factors, including age, history of dementia, smoking and number of siblings, were adjusted , 22. In A recent meta-analysis on risk factors for PD suggested that smoking, alcohol and coffee consumption decreases the risk of PD . In the We found that higher UPDRS III score was positively related with later diagnosis of PDD, whereas Hoehn and Yahr stage was not significantly associated with PDD. This result suggests that severe motor dysfunction is associated with PDD risk, and that the risk is more likely associated with individual motor dysfunctions. In a study that discovered no significant association between UPDRS III and PDD, researchers found that within the UPDRS III section, gait dysfunction was strongly associated with eventual development of dementia . Gait dyWe discovered RBD and hallucination are strongly associated with later diagnosis of PDD. Several studies suggested that patients with RBD had a higher rate of MCI at baseline and a shorter duration towards diagnosis of dementia –44. CholWe only selected factors that were easily obtained in primary care environment. Variables that used less common inventories, like color vision and olfactory dysfunction, were not included in the analysis. Also, genetic tests have been excluded from the analysis for similar reasons. Mild cognitive impairment, an important risk factor of incidence dementia in PD , 51, wasNot all studies adjusted risk factors for confounders, and those adjusted were mostly adjusted for different confounders. We included both factors unadjusted and factors adjusted where possible, which may have increased the degree of significance for some risk factors. Few factors were reported in studies to be positively associated or not associated with later diagnosis of PDD but without specified OR or RR to be extracted. Though we have calculated OR or RR where possible, there may still be data neglected.2 > 75 %). Gender, education, hallucination, UPDRS III, RBD and hypertension were found to have moderate heterogeneity (50 % < I2 < 75 %). The presence of heterogeneity was as expected because of the differences in the characteristics of studies, the length of follow-up, study population scale, population characteristics, diagnostic criteria used and whether factors were crude or adjusted. The follow-up period in the cohort studies and the diagnostic criteria for PDD in both cohort and case–control studies varied, we did not adjust these factors in this meta-analysis due to limited number of included studies. Thus, the results of this analysis should be interpreted cautiously, especially for those factors that were reported in less than three studies and that were with high heterogeneities.Statistically significant heterogeneity was found in 8 of the meta-analyses performed in our study. Two risk factors, age and AOO, were found to have high heterogeneity (IIn the present meta-analysis, we included studies with NOS score higher than 5, which ensured study quality. Also, we performed sub-group analysis by different study design in order to minimize heterogeneity. We combined analytical results according to the heterogeneity analysis, and did not find significant publication bias. Therefore, our results were considered to be robust.This is the first systematic review and meta-analysis on widely evaluated risk factors of PDD. This study found advanced age, male, high UPDRS III scores, presence of hallucination, presence of RBD, ever smoking and history of hypertension are positive predictors to later diagnosis of PDD, whereas education is a protective factor of PDD. This study laid the foundation to future comparative assessment on risk factors for PDD, and lead to a better understanding of PDD risks.AD, Alzheimer’s disease; AOO, Age of onset; CI, Confidence interval; DLB, Dementia with lewy bodies; NOS, Newcastle-Ottawa scale; OR, Odds ratio; PD, Parkinson’s disease; PDD, Parkinson’s disease dementia; PIGD, Postural instability and gait difficulties; PRISMA, Preferred reporting items for systematic review and meta-analysis; RBD, REM sleep behavior disorder; RR, Relative risk; UPDRS, Unified Parkinson’s Disease Rating Scale.


In this meta-analysis, PubMed was searched for case–control studies published through 01 December 2013. The data were extracted, and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. We assessed six published studies on the association between the interleukin-8 -251T/A polymorphism and lung cancer risk. The included studies yielded a total of 3265 lung cancer cases and 3607 controls. For the homozygous A/A and A allele carriers (T/A + A/A), the pooled ORs for all studies combining 3265 cases and 3607 controls were 1.03  and 1.07  when compared with the homozygous wild-type genotype (T/T). When the analysis was stratified by ethnicity, significant risks were found among Asians for both the A allele carriers and the homozygous A/A individuals. However, no significant associations were found in non-Asian populations using any of the genetic models. This meta-analysis suggests that the interleukin-8 -251A allele confer an increased risk for the development of lung cancer among Asians.Many studies have examined the association between the  Lung cancer remains the deadliest cancer worldwide despite improvements in diagnostic and therapeutic techniques Interleukin-8 (IL-8), a member of the chemokine family, is a chemoattractant of neutrophils and lymphocytes Many studies have investigated the associations between the IL-8 -251T/A (rs4073) gene polymorphism and lung cancer risk, but the findings have been inconsistent. A single study may not have sufficient power to detect a small effect of the polymorphism on lung cancer, particularly when the sample size is relatively small. Different types of study populations may also contribute the disparate findings. Hence, we performed a meta-analysis of all eligible studies to derive a more precise estimation of the associations of the IL-8 -251T/A (rs4073) polymorphism with lung cancer.The electronic database PubMed was searched for studies to include in the present meta-analysis using the following terms: ‘IL-8’ or ‘interleukin-8’, ‘-251T/A’ or ‘rs4073’, ‘polymorphism’ and ‘lung cancer’. An upper date limit of 01 December 2013 was applied; no lower date limit was used. The search was performed without any restrictions on language and was focused on studies that had been conducted in humans. Concurrently, the reference lists of the reviews and retrieved articles were searched manually. Only full-text articles were included. When the same patient population appeared in several publications, only the most recent or complete study was included in this meta-analysis.i) evaluated the IL-8 - 251T/A polymorphism and lung cancer risk; (ii) case–control studies and (iii) supplied the number of individual genotypes for IL-8 -251T/A in lung cancer cases and controls.The included studies had to meet the following criteria:  t-test suggested by Egger  Odds ratios (ORs) with 95% CI were used to assess the strength of the association between the IL-8 -251T/A polymorphism and lung cancer risk. The pooled ORs for the risk associated with the genotypes A/A and A allele carriers (A/T + A/A) with the T/T genotype were calculated. Subgroup analyses were performed based on ethnicity. The assumption of heterogeneity was checked by the chi-squared based A total of six publications involving 3265 lung cancer cases and 3607 controls met the inclusion criteria and were included in the analysis P = 0.235 for heterogeneity) and 1.07   and homozygous A/A individuals . Among non-Asian populations, no significant association was found for A/A versus T/T  or for A allele carriers versus T/T .TableA single study involved in the meta-analysis was deleted each time to reflect the influence of the individual data set on the pooled ORs, and the corresponding pooled ORs were not significantly altered (data not shown).versus TT using Egger's test demonstrated that the publication bias was not significant (P = 0.283). In addition, the funnel plots for publication bias (Fig.Begg's funnel plot and Egger's test were performed to access the publication bias of the literature. The evaluation of publication bias for TA + AA nt P = 0.83. In adThe IL-8 gene is located on chromosome 4q13-21 and consists of four exons, three introns and a proximal promoter region. The coding sequence of this gene exhibits several functional polymorphisms, and 15 of these have been characterized When stratified according to ethnicity, Asian carriers of the A allele and homozygous A/A individuals showed an increased risk of lung cancer compared with those with the T/T genotype. However, among the non-Asian population, no significant associations were found with any of the genetic models. These findings indicate that the IL-8 -251T/A polymorphism may be important in lung cancer patients with a specific ethnicity, and the effect of the A allele on the risk of lung cancer may differ by ethnicity. Population stratification is an area of concern, and it can lead to spurious evidence for the association between a marker and a disease, suggesting possible roles for ethnic differences in genetic background and the environment in vitro assays have demonstrated that it influences the production of IL-8 and affects the transcriptional activity of the IL-8 promoter The mechanism by which the A allele of IL-8 -251T/A may reduce the lung cancer risk is not clear. The T/A single nucleotide polymorphism was identified in the promoter region of the IL- 8 gene 251 base pairs upstream of the transcriptional start site, and Some limitations of this meta-analysis should be acknowledged. First, heterogeneity is a potential problem when interpreting the results of a meta-analysis. Although we minimized the likelihood of this issue by performing a careful search for published studies, using explicit criteria for study inclusion and rigorously performing the data extraction and analysis, significant between-study heterogeneity still existed in almost each comparison. The presence of heterogeneity can result from differences in the selection of controls, age distribution, lifestyle factors and so on. Although most of the controls were selected from healthy populations, some studies had selected controls among friends or family of lung cancer patients or patients with other diseases. Second, only published studies were included in this meta-analysis. The presence of publication bias indicates that non-significant or negative findings may be unpublished. Last, our results were based on unadjusted estimates, whereas a more precise analysis should be conducted if individual data were available, which would allow for the adjustment by other covariates including age, ethnicity, family history, environmental factors and lifestyle.In conclusion, this meta-analysis suggests that the IL-8 -251T/A polymorphism is not associated with lung cancer risk among all population, however the A allele is an increased risk factor for developing lung cancer among Asians. In addition, it is necessary to conduct large blind trials using standardized, unbiased methods, homogeneous lung cancer patients and well-matched controls.The authors confirm that there are no conflicts of interest.


