LMP7 (low molecular weight polypeptide 7) –145 C > A may influence the function of immune surveillance of an individual and lead to cancer development. Various studies have investigated the relevance of LMP7 –145 C > A gene polymorphism with cancer risk; but, their results are conflicting and inconsistent. To obtain a comprehensive conclusion, a meta-analysis was performed by including eight eligible published studies retrieved from PubMed (Medline), EMBASE and Google Scholar web search until December 2016. Individuals with AA genotype  of LMP7 -145 C > A were found to have 2 folds higher risk of cancer than those with CC genotype. The recessive genetic model (AA vs AC + CC) also indicated that individuals with AA genotype have 2 folds higher cancer risk than AC and CC genotypes . Also, significant increased cancer risk was observed in Asians but not in Caucasians. No publication bias was observed during the analysis. Trial sequential analysis also strengthened our current findings. These results suggest that genetic variant LMP7–145 C > A has significant role in increasing cancer risk in overall and Asian population, and could be useful as a prognostic marker for early cancer predisposition.Genetic variant  Cancer is one of the ever dreadful disease, and a leading cause of death, and a severe public health problem worldwide . VariousRecent genomewide association studies (GWAS), and other case-control studies have revealed that single-nucleotide polymorphisms (SNPs) are the most common forms of human genetic variations, have important role in defining susceptibility to cancer , 6. ThisMajor histocompatibility complex (MHC) is a set of cell surface glycoproteins that bind with the intracellularly processed peptides from pathogens, and present them on the surface of tumor cells to cytotoxic T lymphocytes (CTL). Therefore, MHC plays a key role in the initiation of CTL linked inflammation and anticancer immune response . MHC resLMP7, also called as PSMB8) gene is located in the class II region of the MHC locus on chromosome 6 [The low molecular weight polypeptide 7  gene polymorphism result in functional alternation, and ultimately deteriorate the capacity of antigen processing [Single-nucleotide polymorphism (SNPs) is one of the most common forms of genetic alterations. Several studies from TCGA and COSMIC were perused to analyze the association between the LMP7 gene mutations and risk of developing cancer including human breast and colorectal cancers , human gMP7 gene . Previouocessing . Thus, aLMP7 gene in antigen processing and presentation, this gene is a promising candidate for carcinogenesis susceptibility. In the last few years, a number of case-control studies have investigated the impact of this gene polymorphism on cancer risk in various populations; but the reported results varied across studies and remain inconclusive [LMP7–145 (C > A) gene polymorphism as genetic marker for cancer progression. Further, the quality of the included studies was checked by performing Newcastle Ottawa Scale (NOS) analysis. Also, type-I statistical errors, i.e., publication bias and random errors occurred due to sparse data were minimized by performing Trial Sequential Analysis (TSA) for quantifying the statistical reliability of the data included in the cumulative meta-analysis with the threshold of statistical significance. Overall, a meta-analysis is a powerful statistical tool for analyzing cumulative data from different studies, in which the individual sample sizes are small and the statistical power is low, and it provides precise and robust conclusion [In view of the crucial restrictive role of nclusive –27. Inconclusive . Therefonclusion .LMP7–145 (C > A) gene polymorphism as genetic marker for cancer susceptibility and progression [LMP7 –145 (C > A) gene polymorphism and cancer risk were found eligible for inclusion in this meta-analysis. All the retrieved articles were examined carefully by reading their titles and abstracts, and the full texts of the potentially germane publications were further reviewed for their appropriateness for this meta-analysis. Published studies either showing LMP polymorphism to predict survival in cancer patients or considering LMP variants as an indicators for response-to-therapy were disqualified straightaway. Likewise, studies related to the investigation of the levels of LMP mRNA or protein expression or pertinent review articles were also disqualified. In this meta-analysis, only case-control or cohort design clinical studies having frequency of all the three genotypes were included. In addition to the online database search, the references listed in the primary retrieved articles were also examined for other relevant potential articles. The major characteristics of all the eight studies included in this meta-analysis, i.e., distribution of genotypes, minor allele frequency (MAF) in controls and cases have been given in Table The confounding conclusions from previous studies regarding the role of gression –27 impelLMP7 –145 (C > A) gene polymorphism included in this meta-analysis. No evidence of publication bias was observed by the appearance of the shape of funnel plots and the results of Egger’s test in all the five genetic models of LMP7 –145 (C > A)  Table  gene polQ-test and I2 statistics were employed to test heterogeneity among the selected genetic association studies of LMP7–145 (C > A) gene polymorphism and cancer susceptibility. Significant heterogeneity was observed in three models of LMP7–145 (C > A). Thus, random effects model was used to synthesize the data (Table LMP7−145 (C > A) polymorphism and cancer risk. Pooled analysis of total 1770 different cancer cases and 2013 controls demonstrated that homozygous AA genotype was significantly associated with 2.6 folds increased risk of overall cancer as compared to the CC genotype . The recessive genetic model also demonstrated OR of 2.21 , indicating that individuals with AA genotype had almost 2 folds higher risk of cancer than those with the AC and CC genotypes. However, other genetic models, allelic , heterozygous , dominant model  did not show any association  and recessive genetic models  in comparison with wild type CC genotype. In addition, variant allele also revealed 1.4 folds increased risk of developing cancer . Marginally significant risk was also observed for the dominant  genetic model, whereas, heterozygous  model failed to show any risk  variant with cancer susceptibility was observed in all the genetic models , homozygous , heterozygous , dominant model  and recessive .For ethnicity-wise subgroup analysis of Caucasian population, only three studies (including 513 controls and 435 different cancer cases) were qualified and included for this analysis. Heterogeneity was observed in four genetic models; hence, random effects model was applied to generate pooled ORs and corresponding 95% CI values  model, for e.g., showed that meta-analysis had enough number of studies  for a significant conclusion, as it crossed the O’Breien-Fleming boundary  AND cancer susceptibility OR risk. The search was limited on published studies that had been conducted in human subjects only. All the retrieve articles were examined by reading their titles and abstracts, and all the published studies matching with the above said eligibility criteria were selected for this meta-analysis. We also did manual search of the reference list from the retrieve articles for other eligible pertinent studies.A systematic search was performed using PubMed (Medline), Google Scholar and EMBASE web-databases to retrieve compatible and peer reviewed research articles for this meta-analysis. Last search was updated on January 2017 with the combination of following keywords: ‘low molecular weight polypeptide 7 OR LMP7 −145 C > A polymorphisms and cancer risk, b) used a case-control design, c) recruited histologically confirmed cancer patients and healthy controls, d) have available genotype frequency in cases and controls, e) and must be published in the English language. In addition to above, when the same patient/subject populations appeared in several publications, only the most recent one or the complete study was included in this meta-analysis.All the published articles included in the current meta-analysis had to meet all the given criteria: a) it must evaluated the association between The major reasons for study exclusion for this pooled analysis were overlapping of the data, case-only studies, review articles, and lack of genotype frequencies or number not reported. The information related to the selection (inclusion/ exclusion) of the studies is appended as Figure For each retrieved article, the methodological quality assessment and data extraction were independently summarized in duplicate by two independent investigators (RKM & SAD) using a standard procedure. Data-collection form was used to ensure the accuracy of the collected data by strictly following the inclusion/ exclusion criteria as stated above. The major characteristic summarized from the retrieved articles included, the name of the first author, year of publication, the country of origin, the number of cases and controls, type of cancer, type of study, association/no-association status, methods of genotyping and genotype frequencies for the cases and controls. The cases related with disagreement on any item of the data from the collected studies were fully debated with the investigators in the presence of adjudicator (SH) to attain a final consensus.The methodological quality assessment of the included studies was also done separately by two independent investigators (RKM & SAD) using the NOS criteria. The NOS criteria majorly included three aspects: (1) subject selection: 0–4 points; (2) comparability of subjects: 0−2 points; (3) clinical outcomes: 0−3 points. The studies that were awarded 5 stars or more can be considered as of moderate to high quality . The assLMP7 single nucleotide polymorphism and cancer susceptibility was assessed by computing crude Odds Ratios (ORs) and the corresponding 95% CI. The pooled ORs were estimated for the allele contrast, log-additive, dominant, and recessive models [Q-test [p-value < 0.05 to avoid underestimation of the presence of heterogeneity. A fixed effect model (if p > 0.05) [p < 0.05) [2 statistics was also applied to efficiently test the heterogeneity among the selected studies [t-test  [p-values were two sided, and the statistical significance was considered as p-value less than 0.05 for this meta-analysis.The potential association between studied e models . Heterog [Q-test . Heterog > 0.05)  or a ran < 0.05)  was used studies . Hardy-Won bias) . All thehttp://www.ctu.dk/tsa/) software program was used for the TSA analysis.According to Cochrane handbook, meta-analyses are considered to be the best if all the eligible trials are included in the analysis. However, it may not be sufficient evidence. Occasionally, the meta-analysis may lead to systematic errors (bias) or random errors (play of chance). In order to minimize errors, a novel statistical analysis based software program, TSA  has been introduced, which estimates the required information size, and an adjusted threshold for the statistical significance, and estimates the power of the current conclusion –44. If t


