Knee osteoarthritis (KOA) is the most prevalent form of knee joint disease and characterized by the progressive degeneration of articular cartilage. Although pathology of KOA remains unknown, genetic factors are considered to be the major cause. Asporin is a group of biologically active components of extracellular matrix (ECM) in articular cartilage, and asporin gene (ASPN) D-repeat polymorphism was reported to be associated with KOA. Thus, our meta-analysis is aimed at investigation of the association between asporin D-repeat polymorphism and susceptibility of KOA.We gathered data from MEDLINE, Embase, OVID, and ScienceDirect to search relevant published epidemiological studies through April 2017. Compared with previous studies, our meta-analysis is the first study to investigate the association of ASPN D15, D16, and D17 alleles and KOA susceptibility by ethnic- and sex-stratified subgroup analysis.P < 0.05).We found no significant association between D15 allele and susceptibility to KOA  in overall population. The same results were observed in the analysis of D16  and D17 alleles . The ethnic- and sex-subgroup analyses did not alter the ORs. However, significant association was detected in the sensitivity analysis of D17 in overall population  and Asian population (OR = 1.78, 95% CI 1.02–3.11, Our results indicated that D-repeat polymorphism of ASPN may not play a major role in susceptibility of KOA in ethnic- and sex-specific analysis. Because of the limitations of the present meta-analysis, firm conclusions could not be drawn based on the current evidence, and further studies are required to detect genuine role of ASPN. Osteoarthritis (OA), which is characterized by the progressive degeneration of articular cartilage in joints, is one of the most common joint diseases that mainly affects the knees , 2. JoinHowever, current therapeutic methods only slow progression of KOA rather than prevent it . The undOne conventional viewpoint is that KOA is produced by an imbalance between synthesis and degradation of the extracellular matrix (ECM) controlled by chondrocytes . AsporinThere may be two reasons for the abovementioned different results. First, there was a gender difference in the occurrence and pathology of KOA. Women usually have a higher incidence of KOA, and postmenopausal women tend to suffer more severe KOA . AnterioHere, we performed a meta-analysis of recent studies to investigate the association between ASPN D15, D16, and D17 alleles and susceptibility to KOA.We gathered data from MEDLINE, Embase, OVID, and ScienceDirect to search published epidemiological studies through April 2017 that were designed to explore the association between ASPN D-repeat polymorphism and KOA susceptibility. Combinations of keywords used in the search were (“ASPN” or “asporin”), (“polymorphism” or “polymorphisms”), and (“osteoarthritis” or “OA”). No restrictions including languages were imposed on our search.To be consistent with other previous meta-analysis protocols, we included observational studies that recruited both KOA patients and healthy controls. The diagnostic criteria of KOA should be based on clinical symptoms, radiographic evidence, or joint replacement. Eligible studies should assess the association between ASPN D-repeat polymorphism and KOA susceptibility and had enough genetic frequency to extract. Interim analyses, overlapping study populations, and comparisons of laboratory methods were excluded. Potential studies for the eligibility criteria were reviewed by two independent readers (Liu and Yuan), with a third reviewer (Peng) to settle any discrepancies.For all eligible published studies, data were independently extracted from full text with the use of a standard data extraction form by two authors (Liu and Yuan). The standard data extraction form contained information of title, authors, year of publication, study design, sample size, gender, ethnicity, allele count, and allele frequency in KOA patients and healthy controls.We used the software Review Manager 5.3  and STATA 14.0  for all the calculations of statistical analysis. The D15, D16, and D17 alleles vs others alleles combined were evaluated respectively because of no specific genotype distribution reported in the included original articles. Thus, we performed meta-analyses of the ASPN D15, D16, and D17 alleles and KOA susceptibility to investigate their association respectively by calculating odds ratios (ORs) and 95% confidence intervals (CIs).P < 0.1 was considered statistically significant. The recently developed measure I2 was also applied to test heterogeneity; values of I2 = 25, 50, and 75% were considered low, moderate, and high, respectively [Q-statistic was used to assess between-study heterogeneity, and ectively .P < 0.05 (two-tailed). When heterogeneity was low, the ORs were obtained by fixed effects models [Data are shown as ORs with a 95% CI, and statistical significance was defined as s models , 28. Oths models . The fixs models . The rans models . A sensis models .The preliminarily literature search yielded 257 articles fulfilling the search criteria of which 51 described case–control studies. Then, we excluded 13 studies for not KOA articles, 23 studies for not ASPN articles, and 5 studies for unusable data. A total of 10 studies fulfilled all inclusion and none of the exclusion criteria , Caucasian , or Latin American  populations  (Table P < 0.05)  Table , indicat5) Table . These rP value for Egger’s and Begg’s test of the asporin D15 allele analysis was 0.354 and 0.213, revealing no proof of publication bias. There was also no significant publication bias in analyses of D16 and D17 alleles (Egger’s and Begg’s test P > 0.1).We estimated potential publication bias by Egger’s regression test and Begg’s test. The In the current study, ten published articles (11 comparisons) were included with a total of 2745 KOA and 3621 controls from Caucasian, Asian, and Latin American populations to examine the relationship between ASPN D-repeat polymorphism and KOA susceptibility by ethnic- and sex-specific meta-analysis. We observed that D15, D16, and D17 alleles had no effect on KOA susceptibility with significant heterogeneity in overall population and subgroups mentioned above.OA is the most common form of joint disorder, leading to physical disability in middle age around the world . The patP < 0.01) between the D14 allele and KOA susceptibility was first reported by Kizawa et al. in a cohort sample (394 cases and 374 controls) and a case–control study (137 cases and 234 controls) in Japanese population [P > 0.1) [P > 0.1) [P < 0.03) in a Greek case–control study (155 cases and 190 controls) [P < 0.05) [P < 0.03), whereas male carriers of D17 allele were more susceptible to KOA  [A positive association  . AnotherP > 0.1) . Kaliaka < 0.05) . Moreove < 0.05) . There w < 0.05) , 35–38,  < 0.05) –34, 39. Compared with the previous meta-analysis, there are three differences in the present study. First, it is the first study to investigate the association of ASPN D15, D16, and D17 alleles and KOA susceptibility. Second, our report enrolled five sex-stratified studies , 37, 39,In the present meta-analysis, we summarized different studies mentioned above to assess heterogeneity and association between D-repeat polymorphism and KOA susceptibility. The pooling results failed to prove significant associations between the D15, D16, and D17 alleles and KOA occurrence in Caucasians, Asians, and Latin Americans, and the same results were also observed in sex-specific subgroups.The heterogeneity between separate studies might be caused by lots of complex factors, including age, gender, quality of included studies, diagnostic criteria, inclusion criteria, racial differences, and environmental factors. In our present study, ethnic- and sex-specific subgroup analyses were performed to reduce heterogeneity. In addition, a sensitivity analysis was performed to evaluate the stability of the association between the D16 and D17 alleles and KOA susceptibility in overall and subgroups. After omitting the case–control study of Kizawa et al. , a positSeveral previous studies had demonstrated the gender differences for patients in allele frequencies –36, 39. For instance, different inclusion criteria could be an essential factor for heterogeneity. The included studies were four studies recruiting patients undergone total knee arthroplasty (TKA) –34, 39, The limitations of the present meta-analysis were briefly discussed in the following section. First, despite the subgroup analyses performed by ethnicity and gender, the existence of heterogeneity could not be totally resolved. We were failed to apply more types of subgroup analysis stratified by personal conditions or clinical variables because lack of enough original data from included studies. Therefore, the result of our meta-analysis should be interpreted with caution. Second, the environmental and genetic factors remained unclear in the present study. Both of them were responsible for the heterogeneity as well. Third, insufficient including studies with enough raw data, particularly in ethnic- and gender-stratified analyses, influenced the statistical efficacy and caused the high heterogeneity. It is also the reason why meta-regression analysis cannot be performed and was failed to detect the cause of heterogeneity. To settle the problems mentioned above, further studies with more different ethnic populations, unified inclusion criteria, functional research of ASPN D-repeat, sufficient raw data, and environmental and genetic interaction are clearly needed.In conclusion, we carried out a meta-analysis of the association between D-repeat polymorphism of ASPN and susceptibility to KOA in Asian, Caucasian, and Latin American populations. Overall, we found no significant relationship between KOA susceptibility and the D15, D16, or D17 alleles. However, results with significant heterogeneity lacked sufficient stability to provide an accurate conclusion on this study. Further studies are required to investigate the role of ASPN; these findings may help to elucidate the pathogenesis of OA and may inform the development of novel therapeutic strategies for OA.