Thyroid autoimmunity is considered the most common type of organ-specific autoimmune disorder and can be associated with other autoimmune endocrine disorders or non-endocrine diseases. Systemic lupus erythematosus is a prototypical autoimmune disorder with multifactorial etiology. The pathogenesis and development of the disease may result from a loss of immune tolerance and the resulting synthesis of autoantibodies against nuclear antigens. Autoimmune factors may be common features of both thyroid autoimmunity and systemic lupus erythematosus, making it likely that both conditions may coexist within some patients.A number of studies have investigated whether an association between thyroid autoimmunity and systemic lupus erythematosus exists. However, the results of these studies have been inconsistent. Furthermore, most of these studies have had relatively small sample sizes, which have rendered them insufficiently powerful to determine whether there is an association between systemic lupus erythematosus and thyroid autoimmunity. The main objective of this meta-analysis is to provide reliable estimates of the extent of any association between thyroid autoimmunity and systemic lupus erythematosus by combining the primary data from all relevant studies. Literature databases were searched, including the Medline, Embase, Web of Science, Chinese Wanfang and CBM databases, from January 1970 to May 2014. A total of 1076 systemic lupus erythematosus cases and 1661 healthy controls were included in this study. From these data, the odds ratio (OR) and the corresponding 95% confidence interval (95% CI) were calculated. The meta-analysis results showed that the prevalence of thyroid autoantibody positivity in patients with systemic lupus erythematosus was higher than in healthy controls .The results of this meta-analysis suggest that thyroid autoimmunity is more prevalent in patients with systemic lupus erythematosus than in a control group. A lot of endocrine glands such as the thyroid, adrenal, and pancreatic islet beta cells are affected by autoimmune diseases. However, thyroid autoimmunity is one of the most common autoimmune endocrine diseases . Graves’Systemic lupus erythematosus (SLE) is characterized by autoantibodies production, immune complex deposition, hyperactive T and B cells and multi-organ damage, which is a prototypical autoimmune disorder with strong genetic influence . AutoantA number of studies have investigated the association between thyroid autoimmunity and SLE by assaying the prevalence of thyroid autoantibodies, including thyroglobulin antibody (TgAb) and thyroid peroxidase antibody (TPOAb). However, the results of these studies have been inconsistent. Furthermore, most of these studies examined a relatively small sample size and were thus not powerful enough to determine whether an association between SLE and thyroid autoimmunity exists. The main objective of this meta-analysis is to provide reliable estimates of the extent of any association between thyroid autoimmunity and SLE using combined primary data from all relevant studies.A completed PRISMA checklist is presented in the Supporting Information in A systematic search without language restriction was conducted for eligible studies listed from January 1970 through May 2014 in the Medline, Embase, Web of Science, Chinese Wanfang and CBM databases using the key words "systemic lupus erythematosus" or "SLE" in combination with the terms "thyroid autoimmunity" or "autoimmune thyroid diseases" or "autoimmune thyroiditis" or "hashimoto’s" or "grave’s" or "thyroid peroxidase antibody" or "thyroglobulin antibody", and the studies were filtered for those containing human subjects. In addition, the reference lists of the retrieved articles were reviewed to identify additional eligible studies. Studies were selected by two independent reviewers. The relevance of studies was assessed using a hierarchical approach on the basis of the title, abstract, and full manuscript. The studies selected by the two reviewers were compared, and disagreements were resolved by consensus.The preliminary search using the above terms yielded 3074 potential articles. The authors read the abstracts of these 3074 publications and identified 689 publications that appeared to contain relevant data. These 689 publications were read in full and scrutinized for the presence of data. This process identified 15 studies appropriate for further analysis based on our inclusion criteria.P value.Eligible studies included in this meta-analysis met all of the following criteria: (1) evaluate the association between autoantibodies directed against thyroid tissue and SLE, (2) case-control design, (3) provide sufficient data of cases and healthy controls that could allow us to calculate the odds ratio (OR) with 95% confidence interval (CI) and a The following information was extracted from each study: first author, publication year, geographical location of the study population, numbers of cases and controls, and numbers of cases and controls positive for each type of thyroid autoantibody. Information was carefully extracted from all eligible publications independently by two of the authors. Disagreement was resolved by discussion between the authors. If a consensus could not be reached, another investigator settled the disagreement.Two investigators performed quality assessments using the Newcastle-Ottawa Scale for included studies . The NewP<0.05 was considered statistically significant), and Cochrane’s Q test was performed to determine the extent of inter-study heterogeneity using a cutoff of P<0.1 as statistically significant. The OR, which was calculated using either a random effects model or a fixed effects model, was determined in accordance with the heterogeneity, as measured using Cochrane’s Q statistics. I2 values of 25%, 50% and 75% were defined as low, moderate and high estimates, respectively. When a significant Q test (P<0.10) or I2 >50% indicated heterogeneity across studies, the random effects model was used for the meta-analysis. Otherwise, the fixed effects model was adopted. The publication bias was examined by Begg’s test. All the statistical analyses were performed using Stata Version 12.0 software.The association between thyroid autoimmunity and SLE was evaluated by OR with the corresponding 95% CI. The significance of OR was determined with a Z test , but not in the Asian or African populations . A positive association between TPOAb positivity and SLE was observed in the African and European populations  but was not observed in either the Asian or the American populations . Forest plots showing the results of these subgroup analyses are presented in To investigate the influence of each individual study on the overall meta-analysis estimate, a sensitivity analysis was performed by omitting each study in turn and calculating the pooled OR for the remaining studies sequentially, thus reflecting the influence of each individual data set on the pooled OR. A study was considered to be influential if the pooled OR excluding that study was not within the 95% CI of the overall mean. The ORs resulting from the sensitivity analysis did not differ substantially from our original estimates, indicating that our statistics were relatively stable and credible .To determine whether a potential publication bias existed in the reviewed literature, a funnel plot was constructed and Begg’s test was conducted. The funnel plot is a relatively straightforward method of determining whether publication bias is present, and Begg’s test was used to examine the symmetries of the plots statistically. The relative symmetry of the distributions indicated that there was no significant publication bias . SimilarThyroid autoimmunity is considered the most common type of organ-specific autoimmune disorder, which can be associated with other autoimmune endocrine problems, as well as non-endocrine diseases . The evaSeveral studies have evaluated the association between SLE and thyroid autoimmunity, but the results of these studies have been inconsistent. Moreover, most of these studies used a relatively small sample size, which limited their power to detect whether an association between SLE and thyroid autoimmunity is present. Our meta-analysis quantitatively assessed whether an association exists between thyroid autoimmunity and SLE. 15 independent, relevant studies with case-control designs were included in our meta-analysis and assessed. The results of this meta-analysis showed that the prevalence of thyroid autoantibodies in patients with SLE was significantly higher than that in the control groups. The results of a subgroup analysis by geographic location showed that the study subjects with SLE drawn from American and European populations were more likely to be TgAb-positive, but that those drawn from Asian and African populations were not. Regarding TPOAb, there was a positive association between TPOAb positivity and SLE in African and European populations, but this association was observed neither in Asian populations nor in American populations, suggesting a possible role for geography-driven differences in genetic backgrounds and living environments.The main purpose of performing this meta-analysis was to shed light on the relationship between thyroid autoimmunity and SLE using statistical methods. However, there were some limitations to our meta-analysis. First, several relevant studies were not included in this meta-analysis because of incomplete raw data or other limitations of the publications. Second, in the subgroup analysis, the number of studies examining Asian populations was relatively small; thus, there was not enough statistical power to evaluate the level of association in this group to a desired level of accuracy. Third, due to the lack of consistent criteria for categorizing thyroid function between different countries, this meta-analysis only addresses the relationship between SLE and thyroid autoantibodies. Furthermore, since the studies included were done by different investigators from different countries and at very diverse time points extending for more than 3 decades, the variability of assays used in each study may have some influence to the consequence. Consequently, these meta-analysis results should be interpreted with caution.In conclusion, the results of our meta-analysis support the hypothesis that the prevalence of thyroid autoantibodies in patients with SLE is higher than that in healthy controls, which suggests that SLE may be associated with increased thyroid autoimmunity risk.S1 PRISMA Checklist(DOC)Click here for additional data file.S1 Fig(TIF)Click here for additional data file.S1 Table(DOC)Click here for additional data file.S2 Table(DOC)Click here for additional data file.