To assess the susceptibility of the hOGG1 genetic polymorphism for bladder cancer and evaluate the impact of smoking exposure.Articles included in PubMed, Medline and Springer databases were retrieved using the following key words: “human 8-oxoguanine DNA glycosylase”, “OGG”, “OGG1”, “hOGG1”, “genetic variation”, “polymorphism” , “bladder cancer”, and “bladder carcinoma” to Meta-analysis was performed to detect whether there were differences between the bladder cancer group and the control group about the distribution of genotypes of the hOGG1 gene.The results showed that there are no significant associations between the hOGG1 326Cys polymorphism and bladder cancer: GG vs. CC ; GC vs. CC ; GG+GC vs. CC ; GG vs. GC+CC; G vs. C . In the smoker population, no significant associations between the hOGG1 326Cys polymorphism and bladder cancer were observed for all the models. However, individuals carrying the hOGG1 Cys326Cys genotype have increased risk for bladder cancer compared to those carrying the hOGG1 Ser326Ser genotype in the non-smoker Asian population.The hOGG1 326Cys polymorphisms aren't a risk factor for bladder cancer, especially in the smoker population. But GG genotype is a risk factor for bladder cancer to the non-smoker Asian population compared with CC genotype. Bladder cancer is the most common malignancy of the urinary system over the world . It had The human 8-oxoguanine DNA glycosylase (hOGG1) gene is located on human chromosome 3p26.2 , major rAll the case-control studies were found out by researching the database of PubMed, Medline and Springer databases using the following key words: “human 8-oxoguanine DNA glycosylase”, “OGG”, “OGG1”, “hOGG1”, “genetic variation”, “polymorphism”,“bladder cancer”, and “bladder carcinoma”. Human-associated studies were concluded, and no language constraints. In addition, references of retrieved publications were searched manually. If the data were missing, we communicated with the author by e-mail. The most recent or complete articles with the largest number of subjects were selected from the overlapping data by the same authors. The last search was updated on 2014. Studies included meet the following criteria:  contain Two investigators independently screened documents and extracted data, and then checked the results of the included studies. In the present study, we sought the following information from each publication: the first author's last name, year of studies, country of origin, ethnicity, source of controls , genotyping method and number of genotyped cases and controls. We used the Newcastle-Ottawa Scale (NOS) to assess the quality of the studies included in our analysis. Different ethnic groups were categorized as Caucasian and Asian to assess the effect of hOGG1 Ser326Cys polymorphism. Gene-by-environment interaction analyses were assessed according to smoker exposure (smoker or non-smoker).2 is >50%, and fixed-effects models when I2 is <50%. Funnel plots was applied to test the publication bias. All analyses were done with Stata software 12.0 using two-sided P values.The intensity of the associations between hOGG1 Ser326Cys polymorphisms and bladder risk was measured by odds ratios (ORs) with 95% confidence intervals (CIs). For hOGG1 Ser326Cys polymorphism, the risk of the dominant model (GG+GC vs. CC), the recessive model (GG vs. GC+CC), the codominant model , and the allele model (G vs. C) were evaluated respectively. Subgroup analyses were also performed by ethnicity and smoker exposure. Hardy–Weinberg equilibrium (HWE) was used to assess the genotype frequency of hOGG1 Ser326Cys polymorphisms among the controls by χ2 test. Meta-analysis's process references Cochrane organization guidelines, using Q statistics to analyze the heterogeneity between the trials, and a P value of <0.10 was considered significant. The fixed-effects model and the random-effects model were based on the Mantel-Haenszel method, using random-effects models when IA total of 10 articles related to the search words and complied with the present inclusion criteria, including 4319 cases and 4716 controls. All studies were case-control studies, in which there were five studies of Asian descendents, five studies of Caucasian descendents. A classic polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) assay, TaqMan assay and amplification refractory mutation specific polymerase chain reaction (ARMS-PCR) assay were conducted in six, three and one of the ten studies, respectively. In most studies, bladder cancer was diagnosed histologically or pathologically. Controls were mainly matched for sex and age, of which one were population based and nine were hospital based. The characteristics of selected studies are summarized in Four of these studies investigated the interactions between hOGG1 Ser326Cys polymorphisms and smoker exposures, including 1774 smokers (927 case and 847 controls) and 1992 non-smokers (748 cases and 1224 controls). The data only showed in recessive model by the studies of Ma et al. In the gene-by-environment interaction analyses, subgroup analysis by ethnicity was also carried out. The studies about smoker exposure are shown in The association between the hOGG1 326Cys polymorphism and bladder cancer risk is shown in In the gene-by-environment interaction analyses, there were no significant associations between the hOGG1 326Cys polymorphism and bladder cancer in different models for the smoker population, and no ethnicity difference. In the non-smoker population, individuals carrying the hOGG1 Cys326Cys genotype have increased risk for bladder cancer compared to those carrying the hOGG1 Ser326Ser genotype . However, this result could not be found in Caucasian population in the codominant model of GG vs. CC for the non-smoker population by subgroup analysis , and no significant association was found in the other model for the non-smoker population. The results are shown in There was significant heterogeneity between studies in some comparisons. Because of the genotype distribution in the control groups deviating from HWE, the study by Karahalil was excluded to test the sensitivity of the meta-analysis, and no substantial change was observed in the corresponding pooled OR was not altered. Funnel plot showed significant symmetry and an absence of publication bias in this meta-analysis. The results are shown in DNA damage response pathways mainly defend DNA damage, mutations and ultimately malignant caused by various factors, and base excision repair plays an important role in the repair of modified and lost bases . As a keA total of 10 case-control studies were included in this meta-analysis. The study subjects of 5 studies were Asians, and the other half were Caucasian. So, we carried out the subgroup analyses by race. The results demonstrated that no significant associations were observed between the hOGG1 gene polymorphism and the occurrence of bladder cancer in all models, and this result was no different between Asians and Caucasians . Additionally, subgroup analyses indicated for smokers, there were also no correlations between the hOGG1 gene polymorphism and bladder cancer in all model and this irrelevance had no racial differences. However, the genotype GG is a risk factor to bladder cancer for non-smokers , especially in Asians. But no associations were observed in Caucasian and other models. The previous meta-analysis showed the hOGG1 gene polymorphism increases the occurrence of bladder cancer for most all non-smokers , but ourThere are some limitations in this study. First, single case-control studies can only support a small test power and often provide false-positive, false-negative, or inconsistent conclusions, and the cases number from eligible studies are relatively small. What's more, some detailed information such as gender and histological type could not be obtained, so we could not proceed to the more in-depth subgroup study. And most of the eligible studies were published by the Asian and Caucasian, various race studies are needed to obtain more convincing results. Third, most of the designs of experiment were hospital-based and some studies genotype distributions among the controls are deviated from the HWE.In conclusion, our meta-analysis suggests that the hOGG1 gene polymorphisms have no significant association with bladder cancer risk, but specifically increase the susceptibility for non-smoker Asian populations. Considering the limited studies in both overall and subgroup analyses, larger sample size and higher quality studies are needed to make further verification.


The 5, 10-methyleneterahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) are two essential enzymes involved in folate metabolism. The relationship between genetic polymorphisms and congenital heart defects (CHDs) is inconsistent. Our aim was to investigate the association between two well-known polymorphisms of MTHFR and MTRR genes, C677T and A66G, respectively, and CHDs in Iranian patients.We enrolled 74 patients with ventricular septal defect (VSD) and 79 with tetralogy of fallot (TOF) along with 147 healthy controls. C677T and A66G polymorphisms were detected using tetra-primer ARMS (amplification refractory mutation system) PCR.Individuals carrying homozygote mutant (TT) genotype of C677T polymorphism represented the highest risk for CHDs . Also, significantly increased risk of VSD was observed in individuals with TT genotype . However, the frequency for variant allele (T) of C677T polymorphism was not statistically different between cases and controls . For A66G polymorphism, we found that AG and GG genotypes had higher frequencies in the patients (48.4% and 21.6% respectively) than controls . In line with this, combined AG+GG genotype represented with significantly elevated risk of CHDs . AG+GG combination was also identified as a risk factor for TOF .We demonstrated that C677T polymorphism of MTHFR gene was significantly associated with VSD in our patients. Our study also suggested that A66G polymorphism of MTRR gene may contribute to the development of TOF in Iranians. Congenital heart diseases (CHDs) are among the most common forms of heart abnormalities in children, and are considered as primary causes of premature death worldwide , 2. VentThese roles are ensured through recruitment of folate biological derivatives in enzymatic reactions of thymidine and methionine synthesis . In the C677T and A66G polymorphisms are two common genetic variants of MTHFR and MTRR genes known to reduce activities of the respective enzymes . C677T pIn recent decades, the role of genetic polymorphisms in propensity to CHDs has acquired attention , 13. In  When considering CHDs as heterogeneous subtypes, the risk association conclusions are uncertain. Besides, it seems that the influence of these polymorphisms on the risk of CHDs development is modulated depending on the population under study  recruited from Cardiac Care Center of Imam Ali Hospital in Zahedan, Sistan and Balouchistan province, southeast of Iran during 2014-2015. 