VEGFA) rs699947 C>A, rs3025039 C>T and rs2010963 G>C polymorphisms with CHD risk, a comprehensive meta-analysis was conducted. A systematic search of EMBASE and PubMed online database for publications on VEGFA polymorphisms and risk of CHD was carried out. Crude Odds ratios (ORs) with their 95% confidence intervals (CIs) were calculated to determine the association. A total of ten publications including 22 trails involving 2097 cases and 2867 controls were included in our pooled analysis. Overall, results of the present meta-analysis demonstrated a significant association between VEGFA rs699947 C>A polymorphism and an increased risk of CHD. After stratifying by ethnicity and CHD type, the association was also obtained. A significant association between VEGFA rs3025039 C>T polymorphism and risk of CHD was also found. For VEGFA rs2010963 G>C polymorphism, the polymorphism was associated with MI risk. In conclusion, our findings suggest that VEGFA rs699947 C>A, rs3025039 C>T and rs2010963 G>C polymorphisms are risk factors for CHD. In the future, large sample size and well-designed epidemiologic studies are needed to confirm these conclusions.Coronary heart disease (CHD) is a common complex disease resulting from the interaction of multiple environmental and genetic factors. To assess the potential relationship of vascular endothelial growth factor ( In case of conflicting evaluations, disagreements over study/data inclusion were resolved by a discussion among all reviewers.The Newcastle-Ottawa Quality Assessment Scale was harnessed to assess the quality score of the eligible studies. And scores ≥ 7 stars were considered as high-quality study .http://ihg.gsf.de/cgi-bin/hw/hwa1.pl) was used to examine the deviation from HWE in controls. The strength of correlation between SNPs in VEGFA gene and CHD risk was assessed by ORs with the corresponding 95% CIs. Type of CHD (MI or non-MI) and ethnicity were considered as characteristics for evaluation of potential heterogeneity. Ethnicity group was defined as Asians and Caucasians. We used Chi-square based I2-statistic test and Q statistical test to analyze the potential heterogeneity among the studies. P < 0.10 or I2 > 50% indicates high heterogeneity, random-effects model (the DerSimonian and Laird method) was used to calculate the pooled ORs and CIs [P < 0.1 was defined as statistical significance. Sensitivity analysis, which assessed the influence of each independent study on the pooled ORs with their corresponding 95% CIs, was also carried out to evaluate the stability of our results. All P values were defined as two-sided at the P = 0.05 level. All data analysis was performed with Stata 12.0 software for windows .A Goodness-of-fit chi-square calculator ( and CIs ; otherwi and CIs . Funnel  and CIs , and a P


I2 = 0%, P = 0.71). Subgroup analysis revealed the prevalence of the virus didn't differ in patients with different tumor stages, in tumor cells with different histologic grades, also in different kinds of specimen (polyp and adenocarcinoma). The results of current study suggested a statistically association between the virus infection and an increased risk of colorectal cancer.Human cytomegalovirus infection (HCMV) has been recently considered as a factor for tumorigenesis. The current study used meta-analytical techniques to explore the prevalence of HCMV in tumor tissues and the relationship between human cytomegalovirus and colorectal cancer (CRC) risk. 11 studies detecting HCMV DNA in tumor tissues were included in meta-analysis. The prevalence rate and odds ratio (OR) were two main parameters. The overall prevalence of human cytomegalovirus DNA in tumor tissues were 27.5% (95% CI = 17.2%−37.8%). Binary logistic regression showed that the studies reported before 2010 involving formalin-fixed specimens from patients in developed region represented a lower proportion of HCMV. The tumor tissues had a significantly higher rate of virus infection compared with normal tissues (OR = 6.59, 95% CI = 4.48−9.69,  In vitro studies have verified the capacity of HCMV for transforming cells and increasing tumourigenicity [Human cytomegalovirus, also known as human herpesvirus-5 (HHV-5), is a ubiquitous opportunistic herpesvirus that infects between 60% and 70% of adults in developed countries and almost 100% in developing countries. As one of the pathogens, HCMV is able to induce the symptoms characterized by sore throat, prolonged fever and mild hepatitis . Currentgenicity , 9. In rgenicity .Colorectal cancer is globally one of the leading causes of cancer-related mortality. It shows a five-year survival rate less than 60% in Europe . The patNevertheless, detection of HCMV in CRC remains controversial. Negative results indicate that HCMV may present lack of association with CRC regardless of type of tissues or detection methods . InadequWe pooled the original literature concerning detection of HCMV in CRC tissues and performed a meta-analysis to investigate the relationship between HCMV infection and CRC patients and their clinicopathological characteristics.The literature search resulted in 192 relevant articles after removing the duplicate ones. By carefully screening the title of these articles, 166 were excluded for not focusing on the desired topic. The criteria of inclusion and exclusion further excluded 16 articles  thus 10 qualified articles were included  , so a fixed-effects model was used to estimate the pooled OR. The result revealed that the tumor tissues had a significantly higher rate of HCMV infection . No evident asymmetry of plots was seen in the funnel plots suggesting no evidence of publication bias  classification system. There was no clear evidence indicating the difference of HCMV infection between different stages of cancer, such as subgroups of stage I+II and stage III+IV  Figure , 8. TherOver the past few decades, great attention had been paid to the relationship between HCMV infection and colorectal cancer. However the exact role of HCMV in patients with CRC still remained unclear. Among the majority of researches, the rate of HCMV detection in tumor samples represented the rate of HCMV-positive cancer, thus the influence of sample types and detection techniques being unneglectable. One single study with insufficient cases inevitably leaded to bias, which made a meta-analysis necessary.In situ hybridization (ISH) and immunohistochemistry (IHC) were available for the detection of gene products. However, as a latent virus, HCMV might not consistently express products during the whole period of infection, which would cause false-negative results and affect the accuracy of analysis [Viral DNA and gene products including encoded RNAs and proteins were two general targets for viral detection. analysis , 27. Theanalysis , 24 ThisP < 0.01).We found that there was a certain prevalence of HCMV DNA 28.7%) in CRC tissues, compared to a high rate of HCMV detection (over 80%) in patients’ plasma , 21. Som.7% in CRIt had been reported that racial and geographic distribution of HCMV infection was existing , 31. HerDetection of HCMV DNA in CRC tissues by itself didn't provide adequate evidence to prove the causal role of HCMV in CRC. So data from 4 studies with total 480 tumor tissues and 480 matched normal tissues were pooled to give a more reliable evidence. Significant difference was seen in HCMV DNA prevalence between cancer and non-cancer tissue . This observation supported the association of HCMV with colorectal tumor formation. The result refuted the conclusion that HCMV was not related to CRC risk, as some studies had drawn , 25. ForIt was important to realize the potential relationship between HCMV and CRC. This relationship could not only provide a deeper insight into the carcinogenic mechanism of CRC, but also offer a novel therapeutic option . This waThere were limitations in the present study. Our study focused only on researches related to DNA detection and didn't analyze the data concerning viral proteins detection. 7 articles were absent of control groups. In addition, none of included studies were random trials.In conclusion, the present study indicated that a HCMV infection was statistically associated with an increased CRC risk and it played a role in the initiation and progression of CRC. Much further researches with larger scale of samples and more abundant date should be conducted to further confirm these results.In vitro studies based on cell lines or cells and review articles without original data were excluded.Literatures published up to January 2016 were searched in the electronic database of PubMed, Medline and EMBASE using the keywords “cytomegalovirus”, or “human herpesvirus-5” and “colorectal cancer” or “colorectal carcinoma”. The retrieved articles and their additional relevant references were reviewed meeting the following criteria: (1) Studies had to use polymerase chain reaction (PCR) technique to detect the presence of HCMV DNA in tumor tissues. (2) The articles should be with full text and published in English. Data was extracted from the selected and qualified articles including the first author's name, the year of publication, geographic regions. The pathological characteristics of CRC specimen were also collected.Q statistic (significance level at P < 0.1) and the 2I statistic (significance level at 2I > 50%). If the Q or 2I value was statistically significant, a random-effects model was adopted, otherwise a fixed-effects model was selected. Binary logistic regression was performed to compare and adjust the prevalence of HCMV by following factors: regions, the year of publication, detection techniques and specimen types with the adjusted OR (aOR) as an effect size. P < 0.05 were considered statistically significant.The two main parameters analyzed for these studies were prevalence rate and odds ratio (OR). The statistical software OpenMeta-analyst  was used to analyze the proportions of samples positive for HCMV. The data from patient and control groups were pooled using Review Manager 5.3 . The meta-analysis was performed based on Mantel-Haenszel and DerSimonian-Laird methods according to heterogeneity which was tested by the


FADS1/2 and PKD2L1 [log10(Bayes factor) ≥ 8.07] and for gondoic acid at FADS1/2 and GCKR [log10(Bayes factor) ≥ 6.22], and also observed improved fine-mapping resolutions at FADS1/2 and GCKR loci. The greatest improvement was observed at GCKR, where the number of variants in the 99% credible set was reduced from 16 (covering 94.8 kb) to 5  after trans-ethnic meta-analysis. We also confirmed the previously reported associations of PKD2L1, FADS1/2, GCKR, and HIF1AN with palmitoleic acid and of FADS1/2 and LPCAT3 with oleic acid in the Chinese-specific GWAS and the trans-ethnic meta-analyses. Pathway-based analyses suggested that the identified loci were in unsaturated FA metabolism and signaling pathways. Our findings provide novel insight into the genetic basis relevant to MUFA metabolism and biology.MUFAs are unsaturated FAs with one double bond and are derived from endogenous synthesis and dietary intake. Accumulating evidence has suggested that plasma and erythrocyte MUFA levels are associated with cardiometabolic disorders, including CVD, T2D, and metabolic syndrome (MS). Previous genome-wide association studies (GWASs) have identified seven loci for plasma and erythrocyte palmitoleic and oleic acid levels in populations of European origin. To identify additional MUFA-associated loci and the potential functional variant at each locus, we performed ethnic-specific GWAS meta-analyses and trans-ethnic meta-analyses in more than 15,000 participants of Chinese and European ancestry. We identified novel genome-wide significant associations for vaccenic acid at  MUFAs are nonessential unsaturated FAs with one double bond in the carbon chain, mainly including palmitoleic acid 16:1n-7), vaccenic acid (18:1n-7), oleic acid (18:1n-9), gondoic acid 20:1n-9), erucic acid (22:1n-9), and nervonic acid 24:1n-9). Oleic acid, the most abundant MUFA in lipids  . PreviouFADS1/2, PKD2L1, HIF1AN, GCKR, 2p13, LPCAT3, and TRIM58) associated with plasma and erythrocyte palmitoleic acid and/or oleic acid levels in populations of European ancestry  have identified seven loci   and the For ARIC, CARDIA, CHS, and MESA, fasting plasma phospholipids were isolated by TLC, and FAs were subsequently quantified by gas chromatography. For