Ureaplasmas spp. including U. urealyticum and U. parvum, have been increasingly reported to be implicated in NGU. However, there are still many contradictions about their pathogenic role in NGU.Nongonococcal urethritis (NGU) is the most common male reproductive tract syndrome. Ureaplasmas spp. with NGU, and to compare the prevalence of Ureaplasmas spp. infection in China relative to the world average.The goals of this study were to evaluate the association of A systematic review and meta-analysis was conducted following standard guidelines for meta-analysis. The quality of included studies was assessed by Newcastle-Ottawa scale.Ureaplasma spp. positive rate between the NGU and control groups. However, the U. urealyticum positive rate was significantly higher in NGU patients compared to controls; the U. parvum positive rate was significantly higher in controls compared to NGU patients. Furthermore, within the NGU patient group, the positive rate of U. urealyticum was significantly higher than that of U. parvum, whereas within the control group, the opposite trend was observed. Compared to the world average, a significantly higher positive rate of Ureaplasma spp. was observed in both the NGU and control groups in China.A total of seven studies involving 1,507 NGU patients and 1,223 controls were eligible for meta-analysis. There was no significant difference in the U. urealyticum, but not U. parvum, is an etiological agent in NGU. More detailed studies of these two species in China and the world could contribute to a better understanding of the epidemiology and pathogenesis, and facilitate the development of better strategies for treatment and prevention of NGU.Our analysis supports that  Chlamydia trachomatis (20–50%), Mycoplasma genitalium (10–25%), and Trichomonas vaginalis (5–15%) Ureaplasmas spp. are perhaps the most extensively studied and the most controversial organisms.Nongonococcal urethritis (NGU), a clinical syndrome consisting of urethral manifestations such as urethral discharge, dysuria and irritation, in the absence of gonococcal infection, is the most common urethritis syndrome observed in men. In general, NGU accounts for 20–50% of urethritis cases among men in sexually transmitted disease (STD) clinics Ureaplasmas spp. were first isolated in 1954 from the urethral discharge of men with NGU Ureaplasmas spp. with NGU, which led to the speculation of existence of different ureaplasma strains or biovars with distinct virulence potential. In 1999, phylogenetic analysis established the classification of Ureaplasma spp. into two species, U. parvum and U. urealyticumU. parvum and U. urealyticum. Since then, intense efforts have been made in differential detection of these two species in NGU patients U. parvum is a non-pathogenic commensal organism in the male urethra U. parvum and U. urealyticum with NGU remain unclear Since C. trachomatis (15.5–41.4%) M. genitalium (6.9–25%) T. vaginalis (9.7%) Ureaplasma spp. infection in NGU patients varies from 31.6% to 43.8% U. parvum and U. urealyticum and their association with NGU China is one of the most populated countries in the world. Over the past two decades, rapid pace of economic and social changes has been followed by a resurgent epidemic of STDs U. parvum and U. urealyticum in NGU, we performed a comprehensive meta-analysis of literature published between January 2000 and December 2013 about the association of U. parvum and U. urealyticum with NGU in patients in China and worldwide.To better understand the role of Ureaplasma spp. OR U. urealyticum OR U. parvum”. Given that U. parvum was not recognized as a new species until 1999, the literature search period was set from January 2000 to December 2013 (prior to the preparation of this manuscript). There was no language restriction in our selection. Additional publications were identified by manual search of the references of the publications obtained by computer search. When there were publications with duplicated or overlapped data from the same investigators, only one of the most recent or complete studies were used.A meta-analysis review was conducted according to the PRISMA Statement Ureaplasma spp., U. urealyticum or U. parvum with NGU; (b) the patient group was men who were diagnosed with NGU; (c) the studies provided enough data for the estimation of odds ratios (ORs) with 95% confidence intervals (CI).The inclusion criteria for NGU were adapted from published studies U. urealyticum or U. parvum.Three reviewers  independently searched the databases described above. We first selected articles on the basis of the title and abstract. Data were extracted using a standardized extraction form. If any of the three reviewers considered any article to be potentially eligible, the full-text of the article was retrieved and evaluated by all three reviewers using the above inclusion criteria. Discordance among reviewers regarding articles with borderline eligibility was resolved by consensus following discussion with an additional investigator (Yunde Liu). For each of the selected articles, the following information was recorded: name of the first author, year of publication, country of origin of study population, total number of patient cases and controls, and number of cases infected with The quality of the included studies was assessed using the Newcastle-Ottawa scale Ureaplasma spp., U. urealyticum or U. parvum with NGU was calculated using ORs and 95% CIs. The distribution rates of U. urealyticum and U. parvum within the control and NGU groups were also compared using ORs and 95% CIs. The statistical significance of the summary OR was determined using the Z test, with P<0.05 considered statistically significant. Statistical heterogeneity between studies was evaluated using the 2χ and 2I tests with significance level set at P<0.1 or 2I>50% chi-square test, with P<0.05 considered statistically significant. All statistical analyses were conducted using Stata software  and two-sided P values.The association of Ureaplasma spp. was culture-based and unable to differentiate U. urealyticum and U. parvumThere were a total of 2,022 relevant articles retrieved . After rUreaplasma spp. positive cases was 425 in the NGU group , and 378 in the control group . All study subjects involved were hospital-based. Data about demographic and sexual behavioural characteristics were available from only some but not all of the studies, and thus were not included for meta-analysis.The seven included studies involved a total of 1,507 NGU patients and 1,223 controls . The numUreaplasma spp. infection between the NGU patients (28.20%) and control groups (30.91%) (OR was 1.10 (95% CI: 0.84–1.45) with Z = 0.69 and P = 0.488 for the overall effect. In the statistical heterogeneity analysis, P value was 0.034 and 2I value was 56.1%. These data suggest that undifferentiated Ureaplasma spp. are not associated with NGU.By including a total of 1,507 patients with NGU and 1,223 controls from seven eligible studies , meta-an(30.91%) . The pooU. urealyticum positive rate between the NGU patients  and the controls , meta-analysis demonstrated a significant difference between these two groups with a pooled OR of 1.57 (95% CI: 1.05–2.35), and Z = 2.19 and P = 0.029 for the overall effect  and control groups , meta-analysis demonstrated a significant difference between these two groups, with a pooled OR value of 1.91 (95% CI: 1.52–2.40), and Z = 5.52 and P<0.00001 for overall effect. In the heterogeneity test, P value was 0.689 and 2I value was 0%. The forest plot is shown in U. parvum in NGU patients than in the controls rejects an association of this organism with NGU.By comparing the U. urealyticum and U. parvum within the 1,507 NGU patient group, the prevalence of U. urealyticum (18.31%) was significantly higher than that of U. parvum (10.22%), with a pooled OR value of 2.00 (95% CI: 1.61–2.47), Z = 6.34 and P<0.00001 for the overall effect, and P = 0.880 and 2I = 0% for the heterogeneity test  was significantly lower than that of U. parvum (17.74%), with a pooled OR value of 1.53 (95% CI: 0.96–2.43), Z = 1.79 and P = 0.074 for the overall effect, and P = 0.001 and 2I = 73.1% for the heterogeneity test  while the prevalence of U. parvum was not . The small sample size from this single study precludes meaningful comparison of the prevalence of these two species between China and the world. There were two other case-controlled studies U. urealyticum was not differentiated from U. parvumUreaplasma spp. in a total of 128 NGU patients and 234 controls. Therefore, we combined these three studiesUreaplasma spp. in China and compared to the global data. One case-control study from England Ureaplasma spp. between the NGU and control groups in China , suggesting no publication bias existed. However, we found potential publication bias in the comparison of the U. urealyticum infection rate between the NGU and control group (Begg’s test P = 0.016). No potential publication bias was detected in the other meta-analysis. The Begg’s test showed P values of 0.540, 0,881 and 0.368, respectively, for comparison of the Ureaplasma spp. prevalence between the NGU and control groups, the U. parvum prevalence between the NGU and control groups, and the prevalence of U. urealyticum and U. parvum within the control group.For each meta-analysis, publication bias was assessed by the funnel plot and Begg’s test. Ureaplasma spp. in NGU. While there are numerous epidemiologic data collected from various study populations examined for either undifferentiated Ureaplasma spp. or differentiated U. parvum and U. urealyticum, it remains inconclusive whether undifferentiated or differentiated species play a pathogenic role in NGU. To summarize the results of and to overcome small sample sizes of existing individual studies, we performed this meta-analysis. To the best of our knowledge, this is the first meta-analysis to assess the association of U. urealyticum and U. parvum with NGU.There has been a great deal of disagreement about the role of Ureaplasma spp. infection between the NGU and control groups  Significant association of U. urealyticum organism loads with the development of NGU U. urealyticumU. urealyticum organisms U. urealyticum organisms U. urealyticum has a pathogenic role in NGU.Our findings of the association of U. parvum with NGU are consistent with most of the previous epidemiologic studies of differentiated ureaplasmas species in NGU patients, including all the 7 studies selected for the meta-analysis U. parvum in NGU patients was very similar or even significantly lower compared to controls. These data support the notion that U. parvum is a non-pathogenic commensal organism in the male urethra U. parvum in controls may explain why undifferentiated Ureaplasma spp. are not associated with NGU in some of the early studies U. parvum with various diseases including adverse pregnancy outcomes U. parvum are association with NGU or other diseases as has been suggested from a recent study by De Francesco et al. U. parvum 3/14 and T960 biovar were significantly associated with genital infections.Our findings of no association of Ureaplasma spp. and their association with NGU. In this report, we searched the literature and found only three case-controlled studies Ureaplasma spp. between the NGU and control groups Click here for additional data file.


