Two case-control studies and four cohort studies met the entry requirements in this analysis. The summary odd ratio (OR) were estimated by a random effect model. The overall OR was 1.76 . The OR of case-control studies was 3.41  and that of cohort studies was1.53 . The association between TF-bearing MPs and the risk of VTE in cancer patients was found in this meta-analysis. Publication bias testing and sensitivity subgroup analysis suggested that results of this meta-analysis were robustness. In conclusion, TF-bearing MPs were associated with increased risk of VTE in patients with cancer. Whereas, more well-designed studies and more comprehensive adjustments for confounders in further studies are warranted to affirm the association.Cancer patients with Tissue Factor (TF)-bearing MPs have been presented association with increased risk of venous thromboembolism (VTE), but results of these studies have not been consistent. We aimed to conduct a meta-analysis to assess the relationship between TF-bearing MPs and risk of VTE in patients with cancer. PubMed, Web of Science and EMBASE Databases were systematically retrieved up to1 The rate of VTE is reported in pancreatic cancer 5.3–26%, brain cancer 1.6–26%, gastric cancer 10–15%, lung cancer 1.6–13.6%, and colorectal cancer 3.1–10.2%4. Although cancer is a known hypercoagulable state with an increased predisposition to VTE, the pathogenesis is rather unclear6. Tissue factor (TF) has been considered a crucial role in the cancer VTE, especially the expression of TF on microparticles (MPs) which were released from tumor cells in the circulating blood9. TF is a main initiator of extrinsic coagulation pathway in vivo. MPs are small (<1 μm) membrane vesicles, whose phospholipid surface can assemble coagulation factors, resulting in procoagulant potential8. The high level of TF-bearing MPs was detected in cancer patients with VTE11, suggesting that TF- bearing MPs maybe play a role in the development of the cancer VTE.VTE is the most commonly complication in patients with cancer15. Anubha, et al.12 studied 117 cancer patients including pancreatic, biliary and pancreaticobiliary cancers. The results showed that elevated TF-bearing MPs activity was associated with VTE. The study of Sartori, et al.14 showed that TF-bearing MPs was also associated with glioblastoma multiforme patients with VTE. However, there have been some studies which show no significant associations were found between elevated TF-bearing MPs and cancer patients with VTE16. Bucciarelli, et al.16 studied 186 cancer patients compared with controls. The results suggested that there was no association between the high levels of TF-bearing MPs and cancer patients with VTE. Therefore, we conducted the meta-analysis to systematically assess the relationship between TF-bearing MPs and the risk of cancer patients with VTE.TF-bearing MPs have been assessed as a high risk factor for cancer-related VTE in several studiesth June 2017 from PubMed, Web of Science and EMBASE Databases. Search terms were used: 1) Microparticles; 2) Tissue Factor; 3) thrombosis OR thromboembolism; 4) cancer OR tumor OR neoplasms. The standard criteria for reporting meta-analyses were followed in this study17.The data were searched up to 1All these articles were screened through the titles and abstracts to find studies that possibly met requirements. Then the full article of eligible studies was read. This analysis included cohort studies and case-control studies that research the relationship between TF-bearing MPs and cancer patients with VTE. These included studies had to meet the following requirements: 1) The outcome was VTE including pulmonary embolism (PE) or deep vein thrombosis (DVT). Thrombosis was diagnosed by standard imaging method. 2) Any type of solid tumor was included in this study. 3) The type of MPs was mainly TF-bearing MPs. 4) Estimates of the relative risk (RR) or odds ratio (OR) or hazard ratio (HR) and its 95% confidence interval (CI) were reported. Review or studies which were impossible to get available information from the published results were excluded.Two independent authors (CC Cui and GG Wang) extracted data from the selected studies. The disagreements were resolved by discussion and consensus. The following data were extracted: the first author’s name, publication year, sample size, cancer type, risk estimates  and 95% confidence intervals.2-statistics and Q statistics18. P ≤ 0.10 represented statistically significant heterogeneity20. If På 0.10, then the fixed-effect model was used; Otherwise, the random-effect model was used in this meta-analysis22 I2 is used to measure of how much of this heterogeneity which is due to studies variation rather