147 healthy sex-age-and ethnically matched case participants were selected. Diagnosis of CHDs was confirmed using specified diagnostic techniques of echocardiography, cardiac catherization and surgical procedures. The controls also underwent echocardiography to ensure the absence of cardiac conditions. Parents were requested to sign an informed contest, and likewise were interviewed for a family history of heart diseases. Our study was approved by the Ethics Committee of Research Deputy of Zahedan University of Medical Sciences.Polymorphism genotyping: For obtaining DNA, 2 ml blood samples in EDTA anticoagulant were obtained from the participants. Genomic DNA was extracted by a standard protocol exploiting proteinase k enzyme : (5'–AAG GCC ATC GCA GAA GAA CTA -3') and backward; : (5'–CAT GTA CCA CAG CTT GCT CAA AC -3') and outer primer with sequences of forward; 5' –ACA TGC CTT GAA GTG ATG AGG A -3' and backward5' –CCC AAC CAA AAT TCT TCA AAG C -3'. For C677T polymorphism. sequences of inner primer were forward, T allele: 5'-AGA AGG TGT CTG CGG GCG T -3' and backward C allele:5'-AAA GCT GCG TGA TGA TGA AAT AGG -3' as well as outer primes which had sequence of forward; 5'-GCT GTT GGA AGG TGC AAG ATC A -3' and backward; 5'-GAG TGG GGT GGA GGG AGC TTA T -3'. Wilde-type (A) and variant (G) alleles of A66G polymorphism were identified by sizes of 140 bp and 102 bp, respectively. As well, product sizes were 177 bp and 230 bp for T and C alleles, respectively. PCR amplification was performed on 1 µl of 100 ng/ml genomic DNA template admixed with 1.5 µl of each inner and 0.9 µl of each outer primer. Taq premix 2X  as well as 5 µl dd H2O was also included into reaction tube. PCR was performed as 30 cycles of denaturation, annealing and amplification phases using appropriate temperature profiles .Briefly, a common 5- minute in 95℃ following with 30 cycles of 95℃ (denaturation), 61℃ for C677T and 56℃ for A66G polymorphism  and 72℃ (extension) each for 30 seconds, as well as a final 5-minute period of extension phase was considered.Statistical analysis: SPSS statistics Version 19 was used to conduct the analysis. In appropriate place, statistical tests such as Chi-square, t student –independent and logistic regression were performed to detect significant associations, differences and correlations.From 153 CHDs patients (74 VSD and 79 TOF cases) 84 (54.9%) were males (including 43 (58.1%) in VSD and 41 (51.9%) in TOF). In comparison, respective gender ratios were 70 (47.6%) and 77 (52.4%) for males and females in controls (P>0.05). There was no significant difference between the mean age of controls (4.9±3.9) and patients with TOF (4.2±3.8); though the patients with VSD had significantly lower mean age . Frequencies of different genotypes of A66G and C677T polymorphisms in controls, CHDs, as well as separate VSD and TOF patients have been represented in For both groups, wild-type allele (A) represented with higher frequency than variant; nevertheless, mutant allele had higher frequency in cases (45.8%) than controls (36.7%). Regarding C677T polymorphism, the most noticeable feature was significantly the higher frequency of homozygote mutant genotype (TT) in patients (4.6%) than controls (0.7%) . Similar to the results obtained for A66G polymorphism, wild type allele of C677T polymorphism was also detected in the majority of participants in both the case (79.1%) and controls (83.7%).Results of logistic regression analysis for determining the overall risk of CHDs, and also the risk of individual VSD or TOF diseases have been shown in Most common recognized haplotypes in controls were A66G:C677T; AA:CC (32%), A66G:C677T; AG:CT (23.8%) and A66G:C677T; AG:CC (20.4%). In CHDs, still, the most identified haplotype was A66G:C677T; AG:CC (30.1%). Interestingly, haplotypes with a mutant allele of either A66G or C677T polymorphisms had significantly higher risk of CHDs. Specifically, A66G:C677T; AA:CT haplotype , A66G:C677T; AG:CC , A66G:C677T; GG:CC  and A66G:C677T; GG:CT  were haplotypes most strongly associated with risk of CHDs. Risk association of different haplotypes in specific subtypes of VSD and TOF have been presented in The main purpose of the current study was to assess the impact of two common polymorphisms in folate metabolic- related genes, C677T polymorphism of MTHFR and A66G polymorphism of MTRR, on the risk of VSD and TOF in an Iranian population. We found that haplotypes bearing mutant alleles of either polymorphism significantly had higher risk of cardiac disorders. In fact, the highest risk of CHDs was observed in subjects carrying A66G:C677T; GG: CT haplotype . We found no study on CHDs to compare such effects with our results. Nevertheless, one possible mechanism for this observation can be the cumulative effect of these polymorphisms in raising homocystein level of plasma. .  It has been described that synergistic behavior of both variant alleles of C677T and A66G polymorphisms with alleles of other genes related to folate metabolism, such as MTR, glutamate carboxypetidase II (GCP II) and methionine synthase (MS), can influence the risk of coronary artery disease (CAD) in different populations -26. In lWhen treating CHDs as a unit entity, homozygote mutant genotype of C677T polymorphism enhanced the risk of disease .  In regression analysis for individuals subtypes, C677T polymorphism of MTHFR seemed to be significantly associated with the risk of VSD . In comparison to our findings, homozygote state of mutant allele of C677T polymorphism was reported to significantly accentuate the risk of CHDs in Egyptian patients  . In accoOur results also demonstrated a role for A66G polymorphism in the pathogenesis CHDs. In general, both heterozygote and mutant homozygote genotypes of this polymorphism were closely related to CHDs . In individual states, as regards AA genotype as a reference, combinations of AG+GG genotype showed highlighted risk of TOF. Additionally, homozygote mutant genotype (GG) also rendered as a risk factor for VSD . Despite this, the association of G allele with neither VSD nor TOF was not statistically significant which may relatively root in a study with low power. In comparison, A66G polymorphism of MTRR was revealed as a risk factor for CHDs specially in the Asian population. LikewisIn addition to heterogeneous patient populations, conflicting data obtained for A66G polymorphism may represent the impact of other genetic or environmental determinants. In particular, the nutritional status of cobalamine may modulate the effect of MTRR polymorphisms on the risk of CHDs. Accordingly, a continuous supply of cobalamin is crucial for methyltransferase activity during MTR . TherefoIn Conclusion, overall, our study showed the role of C677T polymorphism in the pathogenic process of VSD and A66G polymorphism in TOF. Genetic polymorphism involved in folate metabolism seem to influence the risk of CHDs development. Specifically, our results indicate that the role of particular genes and consequently enzymatic reactions may contribute in developing certain cardiac pathologies. Yet, more studies are encouraged to elucidate this.


Hip fracture has increasingly become a social and economic burden. The relationship between serum 25-hydroxyvitamin D levels and the risk of hip fracture reported by previous studies remains controversial. We searched Pubmed and Embase to identify studies reporting the relationship between serum 25-hydroxyvitamin D levels and risk of hip fracture. Fifteen prospective cohort studies with a total of 51239 participants and 3386 hip fracture cases were included. By pooling the Relative Risk of the lowest vs. the highest categories indicated that lower levels of serum 25-hydroxyvitamin D were more likely to be a risk factor for hip fracture with adjusted Relative Risk  of 1.58 . Subgroup meta-analysis examining the stability of the primary results achieved the same results. A dose-response meta-analysis showed that the risk of hip fracture was a descending curve below the line of RR=1. The descending trend was obvious when serum 25-hydroxyvitamin D levels were less than 60 nmol/L and was flat when serum 25-hydroxyvitamin D levels were more than 60 nmol/L. We found that individuals with low levels of serum 25-hydroxyvitamin D have an increased risk of hip fracture, and this effect was evident when the serum 25-hydroxyvitamin D levels were less than 60 nmol/L. Hip fracture as a serious consequence of osteoporosis is becoming an important health problem, and an increasing social and economic burden –3, and hSerum 25-hydroxyvitamin D [25(OH)D] is widely recognized as the indicator of vitamin D . SteingrTherefore, the effect of serum 25(OH)D concentrations on hip fracture remains uncertain, and we conducted this meta-analysis for the purpose of determining the association between serum 25(OH)D concentrations and the risk of hip fracture. Moreover, which is optimal serum 25(OH)D concentration? And will the sex, age, geographic region or study design (cohort or nested case-cohort) influence the outcomes? Dose-response and subgroup analysis  were performed to help us understand more about serum 25(OH)D levels and their relationship to the risk of hip fracture.The detailed steps of our literature selection are shown in Figure The characteristics of the included studies are presented in Table versus highest categories of serum 25(OH)D concentrations were 1.58  without significant heterogeneity , the meta-regression of year, age, follow-up term, study-type, gender and location showed no heterogeneity was found .There were thirteen studies that referred to the relationship between serum 25(OH)D levels and the risk of hip fracture. The results of the meta-analysis are shown in Figure The results of the subgroup meta-analysis are shown in the Table P = 0.110 for non-linearity, Figure Four studies , 24, 26 Hip fracture has been worldwide burden  and the We found that the adjusted relative risk (adj.RR) of low levels of 25(OH)D has a statistically significant 58% increased risk of hip fracture. All of the subgroup meta-analyses of different genders, age ranges, locations, study types, and durations of follow up supported the result that lower serum 25(OH)D levels significantly increased the risk of hip fracture.Serum 25(OH)D is the indicator of vitamin D. Therefore, low levels of serum 25(OH)D may be associated with bone loss, lower bone mineral density (BMD) and higher bone turnover , which mThe guidelines published by the Institute of Medicine (IOM) recommend that serum 25(OH)D levels ≥ 50 nmol/L(≥ 20 ng/ml) can benefit skeletal health . In thisThe strength of this meta-analysis is that our quantitative assessment is based on prospective cohort studies, which can overcome the weaknesses of recall and selection bias in case-control studies and provide more data on hip fracture risk within the population. To the best of our knowledge, this is the first systematic review and meta-analysis of the relationship between serum 25(OH)D levels and the risk of hip fracture based on prospective cohort studies. Moreover, we performed subgroup analyses by gender, age, location, study design and follow-up term, and the results were consistent to the overall result. We also performed dose-response assessments