NAD(P)H: quinone oxidoreductase 1 (NQO1) plays a central role in catalyzing the two-electron reduction of quinoid compounds into hydroquinones. The NQO1 Pro187Ser polymorphism was found to correlate with a lower enzymatic activity, which may result in increased incidence of carcinomas including breast cancer. Previous studies investigating the association between NQO1 Pro187Ser polymorphism and breast cancer risk showed inconsistent results. We performed a meta-analysis to summarize the possible association.All studies published from January 1966 to February 2014 on the association between NQO1 Pro187Ser polymorphism and breast cancer risk were identified by searching electronic databases PubMed, EMBASE, Cochrane library, and Chinese Biomedical Literature database (CBM). The association between NQO1 Pro187Ser polymorphism and breast cancer risk was assessed by odds ratios (ORs) together with their 95% confidence intervals (CIs).Ten studies with 2,773 cases and 4,076 controls were finally included in the meta-analysis. We did not observe a significant association between NQO1 Pro187Ser polymorphism and breast cancer risk when all studies were pooled into the meta-analysis. In subgroup analysis by ethnicity, significant increased breast cancer risk was found in Caucasians . When stratified by source of control, significant increased breast cancer risk was found in population-based studies . However, in subgroup analyses according to menopausal status, quality score, and HWE in controls, no any significant association was detected.Our meta-analysis provides the evidence that the NQO1 Pro187Ser polymorphism contributed to the breast cancer susceptibility among Caucasians. Further large and well-designed studies are needed to confirm this association.http://www.diagnosticpathology.diagnomx.eu/vs/1248639991252504The virtual slide(s) for this article can be found here:  Breast cancer is the most common cancer and the second most common cause of cancer-related death in women. In 2008 there were 182,460 women diagnosed with breast cancer, and 40,480 women died of this disease ,4.http://www.ncbi.nlm.nih.gov/SNP), including the most commonly occurring C-to-T transition at nucleotide position 609 in exon 6 , which results in a proline-to-serine amino-acid substitution at codon 187 (Pro187Ser) in the protein. It was reported that the variant T allele was associated with reduced NQO1 enzymatic activity in both human cell lines and primary human tissues [NAD(P)H:quinone oxidoreductase 1 (NQO1), also known as diphtheria toxin diaphorase (DT-diaphorase), is a cytosolic flavoenzyme which is present in human epithelial and endothelial tissues. NQO1 is considered as an anticancer enzyme because it protect cells from oxidative damage by preventing quinones from entering the one-electron reduction which is catalyzed by cytochrom b5 reductase or P450 reductase to generate semiquinone free radicals and reactive oxygen species ,7. The N tissues . Further tissues -13. GiveIn the past two decades, a number of molecular epidemiological studies have evaluated the association between the NQO1 Pro187Ser polymorphism and breast cancer risk, but the results remain inconsistent. Several studies have previously suggested that the NQO1 Pro187Ser polymorphism was associated with an increased risk of breast cancer ,15. HoweWe conducted a comprehensive literature search in PubMed, EMBASE, Cochrane library, and Chinese Biomedical Literature (CBM) databases form January 1966 to February 2014 using the following search strategy: (“breast cancer”) and (“NAD(P)H:quinone oxidoreductase 1”, or “NQO1”). There was no restriction on sample size, population, language, or type of report. All eligible studies were retrieved and their references were checked for other relevant studies. The literature retrieval was performed in duplication by two independent reviewers (Qiliu Peng and Yu Lu). When multiple publications reported on the same or overlapping data, we chose the most recent or largest population. When a study reported the results on different subpopulations, we treated it as separate studies in the meta-analysis.Studies included in the meta-analysis were required to meet the following criteria: (1) case–control or cohort studies which evaluated the association between NQO1 Pro187Ser polymorphism and breast cancer risk; (2) used an unrelated case–control design; (3) had an odds ratio (OR) with 95% confidence interval (CI) or other available data for estimating OR (95% CI); and (4) the control population did not contain malignant tumor patients. Studies were excluded if one of the following existed: (1) no control population; (2) duplicate of previous publication; and (3) insufficient information for data extraction.Two authors (Qiliu Peng and Xue Qin) independently reviewed and extracted data from all eligible studies. Data extracted from eligible studies included the first author, year of publication, ethnicity, country of origin, genotyping method, source of control, matching criteria, breast cancer ascertainment, total numbers of cases and controls and genotype frequencies of cases and controls. Ethnic backgrounds were categorized as Caucasian, Asian, and Arab. When a study did not state the ethnic descendent or if it was impossible to separate participants according to such phenotype, the group reported was termed as “mixed ethnicity”. To ensure the accuracy of the information extracted, the two authors checked the data extraction results and reached consensus on all of the items. If different results generated, they would check the data again and have a discussion to come to an agreement. If these two authors could not reach a consensus, another author (Shan Li) was consulted to resolve the dispute and a final decision was made by the majority of the votes. Menopausal status was divided into premenopausal and postmenopausal and was additionally recorded for stratified analysis.The quality of eligible studies was evaluated independently by two authors (Qiliu Peng and Yu Lu) according to a set of predefined criteria Table  based onThe strength of the association between NQO1 Pro187Ser polymorphism and breast cancer risk was assessed by odds ratios (ORs) with 95% confidence intervals (CIs). The significance of the pooled OR was determined by a Z test and the p value less than 0.05 was considered significant. The association of NQO1 Pro187Ser polymorphism with breast cancer risk was assessed using co-dominant model (Ser/Ser vs. Pro/Pro and Ser/Pro vs. Pro/Pro), recessive model (Ser/Ser vs. Ser/Pro + Pro/Pro), and dominant model (Ser/Ser + Ser/Pro vs. Pro/Pro).2 based Q test was used to assess the heterogeneity among studies [Q test was PQ < 0.1, indicating the presence of heterogeneity, a random-effects model (the DerSimonian and Laird method) was used to estimate the summary ORs [Q test was PQ ≥ 0.1, indicating the absence of heterogeneity, the fixed-effects model (the Mantel–Haenszel method) was used [The χ studies ,22. If tmary ORs ; otherwi2 test. All analyses were performed using Stata software, version 12.0 .Sensitivity analysis was performed by sequential removal of individual studies. Publication bias was evaluated using a funnel plot and Egger’s regression asymmetry test. The distribution of the genotypes in the control population was tested for HWE using a goodness-of-fit χBase on our search criterion, 112 individual records were found, but only 11 full-text publications were preliminarily identified for further detailed evaluation. According to the exclusion criteria, 2 publications were excluded including 1 provide insufficient information for data extraction , and 1 wP = 0.266; Ser/Pro vs. Pro/Pro: OR = 1.015, 95% CI 0.860–1.198, P = 0.860; Ser/Ser + Ser/Pro vs. Pro/Pro: OR = 1.058, 95% CI 0.899–1.245, P = 0.498; Ser/Ser vs. Ser/Pro + Pro/Pro: OR = 1.317, 95% CI 0.919–1.887, P = 0.133). In subgroup analysis by ethnicity, statistical significant increased breast cancer risk was found in Caucasians .Begg’s funnel plot and Egger’s test were performed to assess the publication bias of literatures in all comparison models. The shape of the funnel plot did not reveal any evidence of obvious asymmetry. Then, the Egger’s test was used to provide statistical evidence of funnel plot symmetry. The results still did not suggest any evidence of publication bias . Subsequently, we performed Galbraith plots analysis to further explore the source of heterogeneity. Galbraith plots analysis showed that the study Menzel et al. [PQ values were greater than 0.10 in all genetic comparison models in overall populations, Caucasians, population-based studies, and studies consistent with HWE. However, the summary ORs in the overall populations, Caucasians, population-based studies, and studies consistent with HWE were not material changed by omitting this study, indicating that our results were robust and reliable. The results indicated that the study Menzel et al. [Heterogeneity is a potential problem when interpreting the results of a meta-analysis, and finding the sources of heterogeneity is one of the most important goals of meta-analysis ,41. In tl et al.  was the l et al. , the hetl et al.  was the However, there are still some limitations in this meta-analysis. First, in subgroup analysis by ethnicity, the included studies regarded only Caucasians, Asians, and Arabs for NQO1 Pro187Ser polymorphism. Data concerning other ethnicities such as Africans were not found. Thus, additional studies are warranted to evaluate the effect of this functional polymorphism on breast cancer risk in different ethnicities, especially in Africans. Second, our results were based on unadjusted estimates. We did not perform analysis adjusted for other covariates such as age, obesity, drinking and smoking status, use of contraceptives, environment factors, and so on, because of the unavailable original data of the eligible studies. Third, subgroup analyses were based on studies with relevant information available. Owing to the lack of detailed information in most studies, the subgroup analysis for menopausal status consisted of only two studies for each subgroup, which might not be sufficient to reach a reliable conclusion.This meta-analysis provided a more precise estimation based on larger sample size compared with the individual studies and previous meta-analysis. Our study suggested that NQO1 Pro187Ser polymorphism might contribute to breast cancer risk, especially in Caucasian populations. However, it is necessary to conduct large sample studies using standardized unbiased genotyping methods, homogeneous breast cancer patients, and well-matched controls to further validate the results of our meta-analysis. Moreover, gene-gene and gene-environment interactions should also be considered in the analysis. Such studies taking these factors into account may eventually lead to a better, more comprehensive understanding of the association between NQO1 Pro187Ser polymorphism and breast cancer risk.HWE: Hardy–Weinberg equilibrium; NQO1: NAD(P)H: quinone oxidoreductase 1; SNP: Single nucleotide polymorphism; OR: Odds ratio; CI: Confidence interval.The authors declare that they have no competing interests.QP performed the literature search, data extraction, statistical analysis and drafted the manuscript. YL, XL, ZP, RL, JS, and XQ participated in data extraction. SL supervised the literature search, data extraction, statistical analysis and drafted the manuscript. All authors read and approved the final manuscript.