than sampling error18. I2-values of 25–50%, 50–75% and >75% represented low, moderate and high heterogeneity, respectively. While a value of I2 < 25% represented no significant heterogeneity18. Because of the higher potential bias in case-control studies, the subgroup analyses were conducted by the study design of included articles to investigate the sources of possible heterogeneity. We also performed subgroup analyses by the detection method of TF-bearing MPs in included articles. Sensitivity analyses were performed to assess the heterogeneity and robustness of the pooled results.All of the data were analyzed by STATA, version 12.0  statistical software. We calculated risk estimates  and 95% confidence interval (CI) of developing VTE in cancer patients by TF-bearing MPs. These studies were weighted by the method of inverted variance through STATA software. Heterogeneity was estimated by the I23 and Egger’s test24). The quality of these studies was evaluated by the Newcastle-Ottawa Scale (NOS)25. Scores of 0–3, 4–6, 7–9 were considered as low, moderate and high quality, respectively.Potential publication bias was evaluated by the funnel plot . Because of the heterogeneity of this meta-analysis was not very good (P ≤ 0.10), then the random-effects model was used in this study.In Fig. 2 = 0.0%) for case-control studies and 1.53  for cohort studies.Subgroup analysis was presented in Figs 2 = 55.4%) for activity assay and 2.97  for flow cytometry. For the results using random- model effect model, the positive associations between TF-bearing MPs and VTE risk in cancer patients were similar to the overall result in subgroups.In Fig. Sensitivity analysis was presented by excluded one study at a time and then re-calculating the pooled OR estimates. From Fig. The publication bias was evaluated by funnel plots Fig. . There w26. Some surface proteins are selective packaged into MPs, such as TF and adhesion molecules. MPs are procoagulant largely due to the exposure of negatively charged phospholipids and the presence of TF. The negatively charged phospholipids surface can assemble the positively charged coagulation protein.MPs are released as small phospholipid vesicles from the outward blebbing of the plasma membrane after proteolytic cleavage of the cytoskeleton27. The results of this study show that the TF-bearing MP is an increasing risk factor for cancer patients with VTE. Sensitivity analysis, publication bias testing and subgroup analysis all supported the results in this analysis.To our knowledge, this is the first meta-analysis of the relationship between TF-bearing MPs and cancer patients with VTE. Two independent authors conduct re-sampling data extraction from the selected studies to make sure the robustness of the conclusions30. VTE can significantly increase the mortality of cancer patients32. Therefore, the studies of pathogenesis for cancer VTE gain increasing attention. Cancer cells have been known to express TF on the surface and release TF-bearing MPs34. A previous study of Hron and colleagues showed that increasing TF-bearing MPs in cancer patients correlated with coagulation activity, as determined by the levels of D-dimer35. Subsequently, the retrospective study of Tesselaar and colleagues suggested that the activity of TF-bearing MPs was significantly higher in cancer patients compared with healthy controls and cancer patients with VTE had higher TF-bearing MPs activity than cancer patients without VTE36. In this present meta-analysis, an increased risk of VTE in those who had high level of TF-bearing MPs . This result consisted with the studies of Bharthuar, Sartori and Zwicker14.The development of VTE is often observed in cancer especial for its therapy37. The study of Haubold showed that there was no significant correlation between TF-bearing MPs activity assay and antigen assays38. But in the study of Geddings, the results presented that there was a strong correlation between TF-bearing MPs activity assay and antigen assay39. Therefore, the methods of detecting TF-bearing MPs maybe contribute to the heterogeneity. In our meta-analysis, the subgroup analysis for MPs detection method was conducted. The results showed that OR was 1.25  for activity assay and 2.97  for flow cytometry. The heterogeneity in the subgroups was relatively reduced. Either TF-bearing MPs activity assay or antigen assay suggested that the TF-bearing MP is an increasing risk factor for VTE in cancer patients. There may be some other potential confounding factors that contribute to the heterogeneity, such as sample-sizes, age, cancer treatments. In addition, interpatient and intratumour heterogeneity maybe also have an important role in affecting the