of the relationship between serum 25(OH)D levels and the risk of hip fracture. Finally, all of the included studies had high quality assessment scores  and long durations of follow-up, with a large population of 51239 participants totally.There are still some limitations of our meta-analysis. Firstly, not all of the studies met the requirement of dose-response meta-analysis; only four of included studies were pooled for dose-response meta-analysis. Secondly, There were some different 25(OH)D assays exist, in general, they can be grouped into 2 different categories: immune based and chromatography based . AccordiIndividuals with low levels of serum 25(OH)D have an increased risk of hip fracture, and this effect was evident when the serum 25(OH)D level was less than 60 nmol/L, and disappeared when the serum 25(OH)D level was more than 60 nmol/L.The present study was completed according to the preferred reporting items for systematic review and meta-analyses (PRISMA) statement (Checklist S1).We systematically searched PubMed and EMBASE on September 15, 2016 using the following keywords: 1) 25-hydroxyvitamin D, 25(OH)D, or vitamin D; 2) hip fractures or hip fracture; 3) cohort study, cohort studies, prospective study, prospective studies, or longitudinal study. We conducted the searches without language and publication year restrictions. In addition, we manually scanned the related articles and used the “related article” function for additional searches to avoid initial misses.The criteria for inclusion in this meta-analysis were as follows: (1) the study was designed as a prospective cohort study; (2) exposure of interest is 25(OH)D; (3) primary outcome of interest is hip fracture; and (4) relative risk (RR) and the corresponding 95% confidence interval (CI) were reported or could be calculated using the data reported. If the data were overlapped or duplicated by multiple publications, the study with the larger number of cases was includedAnd the criteria of exclusion were: (1) the retrospective study; (2) No data of 25(OH)D and hip fracture was described; (2) meeting abstract that couldn't found the full text; (4) the RR and 95%CI were not reported or couldn't be calculated using the reported data.Two authors (QBL and XG) independently scanned the potential studies to determine which studies were eligible. Disagreements were discussed first and resolved by a third independent author (AMW).Three investigators  independently extracted data and the other author (YLC) cross-checked the data for consistency. Differences and disagreements were resolved by consensus. The data were recorded using a standard data extraction form, including the first author's last name, publication year, country where the study was performed, study period, sample size (cases and controls or cohort size), gender and age of participants, measure and range of exposure, variables adjusted for analysis, and RR estimates with corresponding 95% CI for each category of 25(OH)D. If there were more RRs for different potential confounders, we extracted the RRs that reflected the greatest degree of control for potential confounders. If necessary, we contacted the authors of the primary studies for additional information. The nine-star Newcastle-Ottawa scale was used to assess the study quality , 48.vs. the highest categories for synthesis to determine the risk of hip fracture with low 25(OH)D concentrations [First, RR estimates were combined using a fixed-effects model as a common measure of the relationship between serum 25(OD)D levels and the risk of hip fracture across studies. To obtain a more accurate result, we pooled the RRs and 95%CIs of the lowest trations –51.Second, we conducted a subgroup meta-analysis to examine the significance of the difference in RRs by different subgroups, including gender , age (≥ 65 years and ≥ 42 years), location (Europe and USA), study type (cohort study and case cohort study) and the duration of follow-up (< 7 years and ≥ 7 years). And the covariates  meta-regression was performed to observe the potential heterogeneity.Third, to examine the association between 25(OH)D levels and the risk of hip fractures, a dose-response meta-analysis was fitted using 4 knots at the following percentiles of distribution: 5%, 35%, 65% and 95% of the distribution . We used2 statistic [Finally, statistical heterogeneity between studies was quantified by using Cochran's Q and the Itatistic . To invetatistic . All sta


A possible association between the TACC3 rs798766 polymorphism and urinary bladder cancer risk has been indicated in published literature. We performed this meta-analysis as a synthesis of all relevant data to summarize currently available evidence and to provide estimation with increased precision.  EMBASE, PubMed, Google Scholar, and Wanfang Data were searched. “rs798766” and “urinary bladder cancer” were used as the search terms. A total of 6 eligible studies were identified, in which 8194 cases and 50,165 controls were investigated. Meta-analysis was performed using extracted data. Subgroup analysis by ethnicity was also performed. Population attributable risk (PAR) was calculated.  We found a significant association between rs798766[T] and increased risk of bladder cancer, allelic[T] OR = 1.27, 95%CI = 1.20–1.33. Subgroup analysis by ethnicity revealed similar results, allelic[T] OR = 1.24, 95%CI = 1.17–1.32 in Caucasian subjects and allelic[T] OR = 1.33, 95%CI = 1.21–1.46 in Asian subjects. PAR based on pooled allelic ORs and the frequency of the risk allele in control subjects was 4.63% in the overall population and 3.92% in Asians and 4.36% in Caucasians.  rs798766 is associated with increased risk of bladder cancer, and no ethnic difference was found. Urinary bladder cancer (UBC) is one of the most common malignancies worldwide . ClinicaAs revealed in some genome-wide association studies (GWAS) –7, whichThe rs798766 polymorphism is one of the latest found biallelic marker of C/T variation, and the C is the common allele while the T is the risk allele. It is located in the 5th intron of TACC3, 70 kb away from FGFR3. Both the two genes, TACC3 and FGFR3, were reported to have an important role in the transformation of UBC . Thus, iA comprehensive literature search was conducted in EMBASE, PubMed, Google Scholar, and Wanfang Data up to January 2016. “rs798766” and “urinary bladder cancer” were used as the search terms. No limitations of publication language were defined. A reference list of retrieved articles was checked for potential relevant publications.Eligible studies were selected according to the following criteria: (a) the association between rs798766 polymorphism and bladder cancer was evaluated; (b) the study has a case-control design; and (c) adjusted allelic odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were provided. The study with more information was considered where multiple reports based on overlapped population were identified. Reviews, editorials, comments, or animal studies were excluded.Two investigators independently extracted data from the eligible studies. Collected information included the following: name of the first author, year of publication, race of subjects (Caucasian or Asian), genotyping method, total number of cases and controls, frequency of risk allele in controls, Hardy-Weinberg Equilibrium (HWE) status in both cases and controls, study design, and values of ORs and 95% CIs.OR) − ln(LLOR)/2 × 1.96, with ULOR and LLOR representing the upper and lower limits of the 95% confidence interval. Between-study heterogeneity was evaluated using Cochran's Q test and the I2 statistic. No significant heterogeneity was assumed if the P value of Cochran's Q test was not less than 0.1 and I2 statistic not bigger than 50%  was calculated as PAR% = pooled RAFcontrol × (ORpooled − 1)/pooled RAFcontrol × (ORpooled − 1) + 1 × 100%, with pooled RAFcontrol representing the frequency of the risk allele in control subjects and the ORpooled the pooled allelic odds ratio.Risk allele frequency (RAF) among all the controls for Asian, Caucasian, and overall subjects were calculated as the average weighted by control sample size of individual studies, that is, pooled RAFAll the statistical analyses were performed using R 3.1.2 and the analysis package meta.Eight studies were retrieved after initial search , 16–22. The basic characteristics of all the included studies are shown in I2 = 0, P > 0.1 for both), and a fixed-effects model was used. We found a significant association between the frequency of rs798766[T] and increased risk of UBC, with allelic[T] OR = 1.27 and 95%CI = 1.20–1.33. Subgroup analysis by ethnicity revealed similar results, with allelic[T] OR = 1.24 and 95%CI = 1.17–1.32 in Caucasian subjects and allelic[T] OR = 1.33 and 95%CI = 1.21–1.46 in Asian subjects. The forest plot is shown in No significant heterogeneity was detected for both the overall meta-analysis and subgroup analysis .The result of P = 0.37), no evidence of publication bias was found.Since Begg's funnel plot was symmetric  and EggeAs shown in Diseases, particularly complex ones such as UBC, have been considered as a consequence of the interaction between external risk factors and intrinsic susceptibility. In the past decades, epidemiological studies had identified many external risk factors as contributory to the carcinogenesis and progression of UBC –26. On tP values of the association for overall, Asians, and Caucasians were 1.81 × 10–19, 1.45 × 10–9, and 9.58 × 10–12, resp.). Besides, no ethnical difference was found with respect to this issue. The only limitation of our study is a lack of multiplicative risk assessment and cumulative effect of the focused SNP rs798766 together with other most related SNPs and even some external risk factors. This is mainly because of the design or selective result reported in included studies. Yet, it should be emphasized that those results are pretty crucial for an individual. A study exploring the associations between 7 SNPs and risk of UBC demonstrated that individuals with multiple risk alleles had a higher risk of bladder cancer, compared to those with 0–4 risk alleles of 7 variants (P = 3.166 × 10 − 13)  would increase risk of UBC, with substantially increased reliability , and Figueroa et al.  may implicate directly to the regulatory region and enhance the promoter activity of FGFR3, triggering subsequent overexpression of FGFR3 gene which ultimately induces the transformation to tumor. Secondly, the increased frequency of rs798766[T] may accelerate the tumor formation through upregulating the expression of TACC3 which increases the microtubule dynamic stability and massively promotes cell division, possibly enhanced by simultaneously stimulated FGFR3 activation. Thirdly, a possible role of MYC signaling pathways in UBC development has been suggested , 37, andIn summary, this meta-analysis suggests that the TACC3 rs798766 polymorphism is significantly associated with increased risk of urinary bladder cancer. No significant ethnical difference is found in subgroup analysis. However, it is highly recommended to carry out further functional studies to clarify the mechanism behind this association.