Previous studies regarding the association between cruciferous vegetable intake and pancreatic cancer risk have reported inconsistent results. We conducted a meta-analysis to demonstrate the potential association between them.A systematic literature search of papers was conducted in March 2014 using PubMed, EMBASE, and Web of Science, and the references of the retrieved articles were screened. The summary odds ratios (ORs) with 95% confidence interval (CI) for the highest versus the lowest intake of cruciferous vegetables were calculated.P = 0.065). There was no evidence of significant publication bias based on Begg’s funnel plot (P = 0.917) or Egger’s test (P = 0.669).Four cohort and five case–control studies were eligible for inclusion. We found a significantly decreased risk of pancreatic cancer associated with the high intake of cruciferous vegetables . Moderate heterogeneity was detected across studies (Cruciferous vegetable intake might be inversely associated with pancreatic cancer risk. Because of the limited number of studies included in this meta-analysis, further well-designed prospective studies are warranted to confirm the inverse association between cruciferous vegetable intake and risk of pancreatic cancer. Pancreatic cancer ranks as the fourth leading cause of death in the USA, with an expected 17,870 deaths in 2013 ,5. At prFruits and vegetables contain numerous substances with potential anticarcinogenic activity and could therefore play a role in the prevention of pancreatic cancer . Among sThe purpose of the present study was to summarize the evidence on the association between cruciferous vegetable intake and the risk of pancreatic cancer by conducting a meta-analysis on all relevant published epidemiological studies. To the best of our knowledge, this is the first meta-analysis regarding the relationship between cruciferous vegetable intake and pancreatic cancer risk.We conducted a literature search of published papers in March 2014 using PubMed, EMBASE, and Web of Science. We used the following search algorithm: (vegetables OR cruciferous OR brassica OR broccoli OR cauliflower OR cabbage) AND (pancreas OR pancreatic) AND (neoplasm OR cancer). All potentially relevant publications were evaluated by examining their titles and abstracts, and all of the studies matching the eligible criteria were retrieved. We also performed hand searches via cited references from retrieved articles and previous reviews on cruciferous vegetables and cancer. To be included in this meta-analysis, the studies had to meet all of the following criteria: (a) The exposure of interest was the intake of cruciferous vegetables, (b) the outcome of interest was pancreatic cancer, (c) the study had a case–control or cohort study design, and (d) the risk estimates with their corresponding 95% confidence intervals (CIs) were reported . For publications with same population resources or overlapping datasets, the study with the largest number of cases was included in the meta-analysis. This systematic review was planned, conducted, and reported in adherence to the standards of quality for reporting meta-analyses .http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp). NOS is an eight-item instrument that allows for the assessment of the patient population and selection, study comparability, follow-up, and the outcome of interest. Interpretation of the scale is performed by awarding points, or ‘stars’, for high-quality elements. The stars are then added up and used to compare study quality in a quantitative manner. The maximum score could be 9 points, representing the highest methodological quality. We assigned scores of <7 and ≥7 for low- and high-quality studies, respectively. Any disagreements were resolved by a joint re-evaluation of the original article with a third reviewer.We assessed the quality of all included studies by the Newcastle-Ottawa Scale (NOS)  was assumed to be approximately equivalent to the odds ratio (OR), and the OR was used as the study outcome. Data were extracted independently by two investigators using a predefined data collection form, and discrepancies were resolved by consensus, with involvement of a third reviewer when necessary.Q statistical test and I2 score [P ≤ 0.10. The Galbraith plot was also used to detect the possible sources of heterogeneity [P < 0.05. All statistical analyses were done with Stata statistical software, version 11.0.Study-specific ORs and their 95% CIs for highest versus lowest intake of cruciferous vegetable level were extracted from each article. We pooled data using the fixed or random effects models depending on heterogeneity between studies in our meta-analysis. Between-study heterogeneity across the eligible comparisons was quantitatively assessed using the I2 score . Heterogogeneity , and a rogeneity  and Beggogeneity . We alsoogeneity . Statistn = 4), Europe (n = 4), and China (n = 1). All of the included studies were published between 1989 and 2012 and involved a total of 3,207 cases. Information on cruciferous vegetable intake was obtained by interview or a self-administered questionnaire. The study quality scores, assessed by the NOS, ranged from 4 to 8 (with a mean of 6.3). Table The process of identifying and selecting studies is shown in Figure hina n = . All of The multivariable-adjusted ORs of the highest versus lowest categories of cruciferous vegetable intake, for each study and for the combination of all of the studies, are shown in Figure Next, we performed subgroup analyses by study design, study quality, and geographical region Table . In the Q test and the I2 index to evaluate the heterogeneity across studies. As shown in Figure P = 0.065 for heterogeneity, I2 = 46.0%). Through the Galbraith plot , but the overall association was not significantly changed .In this meta-analysis, we used the t Figure , we founIn the sensitivity analysis, the influence of each study on the pooled OR was examined by repeating the meta-analysis while omitting each study, one at a time. The study-specific ORs ranged from a low of 0.73 (95% CI 0.63–0.82) to a high of 0.82 (95% CI 0.72–0.93) via the omission of the study by Heinen et al.  and the Cumulative meta-analysis was also conducted by sorting the studies based on publication time. Figure P = 0.917) or with Egger’s test (P = 0.669). The trim-and-fill analysis identified one possible missing study that would not have altered our results .There was no evidence of significant publication bias with Begg’s funnel plot  were examined in our meta-analysis. There was a wide range of values for the cutoff points for the lowest and highest categories of cruciferous vegetable intake in the included studies, which have contributed to the heterogeneity among studies in the analysis.Cruciferous vegetable intake might be inversely associated with the incidence of pancreatic cancer. Because of the limited number of studies, further experimental and well-designed prospective epidemiologic studies are needed to affirm the findings from our study.