result27.Our meta-analysis included case-control studies and cohort studies. According to study design subgroup analysis, the case-control studies had higher ORs than the cohort studies. But the case-control studies and cohort studies both showed the TF-bearing MP is an increasing risk factor for VTE in cancer patients. The two results were similar to the overall result. So the case-control studies also provide some value. The OR for case-control studies and cohort studies were 3.41 (95% CI: 1.45–8.02) and 1.53 (95% CI: 1.05–2.24), respectively. The methods of detecting TF-bearing MPs included antigen assays and activity assays41. However, TF-MPs have been shown to be involved in tumor growth and metastasis. In the study of Zwicker et al., 50% of the circulating TF-MPs in patients with pancreatic cancer expressed MUC-115. Similar to the study by Tesselaar et al., the plasma levels of TF and MUC-1 double-positive MPs in these patients were reduced after surgical resection of the primary tumor36.In addition to thrombosis, metastasis and recurrence are also the leading cause of cancer related death. There have been many studies of cancer hallmark gene signatures for prognosis43. Whereas, prostate and breast cancer had rather low rates for VTE at 0.5% to 1.3% and 0.4% to 8.1%, respectively43. Different types of cancer could be analyzed in this study. Cancer heterogeneity maybe affects the result27. Because the original studies did not completely separate the types of cancer, it was impossible for us to evaluate the association between TF-bearing MPs and risk of VTE in different types of cancer patients in this meta-analysis. Secondly, case-control studies are more possibly to be interfered by some biases, such as selection bias or recall bias44. More factors were considered in cohort studies, so the reliability of cohort studies was higher than case-control studies. Because there were both cohort and case-control studies in our meta-analysis, the recall or selection bias might have affected the estimation of case-control studies and the overall studies. But, in subgroup analysis the case-control studies and cohort studies both showed the TF-bearing MP is an increasing risk factor for VTE in cancer patients, which suggested that selection biases or recall bias did not entirely affect the association. The case-control studies also provide some value. Thirdly, although the publication bias was not observed using the Begg’s and Egger’s test, the two tests had low power to detect the bias in small numbers of studies24. However, the potential publication bias can’t be totally excluded in this meta-analysis. Because not all potential confounders were adjusted in each study of this analysis, such as cancer treatments, clinical characteristics, cancer types.There were also limitations in this meta-analysis. First, incidence values for VTE in different types of cancer were different. Brain and pancreatic cancer had the highest rates for VTE at 1.6% to 26% and 5.3% to 26%, respectivelyIn conclusion, this meta-analysis shows that TF-bearing MPs were associated with increased risk of VTE in cancer patients. Whereas, more well-designed studies and more comprehensive adjustments for confounders in further studies are warranted to affirm the association.


Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic destructive inflammation in synovial joints. To date, many studies explored the associations between tumor necrosis factor alpha inducible protein 3 (TNFAIP3) gene rs6920220, rs2230926, and rs5029937 polymorphisms and the risk of rheumatoid arthritis (RA), but with contradictory results. We therefore conducted a comprehensive meta-analysis to address the associations. We searched in the databases of PubMed and Embase. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by the Stata 11.0 software. A total of 21 case-control studies for these three single nucleotide polymorphisms (SNPs) were included in this meta-analysis. Meta-analysis indicated that TNFAIP3 gene rs6920220, rs2230926, and rs5029937 polymorphisms were associated with the increased risk of RA. Stratification analysis of ethnicity found that rs6920220 and rs5029937 polymorphisms increased the risk of RA among Caucasians, while rs2230926 polymorphism increased the risk of RA among Asians. In summary, this meta-analysis confirms that TNFAIP3 gene polymorphisms may play important roles in the pathogenesis of RA. Rheumatoid arthritis (RA) is an autoimmune inflammatory disease, which is characterized by inflammation and destruction of synovial joints leading to progressive joint damage and disability. The etiology of RA is still poorly understood. RA is a multifactorial disorder, involving both genetic and