Cadmium (Cd) is a pollutant with multiple adverse health effects: cancer, renal dysfunction, osteoporosis and fracture, and cardiovascular disease. Several population-based studies found an association between Cd and diabetes mellitus (DM), but this association is inconsistent with other research. We conducted meta-analysis to examine relationship between urinary/blood Cd exposure and DM risk. Pertinent studies were identified by searching PubMed and Embase databases, and combined odds ratio (OR) and corresponding 95% confidence interval (CI) were applied to evaluate said association. Meta-analysis showed that high U-Cd exposure is not correlated with DM risk , and high B-Cd exposure is also not associated with increased risk of DM  in the general population. Subgroup and sensitivity analysis proved similar results, with little evidence of publication bias. This meta-analysis suggests that high U-Cd/B-Cd exposure may not be risk factor for DM in general populations. However, large prospective studies are needed to confirm this finding. Burden of diabetes is increasing globally. In 2008, 347 million people worldwide suffered from diabetes, and this number is well above earlier estimations from the World Health Organization , 2. The Health problems related to heavy metal exposure caused worldwide concern recently. Cadmium (Cd) is a naturally occurring, non-essential toxic metal and also an industrial and agricultural pollutant . Cd exhiFollowing development of our search strategy, 767 records were initially identified. A total of 191 duplicate studies were excluded, 576 were subsequently screened, and 408 were excluded because titles and abstracts did not fit our criteria. Thirty full-text articles were reviewed for further assessment. Five articles were excluded because they were duplicate publications , 24, 28;n = 9) [n = 9) [n = 6) [n = 6) [n = 4) [n = 3) [n = 2)8,19, hypertension (n = 2) [n = 2) [Table n = 9) , 29, 31, [n = 9) , 29–31 a [n = 6) , 27, 31, [n = 6) , 27, 31, [n = 4) , 23, 27  [n = 3) , 29, 30, [n = 2) , 27. NonIncluded studies generally showed good methodological quality. Newcastle–Ottawa Scale (NOS) scores ranged from 5 to 7 Table . Mean NOfor heterogeneity= 0.001, I2 = 73.2%)    = 1.19; 95% confidence interval CI = 0.83–1.71) for the highest category of Cd exposure compared with lowest category with significant heterogeneity (P) Figure . In sensi et al. ) to 1.373–1.71 fofor heterogeneity= 0.011, I2 = 69.2%)   (excluding the study by Moon [Five studies examined the association of B-Cd concentration with risk of DM. The summary OR was 1.16 times (odds ratio (OR) = 1.16; 95% confidence interval (CI = 0.84–1.62) for the highest category of Cd exposure compared with lowest category with low heterogeneity (Pdy by Li ) to 1.26P = 0.368) and Begg rank correlation tests (P = 0.446). Funnel plot symmetry  data, urine Cd was positively associated with diabetes [Cd is an ubiquitous industrial and naturally occurring environmental contaminant resulting from anthropogenic activity; it poses toxic effects on lungs, liver, testicles, kidneys, and bone tissues . Recentl animals , 53. Sig animals –29. Usindiabetes , 15, butdiabetes . In a crdiabetes  but not diabetes . In a cadiabetes . No statdiabetes –24. Howediabetes . In thrediabetes  but corrdiabetes . The mosdiabetes . HoweverIn this meta-analysis, we analyzed associations between urinary/blood Cd exposure and DM risk. The present study is the first to provide comprehensive insights into effects of Cd exposure and DM-associated risks. Using random-effects model, 10 observational studies were included, and overall results proved that high Cd exposure is not associated with increased DM risk among the general population.Results from subgroup analyses indicated potential sources of heterogeneity; these sources include geographic region, study design, NOS scale quality, gender, adjusted confounders or important risk factors, and method of Cd assessment. Despite intrinsic limitations of observational studies, subgroup analysis provided notable results. When stratified by gender, association remained nonsignificant for both male and female. Cd concentrations in urine and whole blood are the most common biomarkers for Cd exposure. Therefore, in kidneys, urinary Cd mainly reflects Cd accumulation, which is determined by long-term exposure, whereas whole blood Cd demonstrates combined current and historical exposures. In subgroup analysis results, which were stratified using Cd exposure assessment, both urinary and blood Cd are not associated with increased DM risk. In epidemiological studies, the most common biomarker for Cd exposure may be urinary Cd. However, using urinary or blood Cd levels limits measurement of Cd exposure. Internal or absorbed dose of Cd in renal cortex is higher than that of blood or urine Cd levels in measuring low-level and long-term Cd exposure, because Cd concentration in renal cortex accurately represents lifelong Cd exposure , 57. HowDevelopment of DM represents interaction of environmental exposures, lifestyle factors, and genetic predisposition. Pathogenesis of both diseases can be considered a continuum of dysglycemia with development of impaired insulin secretion and insulin resistance as common pathogenic link. Human tissue sample studies indicated that Cd may preferentially accumulate in pancreatic islets . MechaniThe present meta-analysis exhibited several strengths. First, this study was the first to investigate association between Cd exposure and DM risk. Second, large sample size improved risk estimate accuracy and resulted in well-founded conclusions based on meta-analysis. Pooled estimates were robust across sensitivity and subgroup analyses, and publication bias was not detected. Conclusions from combined estimates were more reliable than from single studies because overall OR was based on large sample size and exhibited sufficient power.Nevertheless, some limitations should be considered in the present meta-analysis. First, almost all related previous studies were cross-sectional or retrospective, except for four prospective studies. Cross-sectional and case-control studies have inherent limitations, such as selective bias and recall or memory bias. Therefore, large prospective studies are needed to confirm such findings. Second, evidence from epidemiological studies indicated that Cd may exacerbate harmful renal effects of diabetes. However, owing to numerous other confounding environmental factors inherent in these epidemiological studies, difficulty arises from establishing cause-and-effect relationships. For example, increased probability of individuals becoming diabetic can be attributed to other environmental toxins, such as arsenic , 62 and In summary, the meta-analysis suggests that high Cd exposure may not be risk factor for DM in the general population. Further prospective studies should be conducted to determine possible association between low-level Cd exposure of general populations and increased risk of DM.Literature search was performed in April 2017 without any limitations. Primary sources were electronic databases of PubMed and EMBASE. To identify eligible studies, main searches employed various combinations of Medical Subject Headings (MeSH) and non-MeSH terms: “diabetes mellitus” OR “diabetes” combined with “cadmium”. Reference lists of all studies and published systematic reviews and meta-analyses were screened to identify other potentially eligible studies. Main search was completed independently by investigators. Discrepancies were solved by consulting a researcher who was not involved in initial procedures.Studies were considered eligible for inclusion in meta-analysis when they met the following criteria: (1) exposure of interest was urinary/blood Cd; (2) outcome of interest was DM risk; (3) study design was cohort, case control, or cross-sectional study; (4) RR, OR, or hazard risk (HR) with corresponding 95% CI were reported or provided sufficient data to estimate crude OR, RR, or HR values with corresponding 95% CI. When included population was duplicated in more than one study, only the study with most comprehensive information was included.Two reviewers extracted data independently using predefined data extraction form. Data included the following: first author, publication year, study design, country, total number of cases and subjects, sex, Cd exposure type, and diagnosis criteria for DM and adjusted variables. Adjusted OR was extracted as preference over non-adjusted OR. Unadjusted OR and CI were calculated whenever OR was not provided. When more than one adjusted OR was reported, the ratio with most number of adjusted variables was selected. Disagreements between authors (JKS and XHY) were resolved through discussion and consensus.Methodological quality of included studies was assessed using NOS , which cI2 was used to assess heterogeneity across studies, with I2 values of 0%, 25%, 50%, and 75% representing no, low, moderate, and high heterogeneities, respectively. Sensitivity analysis was conducted to evaluate data robustness and stability by sequentially omitting one study on each turn. Subgroup analysis was stratified using study design, geographic region, gender, exposure type, adjustment for covariates, and NOS quality.We used OR with 95% CI as common measure across all studies. Cd-caused DM is a rare event. Therefore, in the cohort study, RR and HR were considered OR approximations. Two articles did not report overall risk estimates but instead separately presented results for men and women , 23. We P < 0.10. All statistical analyses were conducted using Stata version 13.1 .Consistent with publication bias, small study bias was evaluated using statistical tests (Begg rank correlation test  and Egge