It has been shown that gene polymorphisms may play an important role in the carcinogenesis of esophageal cancer. This study is to investigate the role of alcohol dehydrogenase 1B (ADH1B) gene Arg47His polymorphism in esophageal cancer susceptibility.Case-control studies published between January 2000 and June 2015 were searched to retrieve relevant articles. The pooled odds ratio (OR) and 95 % confidence interval (CI) were employed to calculate the strength of association.P < 0.00001). This protective relationship was observed under other genetic models as well (P < 0.00001). Subgroup analysis by ethnicity showed that ADH1B Arg47His variant was associated with the decreased esophageal cancer risk under all the genetic models (P < 0.00001) among Asians, especially in Chinese and Japanese; while in non-Asians, no significant correlation was detected in any genetic models (P > 0.05). Furthermore, Arg/Arg genotype of ADH1B Arg47His variant combined with drinking, smoking and males appeared to show a high risk in patients with esophageal cancer.A total of 23 relevant articles were finally selected for the analysis, including 9338 esophageal cancer patients and 14,896 matched controls. Overall, we found that the 47His allele was significant associated with the decreased risk of esophageal cancer when compared with the 47Arg allele in total populations (A vs. G: OR = 0.67, 95 % CI = 0.59–0.76, Our results suggested that ADH1B gene Arg47His variant was associated with the decreased esophageal cancer risk. Genetic-environmental interaction should be further considered in the future researches. Esophageal cancer , a type of cancer arising from the esophagus, is the eighth most common cancer and the sixth leading cause of cancer-related death worldwide . SquamouEvidences have shown that gene polymorphisms may play an important role in the carcinogenesis of esophageal cancer . AlcoholSeveral studies have identified the relationship between ADH1B polymorphism and esophageal cancer susceptibility, but the consistent results were not obtained. For example, Ito et al. demonstrated that ADH1B Arg47His variant was associated with esophageal cancer in Japanese and might be used in personalized prevention programs , while MElectronic databases of PubMed, Web of Science, Medline, Embase, CNKI , and Wanfang were comprehensively searched to retrieve relevant articles published between January 2000 and June 2015. The MeSH terms were as follows: “esophageal cancer or oesophageal cancer or esophageal squamous cell carcinomas or esophageal adenocarcinomas,” “alcohol dehydrogenase or ADH1B or ADH2,” and “polymorphism or variant or mutation” as well as their combinations. The equivalent Chinese characters were used in Chinese database. We also manually searched the references of included studies in order to obtain more related articles. Our analysis only considered studies that were written in English and Chinese.The eligible articles must meet the following criteria. The inclusion criteria were as follows: (1) case-control studies evaluating the correlation of ADH1B Arg47His polymorphism in esophageal cancer occurrence; (2) patents with esophageal cancer should be diagnosed clinically and confirmed histologically, the controls should be age-, ethnicity-matched participants without malignancy and digestive and chronic diseases; (3) the genotype information were available to extract; and (4) the genotypes of controls were consistent with Hardy-Weinberg equilibrium (HWE). The exclusion criteria were as follows: (1) duplicate articles from the same authors or laboratories or conducted among the same populations; (2) conference reports or reviews; (3) without control group; and (4) data could not be extracted.Two of our authors independently assessed the quality of selected studies. Each item of a single study should be achieved a final consensus. The extracted information was as follow: the name of first author, published year, country, ethnicity, mean age, sample size, genotype method, alleles and genotypes distribution, source of cases and controls, and HWE of genotypes in controls.Z test was used to determine the significance of ORs, and P value was less than 0.05 considered as statistically significance. The allelic model (His vs. Arg), the homologous model (His/His vs. Arg/Arg), the heterogeneous model (Arg/His vs. Arg/Arg), the dominant model (His/His+Arg/His vs. Arg/Arg) and the recessive model (His/His vs. Arg/His+Arg/Arg) were examined. The Q test and the I2 test were used to assess the degree and proportion of between-study heterogeneity, respectively. The fixed-effect model was used when the P value of the Q test was more than 0.10 and the I2 of the I2 test was less than 50 %; otherwise, the random-effect model was used. All statistical analyses were conducted in Review Manager 5.2 . All the tests were two-sided.The pooled odds ratio (OR) with its 95 % confidence interval (CI) were employed to estimate the association between ADH1B Arg47His variant and esophageal carcinoma susceptibility. The We firstly identified 105 articles. After the inclusion and exclusion criteria filtering, a total of 23 relevant articles were finally screened out, including 9338 esophageal cancer patients and 14,896 matched controls. Figure P < 0.01 and I2 > 50 %), and the random-effect model was used. Table P < 0.00001) as shown in Fig. P < 0.00001). Subgroup analysis by ethnicity showed that this polymorphism revealed an ethnic difference and geographic variance. In Asians, ADH1B 47His variant was shown to be associated with the decreased esophageal cancer risk under all the genetic models (P < 0.00001); while in non-Asians, no significant correlation was detected in any genetic models (P > 0.05). Figure A significant heterogeneity among all the included studies was observed (P < 0.00001) and lower in the non-drinking group  as shown in Fig. Fifteen studies estimated the combined effect of ADH1B Arg47His polymorphism and alcohol drinking on esophageal cancer risk. However, the relevant data could be extracted only from 12 studies, including 3545 patients and 6909 controls. Based on these data, we could only assess the combined effect on esophageal cancer susceptibility under the Arg/Arg versus His/His+Arg/His model. We divided the subjects into two groups: non-drinking group (1134 cases and 3526 controls) and drinking group (2411 cases and 3383 controls). Our results found that Arg/Arg genotype compared with the His carrier of His/His and Arg/His genotypes was significantly associated with the increased higher risk of esophageal cancer in the drinking group  and smokers  in the random-effect model as shown in Fig. Four articles considered the combined effect of ADH1B Arg47His polymorphism and tobacco smoking on esophageal cancer susceptibility, containing 2382 patients and 4792 controls. Our result demonstrated that the Arg/Arg genotype was associated with esophageal cancer occurrence in both non-smokers , while not in female patients  as shown in Fig. Six articles were selected for gender variance . Our result showed that the Arg/Arg genotype of ADH1B Arg47His variant increased the esophageal cancer risk in male patients  may modify the effects of alcohol on metabolic and clinical phenotypes . Blood ePrevious studies have found that ADH1B Arg47His polymorphism was associated with the pathogenesis of cancers such as colorectal cancer  and headSeveral limitations were presented in this meta-analysis. Firstly, most of the included studies were conducted in the Asian population, while other ethnicities should be considered in the future. Secondly, the stages of patients with esophageal cancer could not be extracted from the included studies, which might limit the application of our results. Thirdly, the combined effect of ADH1B Arg47His variant and age group also should be focused on. Lastly, other polymorphisms in ADH1B gene or other ADH genes which might alter the metabolism of alcohol should be included.In conclusion, our results suggested that ADH1B Arg47His polymorphism might be a protective factor on esophageal cancer susceptibility in Asians. The Arg/Arg genotypes combined with alcohol drinking, tobacco smoking, and males might be strongly increased the risk of esophageal cancer. However, further studies with more ethnicities should be taken into account in future researches.AC, adenocarcinomas; ADH, alcohol dehydrogenase gene; ADH1B, alcohol dehydrogenase 1B; ALD, aldehyde dehydrogenases; CI, confidence interval; OR, odds ratio; SCC, squamous cell carcinomas; SNPs, single nucleotide polymorphisms


There is a lack of systematic and comprehensive evaluations whether food intakes lower or increase risk of chronic diseases. In this network meta-analysis of prospective cohort studies, we aim to evaluate the effects of different foods on risk of chronic diseases.We will search PubMed and EMBASE. This will be supplemented by a hand search and author contacts. Citations, abstracts, and relevant papers will be screened for eligibility by two reviewers independently. Prospective cohort studies will be included if they meet the following criteria: (1) evaluate the association of single food or food groups with all-cause mortality, cardiovascular diseases , cancer  or risk of type 2 diabetes. The following food groups will be evaluated: whole grains, refined grains, vegetables, fruits, nuts, legumes, eggs, dairy products, fish, red meat, processed meat and sugar-sweetened beverages; (2) include participants ≥18 years of age; and (3) study population were free of outcome(s) of interest at the onset of the study. To assess study quality, we will extract the following characteristics: study size, duration of follow-up, dietary assessment method, assessment of outcome and adjustment factors. If the identified studies appear sufficiently similar within and across the different comparisons between pairs of food groups, we will estimate summary-relative effects using random effects network meta-analysis. Subgroup and meta-regression analyses will be performed stratified by different follow-up cut-points, geographical region and sex.This is a presentation of the study protocol only. Results and conclusions are pending completion of this study. Our systematic review will be of great value to national and international authorities for evidence-based nutritional recommendation/guidelines, regarding the implementation of food-based dietary guidelines for prevention of chronic diseases. Moreover, our results can be implemented to develop new diet quality indices/scores.CRD42016037069PROSPERO The online version of this article (doi:10.1186/s13643-016-0302-9) contains supplementary material, which is available to authorized users. Globally in 2013, the total number of deaths across all age groups rose to approximately 55 million. Seventy percent of these deaths were caused by non-communicable diseases, with cardiovascular or circulatory diseases being responsible for 32 % of the fatalities  followed by cancer mortality with 15 % food*[tiab] OR whole grain*[tiab] OR refined grain*[tiab] OR cereal*[tiab] OR pasta*[tiab] OR rice*[tiab] OR potato*[tiab] OR vegetable*[tiab] OR fruit*[tiab] OR nut*[tiab] OR legume*[tiab] OR bean*[tiab] OR egg*[tiab] OR dairy[tiab] OR dairies[tiab] OR milk[tiab] OR yogurt[tiab] OR cheese[tiab] OR fish[tiab] OR seafood[tiab] OR meat[tiab] OR processed meat[tiab] OR sugar sweetened beverage*[tiab]mortality OR incidence OR cardiovascular OR coronary OR stroke OR cancer OR neoplasm