InCHIANTI, fasting FAs were measured in total plasma by gas chromatography. For GOLDN, NHS, HPFS, and NHAPC, fasting erythrocyte FAs were measured by gas chromatography or gas-liquid chromatography. FAs were identified for each study, and concentration of each FA was expressed as percentage of total FAs. Detailed methods of MUFA measurement in each cohort are provided in supplemental Methods. Ethnic-specific GWAS meta-analyses were performed for associations with palmitoleic, vaccenic, oleic, gondoic, erucic, and nervonic acids in Chinese populations, and for associations with vaccenic, gondoic, erucic, and nervonic acids in European populations (P < 10−4 (for NHS and HPFS), P < 10−5 (for ARIC and CHS), or P < 10−6  were excluded. SNPs with minor allele frequency <1% were also excluded from these analyses. The software used for imputation included MACH (r2) <0.3 were excluded  or <97%  were excluded. SNPs with significant departure from Hardy-Weinberg equilibrium expectations at ded MACH  ded MACH  (CHS), aded MACH  . In Chinese- and European-specific meta-analyses, SNPs that were present in only one study were excluded. The linkage disequilibrium (LD) measures (r2) were calculated by using the HapMap Phase II data (http://archive.broadinstitute.org/mpg/snap/ldsearchpw.php).For each individual FA, GWAS analysis of approximately 2.2 million genotyped and imputed SNPs was performed separately in each cohort. Linear regression models were applied to test associations between SNPs and individual FA levels under an additive genetic model. All analyses were adjusted for age, sex, site of recruitment (as needed), and principal components to account for population admixture. Genomic control corrections were applied to each study before meta-analysis to further minimize potential confounding by population stratification . Cohort-10[Bayes factor (BF)] ≥6 is considered as significant evidence of an association, and SNPs with posterior probability of heterogeneity (Phet) >0.5 were interpreted as having significant heterogeneity. Trans-ethnic meta-analysis using the fixed-effect model by METAL software was also performed. The 95% and 99% credible sets surrounding the most significant SNP at each locus based on the European-ancestry GWAS meta-analysis and the trans-ethnic meta-analysis of European and Chinese populations were calculated, respectively. The 95% and 99% credible sets at each locus was established by 1) defining a ±500 kb region surrounding the most significant SNP; 2) ranking the regional SNPs within this region according to their BF values; and 3) adding SNPs until the cumulative posterior probabilities of the ranked SNPs achieved the 95% and 99% confidence. Variants in the 99% credible sets were examined for sequence overlap with potential regulatory sites  by searching the HaploReg V4.1 database (https://www.ncbi.nlm.nih.gov/variation/tools/1000genomes/).Trans-ethnic meta-analysis was performed to identify additional novel loci for MUFA levels, to narrow the functional regions represented by the identified association signals, and also to test the heterogeneity of the identified loci across ethnic groups. Association statistics in the Chinese and European populations were combined by using Meta-ANalysis of Trans-ethnic Association studies  . MANTRA database . The loccis-expression quantitative trait loci (cis-eQTL) analysis, we examined the associations of significant SNPs . Adipose tissue, skeletal muscle, and liver were considered as the most important tissues in FA metabolism . For the pathway-based analysis, aSPUpath (https://cran.r-project.org/web/packages/aSPU/). In total, 4,405 and 4,502 genes mapped to 186 Kyoto Encyclopedia of Genes and Genomes pathways were analyzed in Chinese and European populations, respectively. The significant threshold after Bonferroni correction was set as 0.05/(4405 × 6) = 1.87 × 10−6 and 0.05/(4502 × 6) = 1.85 × 10−6 in Chinese and European populations, respectively, for the gene-based analysis, and 0.05/(186 × 6) = 4.48 × 10−5 for the pathway-based analysis.For the gene-based analysis, sum of powered score (SPUs)  and geneaSPUpath  and GATEaSPUpath  were usehttp://www.cardiogramplusc4d.org/), DIAGRAM (http://diagram-consortium.org/index.html), and GIANT (http://www.broadinstitute.org/collaboration/giant/index.php/) consortia were used to explore the associations of the significant loci ] were significant.The publicly available GWAS results from CARDIoGRAMplusC4D  showed novel genome-wide significant associations with vaccenic acid and/or gondoic acid in the meta-analysis. Minor allele A of PKD2L1-rs603424 was significantly associated with lower vaccenic acid level in the European-specific GWAS meta-analysis , and of TRIM58 with oleic acid  to 14 , 24 (covering 79.6 kb) to 23 , and 15 (covering 54.1 kb) to 12 , for association with palmitoleic, vaccenic, and oleic acid, respectively , and these SNPs show strong LD with each other (r2 ≥ 0.590 in CEU and r2 ≥ 0.927 in CHB+JPT). After trans-ethnic meta-analysis, the 12 highly correlated SNPs, including rs174535, rs174545, rs174546, rs102275, rs174536, rs174537, rs174550, rs174547, rs174574, rs174576, rs174577, and rs1535  in the 99% credible set of oleic acid were shared across the associations with palmitoleic, vaccenic, and oleic acid . We further performed a Fisher’s exact test to evaluate whether the SNPs in the trans-ethnic analysis-based 99% credible sets were enriched for potential regulatory sites  when compared with the SNPs in the European-ancestry GWAS-based 99% credible sets. However, no significant enrichment was observed after trans-ethnic meta-analysis (P ≥ 0.533). These findings suggested that the improved fine-mapping resolution at FADS1/2 locus is likely resulted from the increased sample size after trans-ethnic meta-analysis.The number of SNPs in the 99% credible set at GCKR locus, where the number of SNPs in the 99% credible set was reduced from 16 (covering 94.8 kb) on the basis of the European-ancestry meta-analysis to five  after trans-ethnic meta-analysis. The five SNPs in the 99% credible, in strong LD with each other (r2 ≥ 0.805 in CEU and r2 ≥ 0.827 in CHB+JPT), included one missense SNP , two intronic SNPs , and two SNPs in the downstream of GCKR  .The greatest improvement in fine-mapping resolution was observed at the PKD2L1 locus contained only one SNP (rs603424). Therefore, the posterior probability that rs603424 was functional  was greater than 99% for PKD2L1. PKD2L1-rs603424 is located in the second intron of the PKD2L1 gene and overlapped with an enhancer histone mark  in the adipose tissue when we searched the Roadmap Epigenomics database . Because PKD2L1-rs603424 was the strongest association signal  in the ±500 kb genomic region of HIF1AN-rs10883511 , we could not construct credible sets or perform trans-ethnic fine-mapping at HIF1AN locus.The 99% credible sets based on the European-ancestry and trans-ethnic meta-analyses at database  using Haeic acid  is locatcis-eQTL analysis by searching the publicly available GTEx database in adipose tissue, skeletal muscle, and liver. Results suggested that the minor allele A of PKD2L1-rs603424 was significantly associated with decreased RNA level of SCD  in the adipose tissue . These results further strengthened our findings from the GWAS meta-analyses that the minor allele A of PKD2L1-rs603424 was significantly associated with decreased levels of palmitoleic and vaccenic acids  for association with oleic acid in the Chinese populations and six genes  for association with palmitoleic, vaccenic, oleic, and/or gondoic acid in the European populations reached gene-based significance  using both SPU and GATES methods. Because the association signals at WNT8B and NDUFB8 genes for association with palmitoleic acid in the European populations are in strong LD with the reported SNP HIF1AN-rs10883511 (r2 ≥ 0.832), we did not consider them as novel loci. Pathways, including biosynthesis of unsaturated FAs, α-linolenic acid metabolism, glycerophospholipid metabolism, and PPAR signaling pathway, were significantly associated with palmitoleic, vaccenic, oleic, and/or gondoic acid levels in the pathway-based analyses .Gene-based analysis improves the statistical power by combining all SNPs in a gene into a gene-based score, which reduces the burden of multiple testing and incorporates multiple independent association signals . To iden10883511   and of GCKR-rs780094 with BMI . Suggestive evidence was also observed for associations with CAD  and T2D .Finally, we searched the public GWAS databases of CARDIoGRAMplusC4D, DIAGRAM, and GIANT Consortia to examine whether the significant loci  were assFADS1/2, PKD2L1, and GCKR with vaccenic and/or gondoic acid and replicated the previously reported associations with palmitoleic and/or oleic acid for loci at FADS1/2, PKD2L1, GCKR, HIF1AN, and LPCAT3 in the Chinese-specific GWAS and the trans-ethnic meta-analyses. We also observed substantial improvement in the fine-mapping resolution at the GCKR locus after trans-ethnic meta-analysis.In this first trans-ethnic meta-analysis of MUFA levels in Chinese and European populations, we identified novel associations of SCD, plays an important role in MUFA metabolism . Therefore, PKD2L1-rs603424 may exert its effect on MUFA levels through regulating SCD transcription.The Δ-9 desaturase, encoded by tabolism . It catatabolism  have ideFADS1/2 also showed significant associations with MUFA levels, including palmitoleic, vaccenic, oleic, and gondoic acid. FADS1/2 encode Δ5 and Δ6 desaturases, predominantly involved in the PUFA biosynthesis pathway  activity in liver and pancreas . Association analyses further stratified by the measurement methods (erythrocyte and plasma phospholipid FAs) did not materially changed the association results, and no additional erythrocyte- or plasma-specific loci were identified . Association results after excluding the InCHIANTI cohort, which measured MUFA levels in total plasma, also remained largely unchanged. These results suggested that differences in MUFA measurements did not introduce noise in the association results and were similar to the findings of previously published GWAS of FAs , 51.FADS1/2, PKD2L1, and GCKR with vaccenic and/or gondoic acid levels in the populations of Chinese and European origin. Five previously reported loci  for palmitoleic and/or oleic acid were also confirmed. Trans-ethnic fine-mapping highlighted a missense variant (rs1260326) at the GCKR locus. Our findings shed light on the genetic basis of MUFA biology and establish the foundation for future genetic and functional investigations.In conclusion, this is the first study to provide evidence for the associations of