environmental risk factors . StudiesThe tumor necrosis factor alpha inducible protein 3 (TNFAIP3) gene encodes ubiquitin-editing protein A20 . A20 is Selection for eligible studies included in this meta-analysis was presented in Figure P < 0.001, Figure P = 0.003, Figure P < 0.001, Figure As shown in Table We assessed sensitivity by omitting each study once at a time in every genetic model for the three polymorphisms. This meta-analysis indicated that the data of these three single nucleotide polymorphisms (SNPs) . The data revealed that rs5029937 polymorphism increased the risk of RA. Stratification analysis of ethnicity also found a positive association between rs5029937 polymorphism and RA among Caucasians, but not Asians. There are several possible interpretations for different results of these SNPs between Asians and Caucasians. First, genetic heterogeneity for RA may exist in different populations. Second, the discrepancy may be explained by clinical heterogeneity between the different populations. Third, the sample sizes of the Asian populations might not have been sufficiently large to reach a convincing conclusion when compared with Caucasian populations. Additionally, the different genotyping methods and random errors may also been potential reasons for different findings between Asians and Caucasians. To our knowledge, this is the first meta-analysis to address the association between rs5029937 polymorphism and RA risk.Several potential limitations should be addressed in this meta-analysis. First, due to limited data, we could not perform further stratification analyses of other potential factors, such as rheumatoid factor (RF). Second, our results were based on unadjusted estimates for confounding factors, which might have affected the final conclusions. Third, we could not assess potential gene-gene and gene-environment interactions due to the lack of relevant data. Fourth, we cannot examine the associations between these SNPs of TNFAIP3 and the clinical manifestations of RA. Fifth, some genetic models of this meta-analysis were high, and it is necessary to interpret it with caution. Sixth, the sample sizes of stratification analyses were limited.In conclusion, this meta-analysis indicates that TNFAIP3 gene rs6920220, rs2230926, and rs5029937 polymorphisms are associated with the increased risk of RA. Stratification analysis of ethnicity reveals that rs6920220 and rs5029937 polymorphisms increase the risk of RA among Caucasians, while rs2230926 polymorphism increases the risk of RA among Asians. Further studies are required to determine whether these SNPs of TNFAIP3 gene contribute to RA susceptibility in different ethnic groups.P value, and case-control study. Exclusion criteria were: duplication of previous studies; review, or other non-original studies; studies without detailed genotype data.We systematically searched the PubMed and Embase to identify studies through September 16, 2016. The following search terms were used: “tumor necrosis factor alpha inducible protein 3,” ‘‘TNFAIP3,’’ ‘‘A20,’’ ‘‘Rheumatoid Arthritis,’’ ‘‘RA,’’ ‘‘polymorphism,’’ ‘‘SNP’’ and ‘‘polymorphisms’’. No restrictions were placed on the search. Additional initially omitted studies (such as reference lists of identified studies) have been identified by hand screening. The identified studies conformed to the following criteria: studies that evaluated the association between RA risk and TNFAIP3 gene rs6920220, rs2230926, and rs5029937 polymorphisms, study provided sufficient data to calculate the odds ratios (ORs) and 95% confidence intervals (CIs), and Relevant information was carefully extracted from all eligible studies. The extracted information from all eligible studies included: name of first author, publication year, country of origin, genotype methods, ethnicity, and genotype numbers of cases and controls. Two reviewers independently performed the extraction of data and assessed the study quality based on the NOS . All disP < 0.1 or I2 > 50% indicated heterogeneity across studies, a random-effect model was used. Otherwise, the fixed-effects model was applied [2 test. Potential publication bias was assessed by Begger's and Egger's linear regression test [P < 0.05 was considered to indicate statistically significant. The power of this meta-analysis was calculated with a significant value of 0.05 [All statistical analyses were performed using the Stata 11.0 software . ORs and 95%CIs were used to assess the strength of associations between TNFAIP3 gene rs6920220, rs2230926, and rs5029937 polymorphisms and RA risk. Stratification analyses were carried out by ethnicity and HWE status. When a Q test indicated  applied . Pooled ion test ; P < 0.0 of 0.05 .