TNF) -308 G>A (rs1800629) gene polymorphism isimplicated in the susceptibility to leprosy, but results were inconsistent.Purpose: Earlier studies have shown that tumor necrosis factor(TNF -308G>A polymorphism with leprosy using MEDLINE (PUBMED), EMBASE, and GoogleScholar web databases.Methods: A meta-analysis of 14 studies involving 3327 leprosy cases and 3203controls was performed to appraise the association of P=0.068; OR = 0.836, 95% CI =0.689–1.013), homozygous , heterozygous , dominant , and recessive  genetic models. Subgroup analysis showed noassociation in Asians. Whereas, reduced risk was found in allelic contrast  and dominant models  of the mixed population.Results: Overall, no significant association was observed in allelic (A vs. G:TNF -308 G>A polymorphism is not associatedwith leprosy risk in the overall population. However, subgroup analysisdemonstrated protective effect of the said polymorphism in leprosy risk in theLatin American population, but showed no association in the Asians.Conclusions:  Mycobacterium leprae  is a pleiotropic cytokine that produced as a part of thehost defense against the infection. TNF gene comprises of fourexons with three intervening introns map between the majorhistocompatibility complex (MHC) class I and IIregions on the short arm of chromosome 6. TNF plays a significantrole in the control of mycobacterial growth and spread through the activation ofmacrophages, granulomas formation, and in the orchestration of the cellular immuneresponse [TNF in response to the infection of M. leprae.Also, a previous study of TNF knockout mice showed thatTNF is indispensable for the resistance in infectious disease[TNF-α locus andhave shown to influence the rate of transcription and protein production ofTNF and their association with various infectious diseases[TNF gene has been much more considered than anyother loci (i.e. -238 and -863) in correlation with the outcomes of infectiousdisease manifestation [TNF1 allele has a guanine (G) residue, whereas the less commonTNF2 allele has an adenine (A) at position -308. Invitro studies with human peripheral blood monocytes have decipheredthat the TNF2 allele, whether homozygous or heterozygous, is linkedwith a higher production of TNF [response . Thus, idiseases. The locestation . The mor i.e. -23 and -863TNF in the severity ofclinical manifestation of various infectious diseases, including leprosy, it isimportant to explore its precise role in the development of leprosy. To date,numerous case–control studies have been done to appraise the relationshipbetween the TNF -308 G>A gene polymorphism and risk ofleprosy susceptibility, but results from those studies yielded inconsistent andconflicting outcomes. Still, it is unclear whether this polymorphism is associatedwith increased or decreased susceptibility to leprosy infection [After knowing the clinical significance of nfection –22.TNF -308 (rs1800629) polymorphism as a genetic risk factor forleprosy.A recent study of Oliveira et al.  alsorepTNF gene and leprosy risk. Meta-analysis is a statistical toolthat is mainly used to explore the risk factors associated with the geneticdiseases, as it employs a quantitative method to combine the data drawn fromindividual studies, where the sample sizes are too small to provide reliableconclusions.Generally, the inconsistency in the results across many of the studies could possiblybe related to the ethnicity of the population, sample size, and individual studiesthat have low power to evaluate the overall effect. Hence, in the light ofabove-mentioned contradictory findings from other researchers and theirrecommendations ,15, and TNFA OR TNF-α ORTNF gene (polymorphism OR variant OR mutation) AND leprosysusceptibility OR risk . We examined potentiallyrelevant genetic association studies by inspecting their titles and abstracts,and obtained the most pertinent publication matching with the above said preseteligibility criteria for a closer examination. In addition to the onlinedatabase search, the references given in the retrieved research articles werealso screened for other potentially relevant articles that may have beenoverlooked in the preliminary search.We performed a PubMed (Medline), Google Scholar, and EMBASE online web databasesearch covering all research studies published with a combination of thefollowing key words: i.e. tumor necrosis factor OR tumor necrosis factor-alphaOR TNF-308 G>A genepolymorphism and leprosy risk; (b) clearly described confirmed leprosy patientsand leprosy disease free controls; (c) have available genotype frequency in boththe cases and the controls; (d) published in the English language; (e) datacollection and analysis methodology must be statistically acceptable. Inaddition to above, when the case–control study was included in more thanone research article using the same set of case series, we selected the researchstudy that incorporated the largest number of the individuals. The major reasonsfor study exclusion were: (a) duplicate or overlapping publication, (b) studydesign based on only leprosy cases, (c) genotype frequency not reported, and (d)the data of review or abstract.In order to reduce heterogeneity and facilitate the apt interpretation of thepresent study, the published reports included in the present meta-analysis hadto meet all the below given criteria: i.e. (a) they must have donecase–control studies between For each retrieved study, the procedural quality assessment and data extractionwere independently summarized in duplicate copies by the two independentinvestigators (SAD & RKM) following a standard protocol. During the dataextraction process, data-collection form was used to ensure the accuracy of thecollected data by stringently following the preset inclusion/exclusion criteriaas mentioned above, and sequential exclusion of the unsuitable studies. In caseof disagreement between the above-mentioned two investigators on any itemrelated with the data collected from the selected studies, the issue was fullydebated and deliberated with the investigators to attain a final consensus.Also, in case failure of reaching consensus between the two investigators, anagreement was achieved following an open discussion with the adjudicator (SH).The main characteristics abstracted from the retrieved publications comprise thename of the first author, the country of origin, publication year, number ofcases and controls, source of cases and controls, study type, genotypefrequencies, and association with leprosy.Methodological quality evaluation of the selected studies was performedindependently by two investigators (RKM & SAD) by following theNewcastle–Ottawa Scale (NOS) of quality assessment . The NOSTNF -308G>A gene polymorphism and susceptibility to leprosy risk, pooled ORs andtheir corresponding 95% CIs were estimated. Heterogeneity assumption wasdetermined by the chi-square-based Q-test [P-value < 0.05. The collected data fromsingle comparison was combined using a fixed effects model [I2statistics was used to quantify the interstudy variability and larger valuesindicated an increasing degree of heterogeneity [t-test. Also, ethnicity was adopted toperform the subgroup stratified analysis, when data were available. Acomparative assessment of ‘meta-analysis’ software programs wasdone by using the link: http://www.meta-analysis.com/pages/comparisons.html, and finallythe Comprehensive Meta-Analysis (CMA) software program Version 2., from Biostat(NJ), U.S.A. was used to perform all the statistical investigations involved inthis pooled analysis.In order to appraise the association between the d Q-test . Heterogts model , when nots model  wasemplogeneity . Hardy–WTNFα gene polymorphism to predictsurvival in leprosy patients or considering leprosy variants as indicators forresponse to therapy were excluded straightaway. Likewise, research studiesevaluating the levels of TNF mRNA or protein expression orgermane review articles were also disqualified from this meta-analysis. For thispooled study, only case–control or cohort design studies were includedstating the frequency of all the three genotypes. In addition to the online webdatabase search, the supporting references listed in the retrieved articles werealso reviewed for other potential case–control studies. After cautiousscreening and following the stringent inclusion and exclusion criteria, 14eligible original publications were finally considered for this meta-analysis, EMBASE, and Google Scholar online web-based databases.All the retrieved publications were scrutinized carefully by reading theirtitles and abstracts, and the full-texts for the potentially relevantpublications were further checked for their suitability for this meta-analysis. Researcanalysis. The disBegg’s funnel plot and Egger’s test were done to observe thepublication bias among the selected case–control studies for the presentmeta-analysis. As depicted in Q-test andI2 statistics. Substantial heterogeneity wasfound in three genetic models . Thus,random and fixed effects models were applied to synthesize the data , homozygous , heterozygous , dominant , and recessive  genetic models  onthe relationship between P=0.891; OR = 0.960, 95% CI= 0.535–1.723), homozygous model , heterozygous model , dominant model , and recessive model  population. During the analysis, no publication bias was detected; whereas,significant heterogeneity was observed in three genetic models  (Supplem9–2.508) .P=0.014; OR = 0.832,95% CI = 0.718–0.963) and dominant genetic model . Whereas, remaining three genetic models, i.e.homozygous , heterozygous , and recessive  genetic models showed no association with increased ordecreased risk of leprosy  population. During the analysis, nopublication bias was observed but heterogeneity was found in one model   gene based case–controlstudies are inconsistent in relation with leprosy risk. Some clinicalcase–control studies have found positive association while others havereported negative. Majorly, the results of the studies generated could be ofinadequate statistical power due to individual studies with small sample sizes orvariations that existed in different populations. Therefore, larger sample size withpooled analysis and subgroup analysis is required to evaluate the potential role ofTNF -308 G>A polymorphism as a genetic risk factor forleprosy infection. Pooled ORs generated from large sample size and sufficientstatistical power from different studies have the advantage of minimizing the randomerrors [P-value toappraise the precise association between the TNF -308 G>Apolymorphism and leprosy risk. Most of the included studies scored five or morestars in NOS quality assessment and suggested good to moderate quality by clearlystating about the sample size, genotype, inclusion criteria of leprosy patients, andhealthy controls. Interestingly, we found no association between theTNF -308 G>A polymorphism and leprosy susceptibilityunder any genetic models in overall population analysis. Based upon the findings, wecan speculate that the numerous polymorphic sites (in the promoter and the codingregions of TNF gene) might serve to keep this gene under tightcontrol and influence the expression of TNF. Thus, some haplotypecombinations might be conserved in the certain population to protect againstpathogens and others to control expression. Also, gene reporter assay study reportedthat A allele of -308 polymorphism does not influence TNF genetranscription [TNF production [TNF mRNA in peripheralblood total leukocytes of leprosy patients [Cytokine polymorphism has been considered to be of playing significant role in hostgenetic factors of leprosy. Both, pression . Despitemerrors . Circa, cription . Other soduction ,35. Recepatients .TNF production, which might be protective against leprosy amongLatin American population but not in Asian population. However, more studies ofMexican and Brazilian population should be taken into the meta-analysis to furtherconfirm our results.In the subgroup analysis, no significant association was observed in the Asianpopulation. As the Asian subgroup is possibly diverse genetically, thus colony basedanalysis is needed for more precise conclusion. Whereas, protective association wasobserved in the Latin American population. These findings suggest that there couldbe an interaction of -308 G>A polymorphism and the level ofTNF -308 G>A genepolymorphism and leprosy risk. As a limitation, the meta-analysis of Cardoso et al.included only seven studies and did not examine Asian population. In addition, themeta-analysis presented by Cardoso et al. [Previous meta-analysis by Cardoso et al. also fouo et al. , only evTNF -308G>A genetic polymorphism cannot be solely responsible for the predispositionof leprosy and may this polymorphism