Many previous studies have provided evidence that the ADIPOQ +45T>G polymorphism (rs2241766) might cause metabolic syndrome (MS). As a cardiovascular manifestation of MS, the incidence of stroke is associated with adiponectin; however, the results remain controversial and inconsistent. Systematic searches of relevant studies published up to Dec 2014 and Jan 2016 on the ADIPOQ +45T>G polymorphism and the risk of MS and adiponectin levels and the risk of stroke, respectively, were conducted in MEDLINE and EMBASE. The odds ratio (OR) or risk ratio (RR) and their 95% confidence interval (95% CI) were extracted. Sixteen studies containing 4,113 MS cases and 3,637 healthy controls indicated a weak positive association between ADIPOQ +45 T>G and MS in the dominant genetic model , which was also validated by stratified subgroup analyses. Twelve studies including 26,213 participants and 4,246 stroke cases indicated that 5 μg/ml increments in adiponectin level were not relevant to stroke risk . This study suggested a weak positive association of ADIPOQ +45T>G with MS and a strong association with metabolic-related disease. Additionally, adiponectin level was not a causal factor of increasing stroke risk. Metabolic syndrome (MS) constitutes a group of risk components including abdominal obesity, insulin resistance, hyperglycaemia, hyperlipidaemia, and hypertensionADIPOQ , which is located on chromosome 3q27, spans 17 kb, contains 3 exons and 2 introns36ADIPOQ, which is considered an important factor in MS and metabolic-related disease. Therefore, identifying the intrinsic genetic mechanisms and clarifying the similarities as well as partial distinctions of these mechanisms are issues that we pursue with interest in this study.Adiponectin is the most abundant adipose tissue-derived adipocytokine encoded by ADIPOQ +45T>G (rs2241766) is one of the most common variants of exon 2 on the ADIPOQ gene, and some studies have provided evidence that the ADIPOQ +45 T>G polymorphism is associated with serum levels of adiponectinet al. that differed from oursADIPOQ +45 T>G and MS risk.et al. conducted a meta-analysis including 9 studies on this topic; the overall RR estimate might have been inaccurate due to the significant publication bias and obvious heterogeneity, which both reduced the validity and accuracy of the conclusion.In addition, as a common cardiovascular manifestation of MS, the association between the incidence of stroke and adiponectin has also been inconsistent1011ADIPOQ genetic determinants of MS, the controversy regarding the association between adiponectin and stroke, and the need to update the latest data with stratified subgroup analyses to obtain more accurate conclusions, the objective of the present updated study was as follows: to investigate the latest data among the whole population and obtain greater statistical power to detect the association between the ADIPOQ +45 T>G polymorphism and MS; to further assess the relationship between ADIPOQ +45 T>G and metabolic-related disease in a published meta-analysis and beyond that, compare the similarities and differences in genetic background between MS and metabolic-related disease; and to examine the relationship between adiponectin and risk of stroke.Considering the lack of knowledge on the specific ADIPOQ +45 T>G polymorphism and MS risk, and the secondary one investigated the dose-response relationship of adiponectin and risk of stroke.This study included two meta-analyses. The primary one assessed the relationship of the This study was conducted according to the meta-analysis guidelines defined in the PRISMA statement13ADIPOQ +45 T>G polymorphism and MS risk, the following subject terms were used to conduct the search: “adiponectin” or “ADIPOQ” or “adiponectin gene polymorphism”, “AMP1”, and “metabolic syndrome” or “MS” or “metabolic syndrome X” or “syndrome X”. The relevant articles in English and Chinese published before Dec 31, 2014, were included.For the primary analysis of the th, 2016, were included.For the secondary subject of adiponectin and stroke risk, the following subject terms were used for the search: “adiponectin” and “stroke”. The relevant articles in English published before Jan 26We also conducted a manual search to find additional relevant data based on the references identified in the retrieved articles.ADIPOQ +45T>G (rs2241766) and MS risk; (2) were case-control studies; (3) provided detailed genotype data to estimate odds ratios (ORs) and 95% confidence intervals (CIs).The inclusion criteria of the primary meta-analysis were as follows: the studies (1) evaluated the relationship between The inclusion criteria of the secondary meta-analysis were as follows: the studies (1) used a prospective cohort to investigate the relationship of adiponectin and stroke risk; (2) included stroke as an endpoint; (3) had a follow-up duration of over 1 year; (4) used clear diagnostic criteria for stroke; and (5) provided data on the relative risk (RR) with 95% CI. In all identified studies, all subjects were free of stroke at baseline according to the stroke diagnostic criteria used and participated in the entire follow-up survey.All the articles that met the above requirements were included, regardless of the sample size and the population of the studies. Unpublished conference papers were not included. For overlapping studies, the most recent publication or the largest sample size publication providing more information was selected.Two investigators (H.-P.Y. and L.S.) systematically extracted and reviewed all studies according to a standardized form and then independently entered this information into an electronic database. The following items were reviewed and extracted from each eligible study for the primary meta-analysis when possible: name of the first author, year of publication, ethnicity, country where the study conducted, mean age, total number of cases and controls, allele frequencies, genotyping method, diagnostic criteria of MS, and language of the article. Different ethnicity descents were categorized as East Asian, South Asian, and Southeast Asians.The extracted information for the articles for the secondary meta-analysis included the name of the first author, publication year, name of the study, country, mean age, duration of follow-up, proportion of men, number of stroke cases and total participants, and adjusted variables. In addition, all of the multivariate adjusted RRs and 95% CIs based on a comparison of the highest adiponectin level category with the lowest adiponectin level category and the ORs/RRs with their 95% CIs were extracted. We abstracted the values for each category of adiponectin level, the median value of the adiponectin level for each category, the number of cases and participants/person-time for each category, and the most completely adjusted RRs with 95% CIs  for each category.A quality assessment of the primary meta-analysis was performed by two authors independently according to the Newcastle-Ottawa scaleThe qualities of the identified studies for the secondary meta-analysis were assessed by two authors independently according to a “methodological quality assessment scale” , which w16ADIPOQ +45 T>G polymorphism and MS risk was conducted as follows. ORs and 95% CIs were calculated as estimates of the relative strength of the associations between the ADIPOQ +45 T>G polymorphism and MS risk. The pooled ORs were calculated from a weighted average of OR from each study. Due to the potential functional role of the ADIPOQ +45 T>G polymorphism, carriers with at least one risk allele will present the corresponding phenotype or traits. Moreover, to obtain all of the data included, the dominant model (GG + GT vs. TT) was adopted. Allele contrast (G vs. T) and recessive models (GG vs. GT + TT) were also performed in the meantime. After adjusting for the potential confounding factors that might have contributed to the heterogeneity, the dominant model was adopted for further investigation. Subgroup analyses were also conducted to explore the effects of the following confounding factors: language of the article, diagnostic criteria, and ethnicities.The primary meta-analysis of the relationship between the et al. The detailed methods of the dose-response meta-analysis have been described beforeThe secondary meta-analysis of the relationship between adiponectin and risk of stroke was conducted as follows. Multivariable-adjusted RRs and 95% CIs were used to obtain the overall RR for the highest adiponectin level category compared with the lowest category using random-effects models. RRs and 95% CIs for each SD increase in log-transformed adiponectin were used to obtain the overall RR per SD in log μg/ml. The RR of each 5 μg/ml adiponectin level increment was calculated for studies that provided enough raw data to quantify the association between adiponectin level and risk of stroke using GLST  and VWLS (variance-weighted least square regression model) for the dose-response analysis, as proposed by Greenland, Longnecker, Orsini P value was less than 0.119I2 statistic was used to test for heterogeneity, with values of I2 less than 25%, 25–50%, and greater than 50% representing low, moderate and high degrees of inconsistency, respectively. When the P value was ≥0.1 or I2 ≤ 25%, a fixed effects model (Mantel–Haenszel method) was selected; otherwise, a random effects model (DerSimonian and Laird method) was selected. We then explored the sources of heterogeneity using meta-regression and stratified analysis. Sensitivity analyses were performed to evaluate the stability of the results. A leave-one-out method was used to evaluate each study, and a pooled estimate was calculated for the remaining studies. Begg’s funnel plots were conducted to evaluate the publication bias qualitatively; Begg’s test and Egger’s test were performed to quantitatively assess the publication bias. All P values were two-sided, with the statistically significant level defined as lower than 0.05. The statistical analyses were conducted using Stata .The between-study heterogeneity was calculated using Cochran’s Q test (Mantel-Haenszel chi-squared test) and was considered significant if the The characteristics of each study included in these two meta-analyses are summarized in P > 0.05). The serum adiponectin levels presented in P = 0.0016).9212223242526272829303132333411363738394041424344451136374041433711363738394041424344Quality assessments were performed for the included studies both in the primary and the secondary meta-analyses. All studies had acceptable qualities according to the methodological quality assessment  and the ADIPOQ +45 T>G and MS under the dominant genetic model  (A weak positive association was visible in the relationship between 03–1.65) . ResultsP = 0.389) for the highest adiponectin level category compared to the lowest adiponectin level category (P = 0.059). Additionally, 11 studies with 13 data points that provided sufficient raw data for the dose-response analysis indicated that the RR of stroke for each 5 μg/ml adiponectin level increment was 1.05  . Therefore, there was no association between adiponectin levels and stroke risk.The combined RR of stroke was 1.11  . After eConsidering the significant heterogeneity in both meta-analyses, a stratified analysis and meta-regression were performed successively to investigate the potential sources of heterogeneity.I2 was largely unchanged, data were shown in et al. and CHEN F-2 et al. deviated substantially from most studies. After removal of the two studies, a weak positive association was still visible in the relationship between ADIPOQ +45 T>G and MS under the dominant genetic model . Furthermore, I2 was reduced from 82.5% to 40.1%, with P = 0.050  . Finally, considering the differences in the genetic background of the population and that the risk allele frequency of +45 T>G polymorphism differed greatly among ethnicities, we further performed a subgroup analysis on East Asians. Asian Indians (South Asians) and individuals from Thailand (Southeast Asians) were excluded in this analysis. Data from East Asians leads to the same conclusion   . Further00–1.30) . As we c= 0.035) .I2 was largely unchanged). The meta-regression showed that the association did not substantially differ due to the effect of these potential confounding factors .For the secondary meta-analysis, the stratified analysis was performed based on study design, country, mean age, sex, follow-up duration, and measure of association , T2DM, hypertension, cancer, diabetic nephropathy (DN), cardiovascular disease (CAD), coronary heart disease (CHD) and polycystic ovary syndrome (POVS).Considering the close relationship between ur study . The resI2 = 82.5%, P < 0.001)  . The allI2 = 54.6%, P = 0.009)  .Due to the high heterogeneity in the two meta-analyses, stratified analyses, meta-regression, and sensitivity analyses were conducted. Based on the results above, we found that although some studies were far from the central line in the sensitivity analyses and might have been the sources of the heterogeneity, the conclusions regarding the associations in the two meta-analyses did not change when these studies were excluded. Therefore, the results of the two meta-analyses were reliable and stable.PBegg’s = 0.325, PEgger’s = 0.118). Additionally, the studies by SHEN J et al. and CHEN F-2 et al. were found to have deviated far from the others. For the secondary analysis, there was no obvious publication bias based on the funnel plot, Begg’s test, and Egger’s test  (As shown in = 0.378) .ADIPOQ gene (+45T>G polymorphism) is associated with adiponectin levels and resulting MS949ADIPOQ +45 T>G polymorphism and MS risk. Furthermore, genetic factors like the ADIPOQ +45T>G polymorphism is related to serum adiponectin levels51ADIPOQ +45T>G contribution to MS, adiponectin levels might also contribute to stroke risk, which is considered a cardiovascular manifestation of MS12Adiponectin is a plasma glycoprotein of adipose tissue originet al. and CHEN F-2 et al. deviated potentially from other studies  and the Tau-squared value