Choline acetyltransferase (CHAT) rs3810950 and rs2177369 polymorphisms have been implicated in susceptibility to Alzheimer's disease (AD). Due to the inconsistent results from previous studies, a meta-analysis was performed to estimate the association between these polymorphisms and AD risk more precisely. Pooled results of our meta-analysis indicated CHAT rs2177369 polymorphism was correlated with decreasing AD risk in one of five genetic models , while rs3810950 mutant was associated with AD development in three models . In subgroup analysis by ethnicity, the association between CHAT rs3810950 polymorphism and AD risk was just found in the recessive model  among Caucasians, while four genetic models  assumed this association in Asians. In conclusion, our meta-analysis indicated CHAT rs2177369 polymorphism might play a protective role in AD, while rs3810950 variant was a risk factor for AD but its single heterozygous mutations might not influence susceptibility to AD. It is the most common form of age-related dementia . Today,  protein . Althoug protein , 4–6.Genetic studies revealed that genetic factors played significant roles in the development of Alzheimer's disease . RecentlCHAT gene has several genetic polymorphic loci such as rs1880676, rs2177369, rs868750, and rs3810950. In this paper, we focus only on the influence of the rs3810950 (G>A) and rs2177369 (A>G) polymorphisms on AD risk. We do not include other CHAT polymorphisms for this meta-analysis because all the other available polymorphisms do not meet the performance standard of conducting a mate-analysis due to their limited case-control studies.The mutation of A/G in both rs3810950 and rs2177369 is fascinating due to its functionality. These polymorphisms in the CHAT gene may affect the synthesis of the enzyme, thereby amplifying the cholinergic neurotransmission deficits in AD . The rs3Two investigators searched the PubMed, Embase, CNKI, Wanfang, and AlzGene databases to find all relevant records using the following keywords: “Choline acetyltransferase OR CHAT”, “Alzheimer's disease OR AD” and “polymorphism OR polymorphisms OR variant OR mutation”. The searches were last updated on May 15, 2016. Two authors took responsibility for literature searches to ensure the integrity of the data collection.The inclusion criteria to select eligible articles in this meta-analysis were as follows: (1) the association of CHAT rs3810950 or rs2177369 polymorphism with Alzheimer's disease; (2) a case-control design; (3) complete genotype data including the number of homozygous mutant, heterozygous and wild genotypes to calculate ORs. On the other hand, the literatures were excluded if they met any of the following criteria: (1) abstracts, editorials, review articles, and unrelated meta-analyses; (2) studies without polymorphisms; (3) studies with other diseases or other polymorphisms; (4) studies with incomplete genotype data. Only one could be accepted if the publications were duplicated. Any disagreement regarding the inclusion of articles was resolved by discussion among the authors.One author extracted the following information from each study: (1) the first author's name; (2) the year of publication; (3) the country and ethnicity of the participants (patients and controls); (4) the number of Alzheimer's disease cases and controls; (5) the frequency of genotypes in AD cases and controls; (6) genotyping method; (7) diagnosis criteria of AD. Then, another author checked the data carefully to ensure they are complete and correct. In case-control studies, Hardy Weinberg Equilibrium (HWE) was used for quality assessment of genotype data. A high-quality study was considered that its control group conformed to HWE. A study without HWE in controls was defined as a low quality one. Low quality studies were excluded in the sensitivity analysis. Newcastle-Ottawa Scale (NOS) criteria  were useI2 test were used to calculate the heterogeneity of these genetic models. A P value <0.05 and/or I2 > 50% indicated substantial heterogeneity, and then a random effect model was used; otherwise, a fixed effect model was used to calculate the ORs and 95% CIs of any genetic model with unobserved heterogeneity [ε4 status.In this meta-analysis, the pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the association of CHAT rs3810950 or rs2177369 polymorphisms with the risk of AD. We did not use environmental factors to adjust the poor ORs due to the very limited information provided in each