OR neoplastic disease OR diabetes OR vascular OR myocardial infarctionprospective OR follow-up OR cohort OR longitudinal(#1 OR #2) AND #3 AND #4The search strategy was developed by LS, SS and HB, and will be performed by LS, AB, MSM and KI, and differences resolved by discussion with a third reviewer (HB). We will conduct searches in PubMed (from 1966) and EMBASE (from 1980). We will search for articles of original research by using the following search terms:Moreover, the reference lists from the retrieved articles; systematic reviews and meta-analyses will be checked to search for further relevant studies . There will be no restrictions on language or publication year. Studies published in languages other than English will be translated by international scientists in our institute.Two reviewers will independently screen titles and abstracts of all the retrieved bibliographic records. Full texts of all potentially eligible records passing the title and abstract screening level will be retrieved and examined independently by two reviewers (for each database) with the abovementioned eligibility criteria/exclusion criteria , 20. DisAfter determination of the study selection, two reviewers will extract independently the following characteristics: the first author’s last name, year of publication, study origin, cohort name, sample size, number of cases, age at entry, sex, study length (follow-up in years), outcome, outcome assessment, assessment of diet, quantity of diet, risk estimate (most adjusted measures) (hazard ratios (HR), risk ratios (RR) or odds ratios (OR) with their corresponding 95 % confidence intervals (CIs)) and adjustment factors using our own checklist (piloting of the tool based on three studies will be performed).When a study provides several risk estimates, the multivariate adjusted model will be chosen. If only separate risk estimates for male and female participants will be available in one study, data will be pooled and treated as one study.To assess the risk of bias of the cohort studies, we will assess ascertainment of exposure , assessment of outcome , adequacy of follow-up depending on the outcome , and adjusted basic model and outcome relevant adjustments , based on our own developed tool . StudiesWe will try to obtain relevant missing data from authors of the included cohort studies (by e-mail). If we will not be able to obtain the missing data we will exclude the cohort from the network meta-analysis (NMA). We do not expect high missing data rate, since this phenomenon is not common in meta-analysis of observational studies , 18, 22.We will generate descriptive statistics for study and population characteristics describing the available data and some important variables  for each pairwise comparison. We will present the available direct comparisons between different food groups and control using a network diagram for each outcome . The sizHigh vs. low intake meta-analyses: summary risk will be estimated for high versus low intake of single food or food groups and risk of chronic diseases by applying random effect models.Dose-response meta-analyses: we will investigate the association between intake of dietary factors as a continuous variable and risk of chronic diseases, by performing a dose-response meta-analysis as described by Orsini et al. and Greenland and Longnecker , 26. ThiNon-linear dose-response relation: in addition, we will explore whether there is indication for a non-linear dose-response relation between dietary factors and chronic diseases. We will perform cubic spline regression models and evaluate non-linearity by using a likelihood ratio test .We will perform three types of analysis:To explore heterogeneity between studies, we will use the Q test and the ogeneity ). In addWe will assess the similarity and comparability of each dietary factor as well as for the control/reference groups when they appear in different studies. For example, we will assess whether discrepancies in amount of intake or definition of exposure of the same foods across studies are likely to render some nodes in the network intransitive.We will assess whether the potential effect modifiers  as we do not expect arm-level data to be available. We will account for the correlation in studies with multiple dietary groups when the required data are available to obtain the covariance of the effect sizes from such studies. If we will not be able to obtain these covariances, we will treat the effect sizes from these studies as independent and we will assume different correlation values in a sensitivity analysis. We will present summary HRs, RRs or ORs in a league table. We will also estimate the relative ranking of the different food groups for each outcome using the distribution of the ranking probabilities and the surface under the cumulative ranking curves (SUCRA) . For eacTo evaluate the presence of statistical inconsistency (i.e. disagreement between the different sources of evidence) in the data we will employ both local and global approaches . Specifitatistic , 37.In the presence of important heterogeneity and/or inconsistency, we will explore the possible sources. If sufficient data will be available, we will run network meta-regression analyses to account for differences by duration of follow-up of the studies, sex, dietary assessment method, level of physical activity, body mass index, smoking status and outcome relevant baseline risk factors .We will use the comparison-adjusted funnel plot  to assesWe will assess the sensitivity of results for the primary outcome by analysing only studies considered being at low risk of bias.network package [network graphs package [We will fit all analyses described in a frequentist framework using Stata  (network package ), and we package .We will first use our recently developed NutriGrade-tool to evaluate and judge the meta-evidence for pairwise comparisons, which has been especially developed for nutrition research to address specific requirements for this research field . Then, tThis systematic review and network meta-analysis will be the first to summarize and compare the effects of different foods or food groups on all-cause mortality, cardiovascular disease, type 2 diabetes and cancer, using both direct and indirect evidence. This analysis will show which foods or food groups, if any, might be the most promising in the prevention of chronic diseases. Our systematic review will be of great value to national and international authorities for evidence-based nutritional recommendation/guidelines, regarding the prevention of chronic diseases. Moreover, our results can be implemented to develop new diet quality indices/scores.


Diabetes mellitus is the most common chronic endocrine disorder, affecting an estimated population of 382 million people worldwide. It is associated with microvascular and macrovascular complications, including diabetic nephropathy (DN); primary cause of end-stage renal disease. Different inflammatory and angiogenic molecules in various pathways are important modulators in the pathogenesis and progression of diabetic nephropathy. Differential disease risk in DN may be partly attributable to genetic susceptibility. In this meta-analysis, we aimed to determine which of the previously investigated genetic variants in these pathways are significantly associated with the development of DN and to examine the functional role of these genes.A systematic search was conducted to collect and analyze all studies published till June 2013; that investigated the association between genetic variants involved in inflammatory cytokines and angiogenesis and diabetic nephropathy. Genetic variants associated with DN were selected and analyzed by using Comprehensive Meta Analysis software. Pathway analysis of the genes with variants showing significant positive association with DN was performed using Genomatix Genome Analyzer .VEGFA, CCR5, CCL2, IL-1, MMP9, EPO, IL-8, ADIPOQ and IL-10. rs1800871 (T) genetic variant in IL-10 showed protective effect for DN. Most of these eleven genetic variants were involved in GPCR signaling and receptor binding pathways whereas four were involved in chronic kidney failure. rs833061 [OR 2.08 (95% CI 1.63-2.66)] in the VEGFA gene and rs3917887 [OR 2.04 (95% CI 1.64-2.54)] in the CCL2 gene showed the most significant association with the risk of diabetic nephropathy.After the inclusion and exclusion criteria for this analysis, 34 studies were included in this meta-analysis. 11 genetic variants showed significant positive association with DN in a random-effects meta-analysis. These included genetic variants within or near VEGFA, CCR5, CCL2, IL-1, MMP9, EPO, IL-8, ADIPOQ and IL-10 showed significant positive association with diabetic nephropathy. Gene Ontology or pathway analysis showed that these genes may contribute to the pathophysiology of DN. The functional relevance of the variants and their pathways can lead to increased biological insights and development of new therapeutic targets.Our results indicate that 11 genetic variants within or near The online version of this article (doi:10.1186/s12881-014-0103-8) contains supplementary material, which is available to authorized users. Diabetes mellitus (DM) is a set of metabolic disorders characterized by hyperglycemia resulting from defects in insulin secretion and/or action. The prevalence of the disease, which is becoming a major world-wide health problem, is increasing rapidly . In 2013Mostly, individuals with long durations of diabetes and poor glycemic control develop progressive diabetic nephropathy. However, some patients appear to be at increased risk while others remain relatively protected . GeneticVEGF) and transforming growth factor β (TGF β) in plasma and urine of diabetic nephropathy patients, emphasize the role of angiogenesis [VEGF signaling pathway. Further, a recent study showed anti-angiogenic and anti-inflammatory DNA vaccination ameliorates the progression of glomerular pathology in an animal model of diabetic nephropathy [In recent years, there has been an increased understanding of the genetic and molecular basis of development and progression of diabetic nephropathy. Although diabetic nephropathy is traditionally considered a nonimmune disease, recent findings indicate a significant role of immune-mediated inflammatory processes in the pathophysiology of diabetic nephropathy. These include the up-regulation of inflammatory mediators, higher urinary levels of monocyte chemoattractant protein-1 and increasing macrophage influx with the progression of diabetic nephropathy –8. In stogenesis ,11. Chenogenesis  reportedhropathy . As inflThe articles relevant to this study were searched from PubMed, Embase and Cochrane Library in June, 2013. Different possible variations and combinations of the following search terms were used: ‘diabetes mellitus’, ‘diabetic nephropathy’, ‘ESRD’, ‘inflammatory cytokines’, ‘angiogenesis’, ‘genetic variants’, ‘polymorphism’, ‘SNPs’ and ‘gene’. Additional search query was used by combining the names of the specific genes and genetic variants with the term ‘diabetic nephropathy’. The reference list of each relevant publication was also examined to identify additional studies appropriate for inclusion in the meta-analysis. In the initial search no filter for language preference was used.Only those studies were included in which the cases had diabetes mellitus with macroalbuminuria, overt proteinuria, ESRD due to diabetic nephropathy or diabetic nephropathy