reduced accordingly whereas this positive association still existed. Therefore, we excluded the 2 studies for the further stratified analysis and meta-regression. Taken together, our study indicated that a weak positive association was visible in the relationship between ADIPOQ +45T>G and MS in the dominant genetic model .In the primary analysis, due to the strong heterogeneity, a sensitivity analysis, stratified analysis and meta-regression were conducted in the dominant genetic model. Diversity in ethnicity, diagnostic criteria, and distinction between published English and Chinese language studies might be the common source of heterogeneity5455 studies . The artADIPOQ +45T>G polymorphism and the risk of MS in the whole population and had several limitations. First, the number of subjects in the included studies was still small, and only two studies used data from outside the Chinese population; thus, more large-scale studies are needed to assess the association between ADIPOQ +45T>G and MS. Second, environmental factors such as smoking, drinking, physical activity and family income might have a substantial influence on the progression of MS, but the lack of raw data makes it impossible for us to account for gene-environment interactions. Third, our analysis only focuses on ADIPOQ +45T>G; however, the development of MS is not due to a single gene, and there should be cross-talk between ADIPOQ +45T>G and other gene polymorphisms that should be consideredThe first meta-analysis focused on the relationship between the ADIPOQ +45T>G polymorphism were found to be associated with type 2 diabetes mellitus in Chinese, however, conflicting results have been reported in Asian and European subjects57ADIPOQ +45T>G with MS in the whole population together with a stratified analysis. There was only one prior meta-analysis, conducted by GAO M et al., that showed a significant relationship between ADIPOQ +45T>G and MS that differed from ourset al. performed their meta-analysis specifically in the Chinese population. In the present study, we focused on studies throughout the world that were up to date, and we presented a more comprehensive conclusion rather than studying a single ethnic group. Additionally, considering the distinct genetic backgrounds in the population, we further performed a subgroup analysis on East Asians. Second, GAO M et al.’s study only included 13 studies on ADIPOQ +45T>G in the Chinese population, whereas our study assessed 16 studies including Asian Indian and Thai populations. Furthermore, data from LI YP et al. were updated to the 2010 version. The larger sample size contributed to having greater statistical power to detect associations. Third, we also conducted a stratified analysis for different languages and diagnostic criteria as well as a subgroup analysis in East Asians to derive an accurate evaluation and validated our conclusions. Finally, and most importantly, we summarized the previous meta-analysis with ours and evaluated the pivotal role of ADIPOQ +45T>G in all potential metabolic-related disease risks including MS and metabolic-related disease. A clear risk of ADIPOQ +45T>G for obesity, cancer, NAFLD, T2DM, DN, hypertension, CAD, CHD and POVS was found. These disorders usually co-exist with each other59ADIPOQ +45T>G might be a common genetic factor behind these diseases and could explain the molecular mechanism of comorbidity in some patients.Given the complexity of the MS and the lack of clarity surrounding its definition, most reports to date have been restricted to the examination of the relationship between variant polymorphisms and the individual criteria of MS, rather than with the syndrome as a whole. For example, individuals carrying ADIPOQ +45T>G) that is present in MS and metabolic-related disease. According to the forest plot of our summarized analysis, although the ADIPOQ gene might be the “common soil” of individual MS components and other potential metabolic-related diseases, its contribution to MS as a whole appeared quite differently29ADIPOQ and individual MS parameters. Third, a well-designed follow-up cohort study including patients with both MS and metabolic-related disease that considers confounding factors and assesses a larger sample size with a focus on ADIPOQ +45T>G is required in the future.Therefore, there exist some shared and distinct mechanisms that need to be clarified regarding MS, metabolic-related disease and their comorbidities. The answer might be somewhat as follows. First, the populations in the existing studies on MS and metabolic-related disease were so different that the confounding factors could not be controlled properly. Second, there must be a key individual characteristic on top of general factors (P = 0.069). The conflicting results of the studies published previously may have existed for several reasons. First, the standards of measuring adiponectin level increments were not uniform in the included prospective and nested case-control cohort studies, which suggest it would be inappropriate to combine these measures in the overall RR. In our analysis, we stratified the analysis by the different measurement standards and evaluated the RR of stroke in 3 ways, as follows: stroke risk for the highest adiponectin level category compared with the lowest category; the overall RR per SD in log μg/ml of adiponectin; and the quantified RR of each 5 μg/ml increment in adiponectin level. Therefore, the conclusions we drew from these three analyses would be more accurate and reasonable. Second, serum adiponectin levels are related to various lipoproteinsIn the secondary meta-analysis, various analytical methods demonstrated that there was no association between 5 μg/ml increments in adiponectin level and stroke risk .


Up to now, numerous case-control studies have reported the associations between fat mass and obesity associated (FTO) gene rs9939609 A/T polymorphism and polycystic ovary syndrome (PCOS), however, without a consistent result. Hence we performed current systematic review and meta-analysis to clarify the controversial results.Case-control studies reporting the relationship of rs9939609 A/T polymorphism and PCOS published before April 2015 were searched in Pubmed database without language restriction. Data was analyzed by Review Manager 5.2.P < 0.00001. For AA vs. AT + TT: OR = 1.54, 95% CI = 1.25–1.89, P < 0.0001. For AA vs. TT: OR = 1.74, 95% CI = 1.38–2.18, P < 0.00001. For A vs. T: OR = 1.36, 95% CI = 1.25–1.47, P < 0.00001, respectively) suggesting that A allele was a risk factor for PCOS susceptibility. Furthermore, subgroup analysis in Asian and Caucasian ethnicities also found significant association between rs9939609 A/T polymorphism and PCOS A total of five studies involving 5010 PCOS patients and 5300 controls were included for further meta-analysis. The results of meta-analysis showed that the FTO gene rs9939609 A/T polymorphism was significantly different between PCOS group and control group in different gene models (For AA + AT vs. TT: OR = 1.41, 95% CI = 1.28–1.55, This meta-analysis suggests that rs9939609 A/T polymorphism of FTO gene is associated with PCOS risk, and that A allele is a risk factor for PCOS susceptibility simultaneously. Polycystic ovary syndrome (PCOS), a common endocrine metabolic disorder in women of childbearing age, is characterized by polycystic ovary (PCO), oligomenorrhea or amenorrhea, clinical or biochemical hyperandrogenism, and insulin resistance. In addition to leading to infertility, PCOS is closely associated with diabetes mellitus type 2, cardiovascular diseases and endometrial carcinoma –3. It waThe human FTO gene is located on the chromosome 16q12.2 with a wide expression range of almost all tissues , 9. The Recently, a common single nucleotide polymorphism (SNP) (rs9939609) in the first intron of FTO gene with T to A change is widely investigated in PCOS. However, the results from different studies are controversial. Some studies observed the positive association of FTO with PCOS –15, whilA comprehensive literature research was conducted in Pubmed to identify the studies aimed at exploring the association between FTO rs9939609 polymorphism and PCOS risk. The following keywords were used: “fat mass and obesity associated gene or FTO”, “rs9939609”, “polycystic ovary syndrome or PCOS”. All researched articles were updated on 30 March 2015 without any language limitation. When one eligible article was screened, we would check the references list of this paper manually to identify additional relevant publications.Any study included in current meta-analysis must satisfy the following criteria: (a) Case-control studies aimed at investigating the association between FTO rs9939609 polymorphism and PCOS risk. (b) The number of genotypes and allele frequency in cases and controls were respectively available to calculate odds ratio (OR) with 95% confidence interval (CI). (c) Genotypes in control group meet the Hardy − Weinberg equilibrium (HWE) (d) PCOS patients accorded with one diagnose criteria of the following three: 1990 NIH, 2003 Rotterdam, and 2006 AE-PCOS Society .P value of HWE in control group. If any disagreement was generated, another author would take part in to resolve it and make a final decision.Two investigators (Liu and Xie) independently extracted data from the qualified articles. The following information were extracted: the name of first author, publication time, ethnicity, country, sample size, diagnose criteria in PCOS and controls, genotype distribution in both case and control groups, and The pooled odd ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of association between FTO rs9939609 polymorphism and PCOS. The associations were calculated under the following four genetic models: dominant model (AA + AT vs. TT), recessive model (AA vs. AT + TT), additive model (AA vs. TT) and allele model (A vs. T). Subgroup analysis classified by ethnicity was conducted to explore whether ethnicity has a special effect on this association.2 statistic. When P < 0.05 for Q statistic or I2 > 50%, random effects model was used, otherwise fixed model was applied. To assess the stability of single study in overall effect, sensitivity analysis was performed by excluding each study once a time. Publication bias was estimated via funnel plot. All data analyses were performed by Review Manager 5.2. P < 0.05 was considered statistically significant.Heterogeneity among studies was examined by Q-test and IThe flow diagram of study selection was presented in Fig. P < 0.00001. For AA vs. AT + TT: OR = 1.54, 95% CI = 1.25–1.89, P < 0.0001. For AA vs. TT: OR = 1.74, 95% CI = 1.38–2.18, P < 0.00001. For A vs. T: OR = 1.36, 95% CI = 1.25–1.47, P < 0.00001, respectively), suggesting A allele was a risk factor for PCOS risk.The results of association between FTO polymorphism and PCOS risk were presented in Fig. P = 0.008; OR = 1.43, 95%CI = 1.29–1.59, P < 0.00001, respectively). The relative results were displayed in Fig. In subgroup analysis stratified by ethnicity, significant association between FTO 9939609 A/T and PCOS risk was observed in Caucasian and Asian populations under dominant model  was associated with PCOS only in East Asians, but not in Caucasians . In CaucSeveral limitations of this meta-analysis should be acknowledged. First, the number of studies included in our meta-analysis was relatively small, thus leading to smaller studies in subgroup analysis and weaken statistical power. Second, potential sources of heterogeneity in this meta-analysis should include other factors such as BMI, waist-to-hip ratio (WHR), obese. However, because of limited data, we could not explore these factors in current meta-analysis. Finally, it is well known that the etiology of PCOS involving in gene-gene, and gene-environment interactions. However these interactions could not be investigated in our meta-analysis due to insufficient information.In conclusion, this meta-analysis provided evidence that the FTO rs9939609 polymorphism was significantly associated with risk of PCOS risk not only in Asians but also in Caucasians. Further large studies are needed to clarify the associations among the FTO rs9939609 polymorphism, BMI/obese and PCOS risk in the future.This meta-analysis indicates that rs9939609 A/T polymorphism of FTO gene is associated with PCOS susceptibility, and that A allele is a risk factor for PCOS simultaneously.