of the included studies. We performed this meta-analysis using five genetic models: the allelic, homozygous, heterozygous, dominant, and recessive model. Chi-square test and ogeneity , 27. AddP value of 0.05. “Venice criteria” [http://dx.doi.org/10.1155/2016/9418163) were also applied to assess the credibility of the cumulative evidence of each meta-analyzed association under the genetic models we investigated. The evidence level is graded as strong, moderate, or weak.Statistical power analysis was executed to estimate the suitability of the sample size employed to the power of the study. We assumed an unmatched case-control design and considered a two-sided riteria”  , STATA 14.0 , and Quanto software package .Sensitivity analysis was applied to investigate the influence of the individual studies to the pooled results by omitting one study at a time. Both Begg's and Egger's tests were used to assess publication bias and a As shown in P = 0.03; homozygous AA versus GG: OR = 1.63, 95% CI: 1.09–2.42, P = 0.02; and recessive AA versus AG + GG: OR = 1.65, 95% CI: 1.20–2.26, P < 0.01)    but no a = 0.34) . Power aP = 0.03) established the association of CHAT rs3810950 polymorphism with AD risk among Caucasians, while four genetic models  assumed this association among Asians. The statistical power of an Asian subgroup was 77.90% and 99.45% and that of a Caucasian subgroup was 6.34% and 99.99% calculated from power analysis, respectively, under the dominant and recessive models. Thus, only the homozygous mutant genotype AA might be related with the susceptibility to AD in a Caucasian population but only the heterozygous genotype AG might not be linked to increasing AD risk in an Asian population. In addition, a further analysis of studies involving British only indicated that no association between CHAT rs3810950 polymorphism and Alzheimer's disease was found in British people for all five genetic models (Table S2 in Supporting Information). The statistical power calculated for the British group was 5.41% and 26.56% under the dominant and recessive models, respectively.The results from a subgroup analysis by ethnicity in Caucasians and Asians for all five genetic models are shown in P = 0.02; homozygous AA versus GG: OR = 1.89, 95% CI: 1.00–3.55, P = 0.05; and recessive AA versus GG + GA: OR = 1.94, 95% CI: 1.18–3.19, P = 0.01) while no association was found in all the five genetic models for the nonquantitative PCR group . A substantial interaction was also found between ApoE-ε4 carriers and the AA genotype . All of these evidences manifested that ApoE-ε4 allele could be a vital factor in the Alzheimer's disease caused by CHAT rs3810950 polymorphism. Under the existence of ApoE-ε4, the risk of Alzheimer's disease increased notably when the genotype of rs3810950 was GG + GA or AA.Because four included studies in this meta-analysis provided the genotype data of CHAT rs3810950 polymorphism and ApoE-4 allele , 14, 15,When Venice criteria were applied to assess credibility, results under all five genetic models were graded as “A” for “amount of evidence” of all meta-analyses except “B” for British subgroup analysis, “A,” “B,” or “C” for “replication consistency,” and “A” for “protection from bias” of the overall analysis (Table S3). These results suggested that there was moderate or weak evidence of the association between rs3810950 polymorphism and AD susceptibility.P = 0.02, statistical power = 69.05%) but no connection was detected in the rest four genetic models   . Thus, tP = 0.78; homozygous GG versus AA: OR = 0.91, 95% CI: 0.52–1.59, P = 0.73; heterozygous GA versus AA: OR = 0.83, 95% CI: 0.62–1.10, P = 0.19; dominant GG + GA versus AA: OR = 0.87, 95% CI: 0.67–1.14, P = 0.32, statistical power = 19.62%; recessive GG versus GA + AA: OR = 1.04, 95% CI: 0.63–1.71, P = 0.88, statistical power = 5.97%)   and Scacchi studies, respectively, because these two studies provided entirely opposite effects of CHAT rs2177369 polymorphism on AD risk . The metI2 = 0%, as shown in Tables I2 = 74%), homozygous model (I2 = 72%), dominant model (I2 = 62%), and recessive model (I2 = 66%) and on CHAT rs2177369 polymorphism in the allelic model (I2 = 82%), homozygous model (I2 = 77%), and recessive model (I2 = 82%). Meanwhile, moderate heterogeneity was observed in the remaining two models as the heterozygous model (I2 = 37%) on CHAT rs3810950 polymorphism and the dominant model (I2 = 32%) on CHAT rs2177369 polymorphism. On CHAT rs3810950 