interacts with other polymorphisms present inlinkage disequilibrium of this gene to cause risk.Earlier findings suggest that susceptibility toward leprosy is polygenic in natureand possibly multiple candidate genes are involved in determining the resistance orsusceptibility to leprosy. Hence, because of the multifactorial nature of leprosyinfection and complex nature of the immune system, In addition to the above-mentioned improvements, there are certain limitations of thepresent study that needs to be addressed in future studies with larger sample size.First, significant heterogeneity was observed in some of the genetic models, whenall the studies were included. In subgroup analysis, heterogeneity was much lower inthe Latin American population suggesting that ethnic-specific genetic variationmight be the key factor responsible for heterogeneity. Second, studies published inthe English language and abstracted and indexed by the selected  electronic databases for the data analysis; it ispossible that some relevant studies might publish in languages other than theEnglish or indexed in other electronic databases, may have missed. Third, theabstracted data from the included studies were not stratified by severity of theleprosy infection, and the current results are based on unadjusted parameters.Fourth, authors fail to test the gene–environment interactions due ofinadequate information available in the primary published studies included in thepresent analysis.Despite above limitations, this pooled study has some advantages over previousstudies. First, this meta-analysis included larger number of studies to enhance thestatistical power of the study which provided enough powerful evidence to reach onprecise and robust conclusion. Second, no publication bias was detected and furthersensitivity analysis also supported the reliability of our results. Also, all theincluded studies were of good to modest quality fulfilling the preset needfulcriteria as tested by NOS quality assessment scale.TNF -308 G>A gene polymorphism as a significantbiomarker for leprosy susceptibility in the overall population. However, asignificant protective association was observed in allele and dominant models ofLatin American population, but not in Asian population. As TNFplays a significant role in immune response against M. leprae,further larger well-designed case–control studies are warranted to supportand conclude our current findings. Overall, the present study would greatly aid forcomprehensive understanding of the link between the TNF -308G>A polymorphism and leprosy risk globally.In conclusion, this meta-analysis did not demonstrate powerful evidence to identify


Recently, growing evidence has revealed a significant association between Parkinson’s disease (PD) and cancer. However, controversy still exists concerning the association between PD and prostate cancer. A comprehensive article search for relevant published studies was performed using the online databases PubMed, Web of Science and Embase up to January 1, 2017. The pooled risk ratios (RRs) and their 95% confidence intervals (CIs) were calculated using the method of inverse variance with a random-effects model. Fifteen studies comprising 346,153 PD patients were included in this study. The results of the present study showed that PD was significantly associated with a decreased risk of prostate cancer in the Western population , while an increased risk of prostate cancer was shown in the Asian population . In the subgroup analysis, the reduced risk of prostate cancer in PD patients from Western populations was consistent regardless of study design or study quality. In conclusion, PD was significantly associated with a reduced risk of prostate cancer in the Western population. The relationship between those conditions in the Asian population needs to be confirmed by future studies. Resting tremor, rigidity, hypokinesia, and postural instability are considered the four cardinal motor symptoms of PD, resulting from the loss of dopaminergic neurons in the substantia nigra pars compacta2. However, the pathogenesis of PD is not yet fully understood.Parkinson’s disease (PD) is the second most common neurodegenerative disorder in the world, with a prevalence of 1% in the population over 60 years old3. It has been noted that cancer rates are lower in patients with Parkinson’s disease than in the general population, and PD has different relationships with the risk of different cancers4. For instance, Wang et al.5 reported a lack of association between PD and prostate cancer in a previous meta-analysis. However, its conclusions were not very convincing owing to the relatively small sample size, limited number of studies and duplicate population of some included studies. Controversy still exists regarding the relationship between PD and prostate cancer. Lately, some articles have reported that patients with PD have a decreased risk of prostate cancer7, while some have found no significant negative association between them9, and some even hold the opposite opinion and indicate that an increased risk of prostate cancer could be observed among people with PD10. On the other hand, there is some potential evidence to link PD to prostate cancer. The most commonly used medications for Parkinson’s disease are levodopa, dopamine agonists and anticholinergics11, which all affect neurotransmitter activity, and it is possible that these treatments may affect tumor occurrence.In recent years, accumulating epidemiological and clinical studies have reported the relationship between PD and cancer, lighting the way to explore the potential common pathogenic pathway involved in both diseasesIndeed, differences in characteristics such as ethnicity, study design, PD diagnosis time and PD treatment have led to discrepancies in estimates of the association between Parkinson’s disease and risk of prostate cancer. Therefore, we conducted this meta-analysis to provide a quantitative assessment of current epidemiological evidence on the association between PD and risk of prostate cancer in different subgroups and explore the potential factors which can affect the association.21 . The baseline characteristics of each study are shown in Table 2 = 92%, Fig. The result of 10 cohort studies and 5 case-control studies indicated that the pooled RR of prostate cancer in PD patients versus control patients was 0.88 , but it could not be found in the “before PD” group  AND (prostate cancer or prostate cancers or prostate neoplasm or prostate neoplasms or prostate carcinoma or prostate carcinomas)” were used to search for relevant studies published up to January 1, 2017. Moreover, the references of relevant reviews and included articles were also carefully reviewed to identify additional studies that might be suitable for inclusion.36) were identified, only the most informative study was included21. Case reports and abstracts from meetings were excluded.The eligible studies were included in our meta-analysis on the basis of the following criteria: (1) the study was a cohort and/or case-control study evaluating the relationship between PD and risk of prostate cancer; (2) an estimate of association  with measures of variation  was provided; (3) the study was published in English. When duplicated studies , publication year, patient information , ethnicity, follow-up time in years and outcome of interest. The Newcastle-Ottawa scale (NOS) was used to assess the quality of the included studies38. In addition, studies with NOS scores >6 were considered high-quality studies (Table Data from each study were extracted independently by two authors (Chunli Chen and Haiping Zheng) according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelineses Table .2 statistic39. Begg’s and Egger’s tests were used to evaluate the effect of publication bias41. Cumulative meta-analysis was used to assess the evolution of the combined RR in relation to the year of publication42. STATA software  was used to perform the data analyses in this study. A result was considered statistically significant when its P value was less than 0.05.The pooled RRs and their 95% confidence intervals (CI) were calculated using the method of inverse variance with a random-effects model. Statistical heterogeneity was evaluated using Cochran’s Q test and IIn summary, the result of this study indicated that PD was significantly associated with a reduced risk of prostate cancer in the Western population. Future studies are warranted to confirm the association between those two conditions in the Asian population.Supplementary Information for Association between Parkinson's disease and risk of prostate cancer in different populations: An updated meta-analysis


CYP4F2 (Cytochrome P450 Family 4 Subfamily F Member 2) polymorphisms and the susceptibility to cardiovascular and cerebrovascular diseases.Inconsistent conclusions have been reported for the genetic relationship between CYP4F2 in the risks of cardiovascular and cerebrovascular diseases. The retrieval of four databases, including PubMed, Web of Science (WOS), China National Knowledge Infrastructure (CNKI) and WANFANG DATA, was conducted. Mantel-Haenszel statistics for association test, Cochran’s Q statistic, sensitivity analysis for heterogeneity assessment, and Begg’s/Egger’s tests for publication bias evaluation were performed under allele, homozygote, heterozygote, dominant, and recessive models, respectively.We performed a meta-analysis to assess the potential role of rs1558139 C/T and rs2108622 G/A polymorphisms of P values in association tests < 0.05, odds ratio (OR) < 1]. For rs2108622, a decreased coronary artery disease (CAD) risk was observed in the subgroup meta-analysis based on disease type under all genetic models . Begg’s/Egger’s tests excluded the potential publication bias, while sensitivity analysis data supported the stability of the above results.A total of 597 articles were initially obtained by database searching, and twenty eligible articles were finally included. For rs1558139, a decreased risk of cardiovascular and cerebrovascular diseases was observed in the overall meta-analysis and in “hypertension”, “population-based” and “male” subgroups under models of T vs. C, CT vs. CC, and CT + TT vs. CC [all CYP4AF2 rs1558139 may be linked to the decreased risk of hypertension in the male patients of Asian populations, while CYP4F2 rs2108622 is likely associated with reduced susceptibility to CAD.C/T genotype of The online version of this article (10.1186/s12872-018-0763-y) contains supplementary material, which is available to authorized users. CYP17A1 (Cytochrome P450 Family 17 Subfamily A Member 1) gene or rs2681492 of the ATP2B1 (ATPase Plasma Membrane Ca2+ Transporting 1) gene, are associated with susceptibility to blood pressure or essential hypertension [CYP4F2 (Cytochrome P450 Family 4 Subfamily F Member 2) polymorphism in the risk of cardiovascular and cerebrovascular diseases, such as myocardial infarction (MI), coronary artery disease (CAD), ischemic stroke (IS), cerebral infarction (CI) and hypertension.Single nucleotide change-induced nucleic acid sequence polymorphisms, namely, single nucleotide polymorphisms (SNPs), occur more frequently in the human genome, with an average of