Published association studies have investigated the correlation between interleukin-8 (IL-8) gene polymorphism –251T>A and susceptibility to Alzheimer's disease (AD); however, the results are conflicting. Thus, we conducted the meta-analysis to reassess the effect of IL-8 gene –251T>A variant on the risk of AD.Relevant studies regarding this association were electronically searched and identified from the PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, and the Chinese Biomedicine Database. The odds ratios (ORs) with the corresponding 95% confidence intervals (95% CIs) were pooled to calculate the strength of this association.Nine studies with a total of 1406 cases and 2152 controls were included in the meta-analysis. Overall, a significant association of IL-8 gene –251T>A polymorphism with increased risk of AD was observed in several genetic models . Similarly, such association was also revealed both in Asian and European populations in the subgroup analysis by ethnicity.The current study suggested that IL-8 gene polymorphism –251T>A may contribute to the susceptibility to AD. A growing body of evidence has shown that AD is a progressive neurodegenerative disorder characterized by the loss of memory, mental confusion, and several cognitive disturbances. Numerous studies have proven that the chronic inflammation plays a vital role in the pathogenesis of AD, which involved 2 typical neuropathological alterations in the brain of patients with AD: amyloid plaques and neurofibrillary tangles accompanied with amyloid-beta peptide (Aβ) deposition and tau protein aggregation, which results in neurons damage. Recently, a variety of inflammatory cytokines/chemokines, including interleukin-8 (IL-8), IL-6, IL-1, tumor necrosis factor-alpha (TNF-α), and monocyte chemotactic protein 1 (MCP-1), were detected with a markedly elevated level in patients with AD, supporting the importance of cytokines/chemokines in the development of AD.–8Alzheimer's disease (AD) posting the major global cause of dementia affecting seriously the quality of life has represented a large burden on the health of the elderly, with the increase of life spans and the number of elderly patients in the coming years. The concentration of IL-8 in cerebrospinal fluid and postmortem adult human microglia of patients with AD were significantly increased, suggesting the importance of IL-8 upregulation in the AD pathogenesis. Although the role of IL-8 in the development of AD remained largely unknown, there was a possibility for the underlying mechanism implied by the previous investigations that the abnormal deposition of Aβ stimulated by immunogens in AD patients was able to lead to the activation of microglia and release of inflammatory cytokines including IL-8, and subsequently result in neurons damage through the direct or indirect toxic effects of chronic inflammatory response.,8 During the process of inflammatory response, IL-8 chemokine activity has been found to have a momentous effect on the enhancement of Aβ-induced proinflammatory responses mediated by activated microglia in the AD brain.,12IL-8 as a CXC chemokine is located on chromosome 4q13–21 consisting of 4 exons, 3 introns, and a proximal promoter region, and usually served as a chemoattractant of neutrophils and lymphocytes in inflammatory activity.,13 Given these findings, several lines of evidence have revealed a significant association of IL-8 gene –251T>A with altered risk of AD, however, obtained conflicting results, which may be due to the ethnicity variation and relatively small size of individual study. To derive a more precise estimation on the association between IL-8 gene –251T>A polymorphism and susceptibility to AD, a meta-analysis was carried out with all available case-control studies as yet.Individual differences in the production of IL-8 have been linked to a functional polymorphism (T>A at position –251) in the promoter region of IL-8 gene and the AA genotype was reported to contribute most to the expression and activity of IL-8 chemokine.22.1An overall electronic literature search in PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, and the Chinese Biomedicine Database was undertaken for all the potentially relevant studies focusing on the association between IL-8 gene –251T>A polymorphism and susceptibility to AD up to September 2015. The language was restricted to English and Chinese in the literature search. The search strategy was developed by variable combinations with the following query: [“Interleukin-8” or “IL-8”] and [“Alzheimer's disease” or “AD”] and [“polymorphisms” or “polymorphism” or “variant” or “genotype”]. The references of all identified publications and relevant reviews were individually and manually searched for additional studies. Ethical approval and patient written informed consent were not required owing to that this was a meta-analysis of previously published studies.2.2Studies were included if they satisfied the following inclusion criteria: (1) case-control studies investigating the association between IL-8 gene –251T>A polymorphism and susceptibility to AD; (2) sufficient information offered for calculating odds ratios (ORs) and 95% confidence intervals (95%CIs); (3) original data available to be abstracted for the frequencies of alleles or genotypes in case and control groups; (4) studies definitely describing the diagnostic criteria for AD. Major exclusion criteria were: (1) studies without control population; (2) family-based studies; (3) duplication of the previous study with a smaller sample size; (4) abstracts, comments, reviews, or editorial articles lack of necessary raw data.2.3The following information from identified eligible studies was independently extracted by 2 investigators with a uniformed layout: first author, publication year, study country, ethnicity, numbers of case and control, genotyping methods, frequencies of genotype in case and control, source of control, and evidence of Hardy–Weinberg equilibrium (HWE). Ethnic groups were classified as Asians and Europeans. Any discrepancy was resolved by discussion and consultation with a third reviewer if necessary.2.4Z test (P < 0.05 was considered significant) using Review Manager version 5.2 software . The heterogeneity across included individual studies was assessed by both Q statistic test and I2 test, and P < 0.1 and I2>50% indicated the obvious existence of heterogeneity. A random-effect model (DerSimonian–Laird method) was applied to calculate the pooled ORs in the case of the presence of heterogeneity; otherwise, a fixed-effect model (Mantel–Haenszel method) was selected. Stratified analyses were conducted by ethnicity. Begg's funnel plot test and Egger's regression test were utilized to assess the publication bias using Stata 12.0 software , and P < 0.05 was considered significant.In light of the previous findings that IL-8 gene –251T>A polymorphism was stated to affect the expression and activity of IL-8 chemokine, we analyzed the data for dominant (AA+TA vs TT), allele (A vs T), homozygous (AA vs TT), heterozygous (TA vs TT) and recessive (AA vs TT+TA), and hypothesized that this polymorphism is a risk factor for AD. The pooled ORs and 95% CIs were calculated to assess the associations between IL-8 gene –251T>A polymorphism and the risk of Alzheimer's disease. The significance of the pooled OR was determined by 33.1,12,18–24 Of which, there were 4 studies conducted in Asians and 5 studies in Europeans. The frequencies of genotypes in controls of all included studies were in agreement with HWE except for the study by Li et al. Moreover, as only the frequency of AA+TA genotype was provided in the studies of Combarros et al and Infante et al, the 2 studies were pooled into the meta-analysis only in the dominant model. The flowchart of study selection procedure is shown in Fig. In total, 20 potentially relevant papers were retrieved by the initial search according to the established search strategy. After a further review, 11 studies were excluded due to the following reasons: 2 articles identified as reviews were first excluded, 2 articles were excluded due to the topic apparently irrelevant to the concern in the current study, 4 articles were also excluded because these studies focused on the association of AD risk and polymorphisms of other genes, 2 articles were excluded for that they concerned the relationship between other polymorphisms of IL-8 gene and AD risk, and 1 article was excluded because of the lack of sufficient data of genotype distribution. Finally, a total of 9 case-control studies with 1406 cases and 2152 controls were included to investigate the association of IL-8 gene –251T>A polymorphism and susceptibility to AD in the meta-analysis.3.2P > 0.1) except for the dominant model, an appropriate effect model based on the heterogeneity was thereby selected for the pooled analyses. Overall, a significant association of IL-8 gene –251T>A polymorphism with increased risk of AD was observed . Similarly, such association was also revealed both in Asian and European populations in the subgroup analysis by ethnicity. The main results of meta-analysis are summarized in Table As shown in Table 3.3 or Infante et al  in the dominant model, suggesting that the significance of the polymorphism may be masked by the considerable heterogeneity across studies. Publication bias was assessed by Begg's funnel plot test and Egger's test. As shown in Fig. P = 0.075, data for other genetic model not shown).Sensitivity analysis was performed by sequential removal of the individual study and the results showed no significant alteration of pooled ORs in all genetic models except for the exclusion of studies by Combarros et al4The present study is the first to evaluate the association between IL-8 gene polymorphism –251T>A and AD risk with a quantitative approach, representing the largest study so far. The results of the meta-analysis provided strong evidence demonstrating a significant association of IL-8 gene –251T>A variant with an increased risk of AD. To date, although the pathogenesis of AD was not fully understood due to the complexity of the etiology, the critical role of genetic components in the development and progression of AD has been firmly confirmed by evidences.,26,27 A functional polymorphism –251T>A in the proximal promoter region of IL-8 gene has been ever found to be associated with several inflammatory diseases, such as bronchial asthma, gastritis, and pancreatitis, which may be due to the frequently reported relationship between –251A allele and higher IL-8 transcription activity, thereby which is able to result in altered susceptibility to diseases. Likewise, studies regarding the association of IL-8 gene polymorphism –251T>A with susceptibility to AD in populations have emerged in recent years, however, obtained discrepant results. Mai et al and Kang et al found an overall significant association between the IL-8 gene –251T>A variant and increased individual susceptibility to AD, whereas other studies failed to reveal such association,,22,24 which prompted the further investigations to verify the association