identified by biopsy and controls had diabetic mellitus with normoalbuminaria after > 10 years of diabetes duration. Cases with macroalbuminaria and/or overt proteinuria and/or ESRD were merged together for comparison with controls. The selected studies should provide detailed genotypic data of the genes in the inflammatory and angiogenic pathways. Only articles in English language were included. The cases and controls in the studies included were matched by duration of diabetes and/or age. Lack of information related to the distribution of genotypes or alleles within the case and control groups is one of our exclusion criteria. Studies in which the controls were non-diabetic and/or there was comparison of different stages of diabetic nephropathy were excluded. Review and meta-analysis articles were excluded.Following information was extracted from each selected study like PMID No, first author’s surname, journal & year of publication, sample size, ethnicity, methodology, type and duration of diabetes, criteria for diabetic nephropathy and frequency of alleles.http://ihg.gsf.de/cgi-bin/hw/hwa1.pl) for all the studies. The percentage of variation across studies due to heterogeneity rather than chance was estimated via Higgins I2 statistics using Comprehensive Meta Analysis Version 2.0 software . I2 is estimated by the ratio (Q-df)/Q, where Q is the Cochran’s Q statistic and df is degrees of freedom. I2 lies between 0 and 100% with values over 50% indicating high heterogeneity [For each SNP, the allelic data from different studies was pooled and minor allele frequencies were calculated and compared between cases and controls. Data were entered into a database and a statistical analysis was performed using SPSS . The pooled odds ratio was used to estimate the association between the genetic variants and diabetic nephropathy in this meta-analysis. The Odds Ratio (OR), at allele level and statistically significant P-values were validated for all the studies and recalculated for some of them, in order to remove any adjustments made within each study in cases where two different groups merged together, such as in the case of macroalbuminaria and ESRD groups. A p-value <0.05 was considered to be statistically significant. Deviation from Hardy–Weinberg equilibrium (HWE) was tested using the De Finetti program , CCL2 (Chemokine ligand 2), IL-1 (Interleukin-1), MMP9 , EPO (Erythropoietin), IL-8 (Interleukin-8), ADIPOQ  and IL-10 (Interleukin-1). The odds ratios of the significant associations with diabetic nephropathy were between the range of 1.24 to 2.08 for increased risk effect. After meta-analysis, 2 genetic variants- rs833061 in the VEGFA gene and rs3917887 in the CCL2 gene showed the most significant association with risk of diabetic nephropathy. Genetic variant rs833061 was analyzed in 2 Irish studies resulting in a pooled odds ratio of 2.08 (95% CI 1.63-2.66). For rs3917887, the pooled OR was 2.04 (95% CI 1.64-2.54) obtained from 2 Indian studies. rs833061 showed significant association in type 2 diabetes mellitus whereas rs3917887 was studied in type 1 diabetes mellitus. Genetic variant rs1799987 in CCR5 was the most studied SNP with ten studies of which six were of caucasian and four Asian. Five studies involved type 1 diabetes mellitus while the other five included type 2 diabetes mellitus resulting in a pooled odds ratio of 1.29 (95% CI 1.20-1.38). Figures CCR5 gene had a pooled odds ratio of 1.24 (95% CI 1.08-1.43) from four studies. Among these four studies, two Asian studies involved type 2 diabetes mellitus whereas two Caucasian studies were for type 1 diabetes mellitus. The association was reproduced in the subgroup analysis . rs4073 SNP in IL-8 gene had a pooled OR of 1.45 (95% CI 1.16-1.82) from two Indian studies involving type 2 diabetes mellitus. In the same Indian studies, another genetic variant rs17576 in the MMP9 gene was significantly associated with diabetic nephropathy with a pooled OR of 1.91 (95% CI 1.54-2.38). The genetic variant rs3025039 in the VEGF gene was found to be significantly associated with diabetic nephropathy with a pooled OR of 1.63 (95% CI 0.98-2.70). Two studies in the Korean population investigated rs3025039 in type 2 diabetic patients. The genetic variant rs1617640 in the EPO gene was investigated in three American studies in which one study included type 2 diabetes mellitus whereas other two were for type 1 diabetes mellitus. After meta-analysis, the pooled OR of 1.47 (95% CI 1.31-1.65) showed a significant association with diabetic nephropathy. There was only one study in type 1 diabetes Caucasian population for the SNP IL1B in the IL-1 gene. IL1B showed a significant association with risk of diabetic nephropathy having an OR of 1.97 (95% CI 1.22-3.18).The genetic variant rs17300539 in IL-10 gene was studied in a Tunisian study and had an OR of 0.77 (95% CI 0.63-0.98). In our meta-analysis, there were 44 genetic variants in the genes involved in inflammatory cytokines and angiogenesis that were not found to be significantly associated with DN  , whereas, other genes are activated by TNF. VEGFA is activated by SMAD3 (Mothers against decapentaplegic homolog 3) present in the intra-cellular region  gene expression. ACE further interacts with G-protein beta3-subunit (GNB3) and this interaction is also associated with hypertension in many populations  or seven-transmemebrane receptors are the most prevailing class of signaling transduction molecules in humans. In the GPCR signaling pathways, inflammatory cytokine and angiogenic genes positively associated with diabetic nephropathy encode proteins present on the extra-cellular membrane. Among the nine genes showing significant association with diabetic nephropathy in our study- y Figure . In the n Figure . Diseases Figure .Figure 5Thirty six genetic variants were lacking a good number of studies (i.e. less than three studies), thus it was not possible to calculate the publication bias. Of the other nineteen studies, six SNP studies  did not account for publication bias as evident from the symmetric funnel plot and thirteen did show evidence of publication bias , CCR5 (two variants), CCL2, IL-1, MMP9, EPO, IL-8, ADIPOQ and IL-10 were significantly associated with diabetic nephropathy. Three genetic variants (two in the VEGFA and one in the EPO gene) belonged to angiogenesis pathway whereas the other variants were included in inflammatory cytokines. These results support a role of the inflammatory cytokines and angiogenesis pathways in the pathogenesis of diabetic nephropathy.In this meta-analysis, variants within or near VEGF expression in patients with diabetic nephropathy and antibodies against VEGF in the early stages of experimental diabetes can ameliorate the renal dysfunction [VEGFA gene were significantly associated with diabetic nephropathy. Both genetic variants were analysed in studies with moderate sample size. and more studies are needed to establish true effect sizes in such cases [VEGFA gene was found to increase the risk of diabetic nephropathy whereas Mooyaart et al. [It has been reported that there is an increased function . In thisch cases . T allelt et al.  in theirCCL2, also known as Monocyte chemo-attractant protein-1(MCP-1), is the strongest known chemo-tactic factor for monocytes and is upregulated in diabetic nephropathy [CCL2 rs3917887 showed two fold higher risk of diabetic nephropathy as compared to controls. Chinoy et al. have reported the association CCL2 rs3917887 with development of inflammatory myopathies [hropathy . In thisopathies .CCR5 is a β-chemokine receptor involved in a migration of monocytes, NK cells and some T-cells to the inflammation site [CCR5 rs1799987 was the most studied genetic variant in inflammatory cytokines. This SNP is reported to increase the protein level by increasing the transcriptional activity of the CCR5 gene [CCR5 gene A allele was the risk factor for diabetic nephropathy in our study whereas Mooyaart et al. [CCR5 rs333 changes the open reading frame of the gene resulting in a trunacated protein [ion site . CCR5 rsCR5 gene . Also, ft et al.  consider protein . This po protein .ADIPOQ encodes adiponectin, a hormone exclusively secreted by the adipose tissue [ADIPOQ is a risk factor for DN. It has been suggested that this genetic variation may contribute to an increased risk of developing nephropathy partly through the increase in adiponectin levels [e tissue . A alleln levels .IL-8 is a member of the CXC chemokine family and is associated with a variety of proinflammatory activities [IL-8 in DN patients has been reported [IL-8 is an antibody therapeutic target in inflammatory diseases [tivities . rs4073 reported . In theidiseases .The pro-inflammatory cytokine interleukin 1 (IL-1) stimulates kidney mesangial cell proliferation and extracellular matrix expansion, contributing to pathogenesis of DN . In thisMMP9 rs17576 lies in the substrate binding region and leads to over-accumulation of extracellular matrix, leading to renal damage [l damage . Rysz etl damage .EPO gene was a risk allele for diabetic nephropathy in this meta-analysis. This finding was in agreement with Williams et al. [EPO is a potent angiogenic factor involved in diabetic micro-vascular complications . Garcia s et al.  who in ts et al.  considerInterleukin-10 (IL-10) fulfils the criteria for an anti-inflammatory and immunosuppressive cytokine . Wong etAn important factor that bears on the interpretation of meta-analysis of the genetics of diabetic nephropathy is the adequacy of phenotype definition. This problem is reflected in studies showing that most patients with type 1 diabetes categorized initially as having microalbuminaria, undergo regression to normoalbuminaria . To avoiIn this study, enrichment analysis of the genes significantly associated with diabetic nephropathy, generated three functional pathways- GPCR signaling, receptor binding and chronic kidney failure. GPCRs transduce extracellular signals inside the cell through activation of heterotrimeric G proteins and/or via other G protein-independent signaling pathways. Agonist-induced GPCR phosphorylation by G protein-coupled receptor kinases (GRKs) are involved in a number of important systems related to the development and progression of Diabetic nephropathy . PresencConsidering a worldwide increase in diabetes, there is an urgent need to provide patients protection from the development and progression of diabetic nephropathy. Identification of genes involved in the primary mechanisms contributing to onset and progression of diabetic nephropathy is important for developing new therapeutic interventions. Inflammatory cytokines and angiogenic factors play a diverse role in the pathogenesis of diabetic nephropathy. The recognition of the genes/genetic variants as having a significant association with risk of diabetic nephropathy will provide new therapeutic targets. Furthermore, this will also help to identify patients with increased risk of diabetic nephropathy.VEGFA, CCR5, CCL2, IL-1, MMP9, EPO, IL-8, ADIPOQ and IL-10, significantly associated with diabetic nephropathy. Further studies are required to better understand their functional relevance in the pathogenesis of diabetic nephropathy. These genetic variants within the inflammatory cytokines and angiogensis pathways might be good candidates for identifying genetic predisposition to DN as well as revealing the pathogenesis of diabetic nephropathy.This study identified 11 genetic variants in or near 9 genes -