approximately one polymorphism per 1000 bases, and functional SNPs may help to guide population genetics research, as well as the mechanistic, epidemiologic or diagnostic study of some clinical genetic diseases . EmerginCYP4F2 gene is located on chromosome 19 and contains 12 introns and 13 exons [CYP4F2 gene, while rs2108622  is located in the exon region of this gene [Human 13 exons . There a13 exons , 9. The his gene . IncreasCYP4F2 SNPs and the risk of cardiovascular and cerebrovascular diseases via meta-analysis based on the publicly published data. To our knowledge, one meta-analysis of hypertension [CYP4F2 rs2108622. However, no meta-analysis for the other SNPs of the CYP4F2 gene have been reported. Additionally, there is no meta-analysis regarding the role of CYP4F2 rs2108622 in the risk other cardiovascular and cerebrovascular diseases.Considering the conflicting conclusions, we quantitatively measured the genetic correlation between rtension  and anotrtension  were preIn accordance with the methodology of “Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)” , we perfCYP4F2 gene in each case/control group. The following exclusion criteria were considered: a) animal or cell experiments; b) other genes/diseases or non-SNP gene variants; c) meeting abstract; d) meta-analysis; e) review or letter; f) undetected variants; g) the absence of genotype frequency data; h) duplicated articles; and i) not in HWE (Hardy-Weinberg-Equilibrium).After screening, eligible case-control studies provided the sufficient genotype frequency data of 2 and P values of HWE, and source of control. The paper quality was assessed by the Newcastle-Ottawa Scale (NOS) system [We extracted the basic information from the eligible articles, namely, first author, year, ethnicity, genotyping assay, SNPs, genotype frequency, disease type, gender, mean age, study number, sample size of the case/control, X) system , which iP value of association test was generated under the allele, homozygote, heterozygote, dominant, and recessive models. A fixed-effect model was used when the P value of heterogeneity from Cochran’s Q statistic was larger than 0.05 or I2 less than 50.0%. Subgroup meta-analyses by ethnicity (Caucasian/Asian), disease type (hypertension/CAD/IS/CI/MI), source of control , and gender , were also conducted through Mantel-Haenszel statistics. For publication bias assessment, Begg’s/Egger’s tests were performed. Stata/SE software version 12.0  was used for the above statistical analyses.Based on Mantel-Haenszel statistics, the value of OR (odds ratio), 95% CIs  and CYP4F2 gene (rs1558139 C/T and rs2108622 G/A) were analyzed. The NOS system data suggested that no included studies showed poor quality, as all NOS scores were larger than five , and fixed-effect model was applied. In pooled data from overall meta-analysis . Moreover, similar results were observed under allele, heterozygote and dominant genetic models in “hypertension” and “population-based” subgroups . We also performed a subgroup analysis based on gender. As shown in Additional file P value in association tests < 0.001, OR = 0.79), homozygote , heterozygote  and dominant  genetic models. Figure CYP4AF2 rs1558139 might be associated with a reduced risk of hypertension in the male patients of Asian populations.We first conducted a meta-analysis to analyze the association between CYP4AF2 rs2108622 G/A polymorphism and the risk of cardiovascular and cerebrovascular diseases was subsequently performed. A total of 17 case-control studies were enrolled [P value of heterogeneity < 0.05). A decreased CAD risk was observed in the subgroup meta-analysis by disease type under all genetic models . However, no significant associations were observed for other factors , suggesting the absence of large publication bias. Fig. CYP4AF2 rs2108622 G/A polymorphism. Furthermore, we observed the stability of the above data based on the sensitivity analysis , partly by CYP4F2 protein, 20-HETE induces the transcription of ACE (angiotensin-converting enzyme) gene through stimulating the NF-ΚB pathway and contributes to the pathophysiology of hypertension [CYP4AF2 rs1558139, located in an intron region, likely affects the enzyme activity of CYP4F2 protein during 20-HETE metabolism through altering the gene transcription level, RNA secondary structure or RNA splicing of the CYP4AF2 gene, which is worth further investigation of the molecular mechanism. In addition, CYP4F2 rs2108622 was tightly associated with systolic blood pressure as well as the excretion of 20-HETE [CYP4F2 rs2108622 in hypertension risk.in India  or Northin India . Howeverin India . In 2015in India , 23, 32 ion risk . Here, eion risk , 29, 32 CYP4AF2 gene rs2108622 polymorphism was associated with the risk of coronary artery disease in a Han Chinese population [CYP4AF2 rs2108622 and coronary heart disease risk was reported in Mongolian cases in China [CYP4AF2 rs2108622 polymorphism is likely associated with the reduced susceptibility to coronary artery disease. Here, the meta-analysis provided evidence of the involvement of CYP4AF2 rs2108622 in susceptibility to coronary heart disease. Given the reported correlation between CYP4AF2 rs2108622 and 20-HETE [CYP4AF2 rs2108622 may mediate the nonsynonymous mutation of a valine (V) located at residue 433 to a methionine (M), namely, V433 M, which then leads to the alteration of CYP4F2 protein function and 20-HETE synthesis, thereby influencing the occurrence of coronary heart disease.Coronary heart disease results from the interplay between polygenic predisposition and complex environmental factors . The CYPpulation . Howeverin China . In the  20-HETE , functioCYP4AF2 SNPs and ischemic stroke risk. For example, no detectable difference was reported by Liao, et al. for the genotype distribution of CYP4AF2 rs2108622 between the control and cases of ischemic stroke [CYP4AF2 rs2108622 SNP as an important risk factor for ischemic stroke in an Indian population [P < 0.0001 [CYP4AF2 gene rs2108622 polymorphism. Different searches and analysis strategies might contribute to this finding.The early evaluation of genetic risk factors is essential for the effective diagnosis and treatment of clinical ischemic stroke , 37. We c stroke . Howeverpulation . In 2015pulation , enrollipulation , 30, 38,< 0.0001 . In the < 0.0001 , and fin< 0.0001 , 26, 30 CYP4AF2 rs1558139 C/T polymorphism and risk of cardiovascular and cerebrovascular diseases was obtained under allele, heterozygote and dominant genetic models. In addition, sensitivity analysis indicated the stability of the statistical results. Nevertheless, the small sample size of the included case-control studies, to a certain extent, limits the statistical power. Limited data were extracted for the CYP4AF2 rs1558139 C/T polymorphism subgroup with the diseases of ischemic stroke or myocardial infarction.We found that not all control data in these studies were population-based. After removing studies with hospital-based control data, the same positive correlation between the CYP4AF2 rs1558139 polymorphism, high heterogeneity was observed in most of the overall meta-analyses of CYP4AF2 rs2108622. Apart from coronary heart disease and hypertension subgroup analyses, high heterogeneity still existed in other “Asian”, “ischemic stroke” and “population-based” subgroups. The complexity of disease feature might be the source of the large publication bias. In addition, unpublished data or articles in other languages may bias the selection of the studies analyzed.Although no high degree of heterogeneity was observed in all meta-analyses of the CYP4AF2 rs1558139 and hypertension risk, while six studies [CYP4F2 rs2108622.Given the complicated etiologies in different types of cardiovascular and cerebrovascular diseases , 39, add studies , 27, 32 CYP4F2 gene, such as rs3093100, rs3093105, rs3093166, and rs3093135. The “G/G/G/T” haplotype of rs2108622-rs3093100-rs3093105-rs3093135 has been associated with an increased risk of coronary artery disease, however the “G/G/T/A” haplotype was associated with a reduced risk of coronary heart disease [CYP4F2 and other genes, such as CYP4A11 (Cytochrome P450 Family 4 Subfamily A Member 11), should be analyzed upon the publication of sufficient data.Adequate data on the genotype frequencies of both case and control studies are necessary to conduct SNP meta-analyses or subgroup analyses. Thus, only two SNPs  were studied in the present meta-analysis based on the available data. We did not examine the role of other variants within the CYP4AF2 rs1558139 polymorphism might serve as a protective factor for male patients with hypertension in Asian populations, and CYP4AF2 rs2108622 may confer reduced genetic susceptibility to coronary heart disease.Overall, the C/T genotype of the Additional file 1: Table S1-S7.Table S1. Details of the search strategy based on four databases. Table S2. Basic information of the eligible studies in the meta-analysis. Table S3. Data of NOS assessment system. Table S4. Genotype frequencies of the eligible studies in the meta-analysis. Table S5. Genotype frequencies of the male/female group in some eligible studies. Table S6. Subgroup analysis by gender for the association between CYP4AF2 rs1558139 and hypertension risk. Table S7. Subgroup analysis by gender for the association between CYP4AF2 rs2108622 and hypertension risk. (DOCX 63 kb)Additional file 2: Figure S1.CYP4AF2 rs1558139 polymorphism and the risk of cardiovascular and cerebrovascular diseases under the allele (T vs. C) model.. (TIFF 887 kb)Subgroup analysis by disease type of the association between the Additional file 3: Figure S2.CYP4AF2 rs1558139 polymorphism and the risk of cardiovascular and cerebrovascular diseases under the dominant (CT + TT vs. CC) model. (TIFF 967 kb)Subgroup analysis by disease type of the association between the Additional file 4: Figure S3.CYP4AF2 rs1558139 polymorphism and the risk of cardiovascular and cerebrovascular diseases under the allele (T vs. C) model. (TIFF 1958 kb)Subgroup analysis by gender of the association between the Additional file 5: Figure S4.CYP4AF2 rs2108622 polymorphism and the risk of cardiovascular and cerebrovascular diseases under the homozygote (AA vs. GG) model. (TIFF 1760 kb)Subgroup analysis by disease type of the association between the Additional file 6: Figure S5.CYP4AF2 rs2108622 polymorphism and the risk of cardiovascular and cerebrovascular diseases under the heterozygote (GA vs. GG) model. (TIFF 1717 kb)Subgroup analysis by disease type of the association between the Additional file 7: Figure S6.CYP4AF2 rs2108622 polymorphism and the risk of cardiovascular and cerebrovascular diseases under the dominant (GA + AA vs. GG) model. (TIFF 1689 kb)Subgroup analysis by disease type of the association between the Additional file 8: Figure S7.CYP4AF2 rs2108622 polymorphism and the risk of cardiovascular and cerebrovascular diseases under the recessive (AA vs. GG + GA) model. (TIFF 1792 kb)Subgroup analysis by disease type of the association between the Additional file 9: Figure S8.CYP4AF2 rs2108622 polymorphism and the risk of cardiovascular and cerebrovascular diseases under the allele (A vs. G) model. (TIFF 1045 kb)Subgroup analysis by gender of the association between the