with a large-scare sample size.Accumulative evidence has demonstrated the vital role of IL-8 in most inflammation-related disorders, including AD. Mechanistically, the further exploration suggested that IL-8 might serve as an important mediator of neuronal death in AD both via its effects on release of neurotoxins such as MMP-2 and MMP-9 as well as by induction of cell cycle protein cyclinD1 and pro-apoptotic protein Bim.In the current meta-analysis, we found evidence of a significant association between the IL-8 gene –251T>A polymorphism and increased risk of AD by the overall analysis with 9 case-control studies involving 1406 cases and 2152 controls, which was not in line with some individual studies, indicating that the sample size was likely significant for the assessment concerning the IL-8 gene –251T>A polymorphism and the risk of AD. In the stratification analysis based on ethnicity, a significantly increased risk of AD associated with IL-8 gene –251T>A variant was revealed among Asians in all 5 genetic models and Europeans in 3 genetic models, suggesting that the ethnicity variation might contribute less to this association. Nevertheless, this association should be further validated in more populations, especially Europeans due to the limited number of included studies and obvious heterogeneity and there was a lack of Africans involved in the association, which would restrict the comprehensiveness and representativeness of the results. Additionally, gene–environment interactions may be involved critically in the development of AD, which should be considered for the association as well. Nevertheless, relatively less heterogeneity and no obvious publication bias together suggested the reliability and robustness of the results in the meta-analysis, which was of great importance for a quantitative approach.Despite these interesting results, several possible limitations of this meta-analysis should be acknowledged. First, though there was no obvious publication bias suggested in present meta-analysis, the possibility of publication bias were inevitable because studies with positive results were easily to be published in general, while studies with negative findings may not have been published. Second, the data from included studies were primarily based unadjusted estimates due to the lack of original information, some important compounding factors such as age, gender, and education should be taken into consideration. Third, AD is a complex disease that may result from the combined effects of multifactor, including gene–gene interactions. For example, the interactions between a well-known risk factor of AD risk apolipoprotein E gene ε4 and IL-8 gene locus, IL-8 gene –251T>A, and IL-1α gene -899C>T variants have been reported to influence the susceptibility to AD.5In conclusion, the current study suggested that IL-8 gene polymorphism –251T>A was associated with an increased risk of AD. Large well-designed studies with diverse populations and functional evaluations concerning this association are warranted to confirm and extend our findings.


Xeroderma pigmentosum group G (XPG) gene promotes recognition and excision of damaged DNA during the DNA repair process. We conducted a comprehensive search of the MEDLINE, EMBASE, and Chinese Biomedical databases for publications evaluating the association XPG gene rs751402 C>T polymorphism and overall cancer risk. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were adopted to assess the strength of the association. A total of 22 publications encompassing 10538 cases and 10511 control subjects were included in the final meta-analysis. We found the polymorphism to be associated with increased cancer risk . Stratification by cancer type indicated that this polymorphism may increase the risk of gastric cancer and hepatocellular carcinoma, which was further confirmed by a false-positive report probability analysis. Genotype-based mRNA expression provides further evidence that this polymorphism is associated with altered XPG mRNA expression. This meta-analysis suggests XPG gene rs751402 C>T polymorphism correlates with overall cancer risk, especially for gastric cancer and hepatocellular carcinoma.The  According to an estimation by GLOBOCAN, approximately 14.1 million new cancer cases, including 8.2 million deaths, occurred worldwide in 2012 –8.Xeroderma pigmentosum group G (XPG), which is also known as excision repair cross-complementing group 5 (ERCC5), can recognize and excise DNA lesions on the 3′ side to repair damaged DNA [Human DNA repair genes maintain the integrity and stability of genomic DNA, consequently preventing carcinogenesis and influencing clinical outcomes , 10. Managed DNA .XPG gene polymorphisms were reported to be associated with the susceptibility of various types of cancers [XPG gene rs751402 C>T polymorphism  and cancer risk has been investigated in several studies [XPG gene rs751402 C>T polymorphism with overall cancer risk. cancers –18. Thus studies –40, but As shown in Figure XPG gene rs751402 C>T polymorphism associated with increased overall cancer risk . As shown in Figure As shown in Table We performed false-positive report probability (FPRP) analysis for all significant findings and confirmed that the findings were significant at the priority of 0.1 for gastric cancer and hepatocellular carcinoma Table .XPG mRNA expression among Asians (not significant), Africans (TT vs. CC: P = 0.029), and Caucasians , as well as all subjects .As shown in Table P = 0.111; CT vs. CC: P = 0.251; TT vs. CT/CC: P = 0.236; CT/TT vs. CC: P = 0.249; and T vs. C: P = 0.298).By omitting each publication once in every genetic model in the sensitivity analysis, we did not find any individual publication that could significantly alter the pooled ORs, which indicated that our data were stable and trustworthy. As shown in Figure As shown in Figure XPG gene rs751402 C>T polymorphism and cancer risk. The pooled results suggest that this polymorphism is associated with increased cancer risk, especially for gastric cancer and hepatocellular carcinoma.In the current meta-analysis, we investigated all available publications that contained studies of the association between XPG gene, which is located at 13q33 and consists of 15 exons, promotes the removal of damaged DNA in the NER process [XPG gene is an essential component of the NER pathway, and it activates the cleavage of DNA on the 3′ side of the lesion [XPG gene promotes cellular processes such as RNA polymerase II transcription and transcription-coupled DNA repair [XPG gene polymorphisms might affect the expression or function of the XPG protein. Studies in several publications investigated the function of XPG gene rs751402 C>T polymorphism in cancer susceptibility. However, inconsistent results have been reported. Duan et al. [XPG gene rs751402 C>T polymorphism and overall cancer susceptibility. We included 22 available publications, encompassing 10588 cases and 10511 control subjects, and found that this polymorphism was associated with increased overall cancer risk, especially for gastric cancer and hepatocellular carcinoma. We also performed FPRP analysis to confirm that the significant associations were trustworthy and robust. In addition, the genotype-based mRNA expression analysis as performed also indicated that this polymorphism might be associated with XPG gene mRNA expression alteration.The  process . When DN process , 21. Thee lesion . StudiesA repair . XPG genn et al.  in a stun et al. , and in n et al. . Hua et n et al.  found thXPG gene. Fourth, we performed FPRP analysis, which can confirm whether the significant associations are trustworthy and robust. Fifth, we performed TSA to strengthen the robustness and minimize random errors of our conclusions.The current meta-analysis has five advantages. First, we searched the latest publications and we also included the publications written in Chinese. Second, we assessed the quality of each investigation and conducted stratification analysis by the quality score to search for publication bias. Third, we performed genotype-based mRNA expression analysis to provide further evidence that the rs751402 C>T polymorphism can influence the expression of the XPG gene rs751402 C>T polymorphism and overall cancer susceptibility, four limitations must be considered. First, because of the heterogeneity in the current meta-analysis, the conclusions on the overall cancer risk should be interpreted cautiously. Second, the results of this study were based on the unadjusted ORs, which might suppress the final results. Third, all the study subjects were Asians. Other ethnicities are needed as subjects in future studies. Fourth, despite the adequacy of the total number of publications, the number of publications that contain studies for some cancers were inadequate. Investigations into other cancers are needed.Although in the present study we performed the latest and largest meta-analysis for assessing the association between XPG gene rs751402 C>T polymorphism is associated with increased overall cancer risk, especially with respect to gastric cancer and hepatocellular carcinoma. Investigations of different cancers and ethnicities are needed to validate our findings.Our meta-analysis found that ERCC5 or xeroderma pigmentosum group G or XPG or rs751402,” and “polymorphism or variant or single nucleotide polymorphism (SNP) or variation.” We also manually searched the reference lists of the articles in the included publications.We systematically searched publications from the MEDLINE, EMBASE, and CBM databases  using the following search terms: “cancer or carcinoma or tumor or neoplasm,” “excision repair cross-complementing group 5 or XPG gene rs751402 C>T polymorphism and cancer risk, (2) the study was on human beings, (3) the study was a case-control or cohort design, (4) sufficient data were provided to calculate the ORs and 95% CIs, and (5) the study was published in English or Chinese.The studies in the included publications met the following criteria: (1) the study evaluated the association between Exclusion criteria were (1) the study was not a case-control design, (2) the study was duplicated from previous studies, (3) articles were case reports or review articles, and (4) the studies were without detailed genotype data.Two authors (Haixia Zhou and Ting-Yan Shi) performed the publication search and data extraction independently. The extracted information includes surname of the first author, publication year, cancer type, country of origin, ethnicity, genotyping methods, and numbers of cases and control subjects with rs751402 CC, CT and TT genotypes. We assessed the quality of each publication based on the quality score assessment . All conXPG gene rs751402 C>T polymorphism can influence expression of the XPG gene, we conducted genotype-based mRNA expression analysis as previously described [XPG gene rs751402 C>T polymorphism for 270 individuals were obtained from HapMap Phase II Release 23. The mRNA expression data for the corresponding individuals were from SNPexp [To determine whether the escribed , 45, 46.m SNPexp .XPG gene rs751402 C>T polymorphism and overall cancer risk under the homozygous (TT vs. CC), heterozygous (CT vs. CC), recessive (TT vs. CT+CC), dominant (CT+TT vs. CC), and allele contrast (T vs. C) models. A goodness-of-fit χ2 test was adopted to assess the Hardy-Weinberg equilibrium for the control subjects. Stratification analysis was carried out by cancer type (publications with no more than two were merged as the Others Group) and quality score (>9 and ≤9). Heterogeneities were assessed by χ2-based Q test, and a fixed-effect model was adopted when P > 0.1. Otherwise, the random-effect model was applied [P < 0.05 was statistically significant. All statistical analyses were performed by the STATA software .Pooled ORs and 95% CIs were used to investigate the strength of the association between  applied . Sensiti applied  and Egge applied . FPRP an applied . All the


To quantify by meta-analysis the relationship between waterpipe smoking and cancer, including cancer of the head and neck, esophagus, stomach, lung and bladder.We performed a systematic literature search to identify relevant studies, scored their quality, used fixed and random-effect models to estimate summary relative risks (SRR), evaluated heterogeneity and publication bias.We retrieved information from 28 published reports. Considering only highquality studies, waterpipe smoking was associated with increased risk of head and neck cancer , esophageal cancer  and lung cancer , with no evidence of heterogeneity or publication bias. Increased risk was also observed for stomach and bladder cancer but based mainly on poor-quality studies. For colorectum, liver and for all sites combined risk estimates were elevated, but there were insufficient reports to perform a meta-analysis.Contrary to the perception of the relative safety of waterpipe smoking, this meta-analysis provides quantitative estimates of its association with cancers of the head and neck, esophagus and lung. The scarcity and limited quality of available reports point out the need for larger carefully designed studies in well-defined populations. For several hundred years, waterpipe smoking, sometimes known as “Shisha” or “Hubble bubble” smoking, has been a common form of smoking in the Middle East. It is especially popular with younger smokers and rapidly becoming popular in other regions Maziak , 2015. WThe reasons for its growing popularity include: (1) the perception that this form of tobacco exposure is much safer than cigarette smoking, since tobacco smoke is filtered through water . In particular, we retrieved from Web of Science papers citing any of the study reports previously identified or any of the major reviews on the topic. We also scrutinized references of relevant papers. Finally, we searched PubMed in a more empirical manner for observational studies on the association between tobacco smoking and cancer conducted in Middle East countries, where waterpipe is a common form of smoking . Only reports fulfilling the following inclusion criteria were included in the meta-analysis.One reviewer (PM) was involved in the appraisal of papers identified through the main PubMed search and extracted data necessary for the study in a pre-defined spreadsheet. A second reviewer (ABL) controlled the suitability of the studies identified by the first reviewer and verified the accuracy of the data extracted.P value of the significance of the estimate].Studies that contained the minimum information necessary to estimate the relative risk (RR) of any form of cancer associated with waterpipe smoking and a corresponding measure of uncertainty  OR “neoplasms” OR “cancer”)) OR ((Iran OR Iraq OR Egypt OR Oman OR Qatar OR Jordan OR Syria OR Libya OR Yemen OR Tunisia OR Saudi Arabia OR Pakistan OR Kashmir) AND (“neoplasms”[MeSH Terms] OR “neoplasms” OR “cancer”) AND (“case–control studies”[MeSH Terms] or “case–control” or “case control”) AND (“smoking” OR “tobacco”)). Titles and abstracts available in PubMed were evaluated and full text of 38 study reports was obtained. Full texts of 12 additional study reports identified from other sources (mostly citations in published reviews on the topic) were also evaluated for inclusion in the meta-analysis. Twenty-two were excluded: eight were lacking a control group, four contained no original data, three referred to non-malignant lesions, four presented data included in other reports and in three studies no distinction between waterpipe and other forms tobacco smoking was made. Twenty-eight studies satisfied the eligibility criteria and were included in the synthesis  of the 28 studies had a NOS score ≥7 and were considered high-quality studies, respecting generally most of the following criteria: cancer cases were either histological confirmed or identified through hospital records and were representative of all cancer in a defined catchment area over a defined period of time; controls derived from the same population, were selected from the community and had no history of the outcome; analysis was adjusted for other form of smoking if not restricted to exclusive waterpipe smoking and was adjusted for other potential confounders; exposure was assessed by the same method for cases and for controls. Studies with NOS score <7 generally made use of hospital controls, did not provide risk estimates adjusted for other form of tobacco smoking or for additional confounding factors.Results from the meta-analysis including summary relative risk estimates and 95 % confidence intervals, measures of heterogeneity, forest plots and funnel plots are presented in Table I2 = 79 %), with no evidence of publication bias (Macaskill test P = 0.68). In three studies, risk estimates were adjusted for other forms of tobacco smoking  with no evidence of publication bias (Macaskill test P = 0.36). In one study, the risk estimate was adjusted for other forms of tobacco smoking  or publication bias (Macaskill test P = 0.80). . Table  and in o). Table . The sum). Table  was weakI2 = 57 %) but no evidence of publication bias (Macaskill test P = 0.54). The odds ratios reported in each individual study ranged from 1.78 (95 % CI 0.80–4.20) .We identified six case–control studies reporting information on waterpipe smoking and lung cancer risk , but none were classified as of high-quality. Examination of the funnel pot indicated no evidence of publication bias although the test proposed by Macaskill et al. was statistically significant (P = 0.03), being largely influenced by estimates of the largest study .Five studies, four from Egypt Makhyoun  and one Four studies reported on the association between waterpipe smoking and other various form of cancer Table  for whicIn this report we have used previously reported data on the relationship between waterpipe smoking and neoplasms in a meta-analytic approach to define the association between this type of tobacco exposure and cancer. We found 28 published studies with sufficient exposure data and statistical information to allow us to calculate summary odds ratios for the risk of several cancers known to be linked to tobacco exposure. The overall report is based upon 8,714 cancer cases and 35,746 controls, making this study more comprehensive than previously published reports  or the use of different control groups—either non-waterpipe smokers, or non-smokers of any type of tobacco. Another source of heterogeneity is that the reports originated from 10 different regions with different smoking patterns, and where waterpipe smokers used different types of equipment. A final source of variation could be related to temporal-related changes in smoking occurring over the 40 years spanning the publication of these reports. In fact, waterpipe is becoming the most popular form of tobacco smoking among youth in the Middle East, and is gaining popularity elsewhere  indexes and 12 from other sources, including references or citations of major papers on the topic. We assessed publication bias visually inspecting asymmetry of the funnel plot and using the test proposed by Macaskill et al. . We founUnfortunately, there were not enough reports to assess geographical patterns of the cancer site-specific risk associated with waterpipe smoking. For various reasons  related studies were often conducted in similar areas: all studies reporting on stomach cancer were conducted in Iran, those reporting on esophageal cancer risk were conducted either in the Kashmir valley or in Iran; four of the five studies reporting on bladder cancer risk were conducted in Egypt.This study clearly shows that waterpipe smoking increases the risk for several common cancers. For esophageal and stomach cancer, the risk resembles the risk associated with conventional cigarette smoking. If cigarette smokers switch to waterpipe smoking, the proportion of tobacco-related cancer in these organs will remain the same  (Dar et al. Using pack-years, it is possible to calculate a dose response for the risk of cancer associated with cigarette smoking. Despite the availability of software for comparing waterpipe exposure to cigarette exposure (Masters et al. Reports on exposure to cancer-related carcinogens in waterpipe smoke support the case–control data used in this meta-analysis. These reports disprove the widely held belief that filtering tobacco smoke through a container of water removes carcinogens derived from burning tobacco (Al Ali et al. Just as second-hand cigarette smoke is a known risk factor for cancer, the high levels of side-stream smoke in waterpipe cafes can lead to increased levels of tobacco-related nitrosamines in both smokers and non-smokers exposed to the ambient air of waterpipe cafes posing a risk to both smokers and non-smokers exposed to this environment. (Radwan et al. This report has several weaknesses. In comparison to the thousands of articles looking at the cigarette-associated cancer risk, there were very few studies available for this meta-analysis; many were small studies with only a limited number of cancer patients in each report. In addition, it is probable that in some reports waterpipe smokers included current or previous cigarette smokers, which would bias the results. Also, for the comparison control population, most of the studies used hospital controls or hospital visitors, rather than a random sample of the population. The limitations of the available data point out the need for larger carefully designed studies in well-defined populations.In summary, this report supports and quantifies the risk of cancer in waterpipe smokers. In general, the types of cancers reported in waterpipe smokers are similar to the types of tumors observed in cigarette smokers but the number and quality of studies available for a definite assessment is very limited. Results from high-quality studies, however, indicate significant increased risk for cancer of the head and neck, esophagus and lung. More high-quality studies would be necessary to properly assess the risk for other forms of cancers. Controlling the impending epidemic of waterpipe smoking will require the combined efforts of health educators, legislators, public health officials, and research scientists.