polymorphism, the results of the meta-regression showed that the sample size, ethnicity, and genotyping method did not contribute to the heterogeneity of genetic models (data not shown here). Sensitivity analysis was then performed to assess the impact of the independent studies which caused obvious heterogeneity in those four models on CHAT rs3810950 polymorphism. We explored the influence of these studies on the pooled OR by removing each one at a time and found no significant change of our meta-analysis results. We did not perform both meta-regression and sensitivity analysis on CHAT rs2177369 polymorphism due to only four case-control studies involved.Our meta-analysis showed evidence of genetic heterogeneity in all the genetic models of the two polymorphisms except for CHAT rs2177369 polymorphism in the heterozygous model . In general, the effect of publication bias could be negligible in the included studies on CHAT rs3810950 polymorphism. However, we estimated the risk of publication bias neither in the subgroup analyses nor in the meta-analysis on CHAT rs2177369 polymorphism because the number of case-control studies in these studies was less than ten.We further performed Begg's and Egger's tests to assess publication bias in the study of the genetic association between CHAT rs3810950 polymorphism and AD risk. As shown in Table S4, no obvious publication bias was detected according to the obtained The association of CHAT rs3810950 polymorphism with Alzheimer's disease was previously reported in one published meta-analysis . HoweverIn order to get more detailed information about this association, we further carried out subgroup analyses by ethnicity and by genotyping method, respectively. On one hand, subgroup analysis by ethnicity indicated that Caucasians might have a lower risk of Alzheimer's disease than Asians . In addiε4 status showed that, with the same rs3810950 polymorphism, ApoE-ε4 carriers exhibited a significantly higher incidence of AD than the non-ApoE-ε4 carriers , education, vascular risk, ApoE-AD onset –34. Theri et al.  and othei et al. , respectε4 status was also carried out in our study. This analysis assisted us to detect the promising effect of gene-gene interaction on the development of disease. Fifthly, we not only used Begg's and Egger's tests to assess the risk of publication bias but also employed the trim and fill method to identify and correct funnel plot asymmetry arising from publication bias. Sixthly, the NOS criteria were performed to evaluate the quality of the included studies and Venice criteria were applied to assess the cumulative evidence of the associations in our meta-analysis. Finally, statistical power analysis was also executed to estimate the effect of the sample size on the power of the study and this increased the credibility of our result.Our meta-analysis had several advantages. Firstly, this study is the first meta-analysis to investigate the association of CHAT rs2177369 polymorphism with the development of Alzheimer's disease. In addition, though a previous meta-analysis  has explSome limitations should be also recognized in this meta-analysis. Firstly, a subgroup analysis based on age, gender, or lifestyle habits may also contribute to the association of CHAT rs3810950 and rs2177369 polymorphisms with Alzheimer's disease , 36, butAlzheimer's disease is the most prevalent neurodegenerative disease in the elderly and it has caused serious damage to our health , 2, 6. SConsiderations for epidemiologic credibility in the assessment of cumulative evidence on genetic associations.


LPL gene polymorphisms and CAD susceptibility. The pooled odds ratio (OR) and 95% confidence interval (CI) were calculated to estimate the strength of the relationship between LPL gene polymorphisms and CAD risk. Comprehensive electronic databases, including PubMed, EMBASE, Web of Science, and the Cochrane Library, were systematically searched. A total of 45 records containing 80 eligible studies were analyzed. The results indicated an increased risk between the LPL D9N polymorphism and susceptibility to CAD in the dominant genetic model , whereas the LPL HindIII polymorphism showed a protective effect against CAD under all tested models . No significant association was identified for the LPL N291S and PvuII polymorphisms. Stratification analysis by ethnicity suggested a significant correlation between the LPL S447X polymorphism and CAD susceptibility in Caucasians under the dominant and allele genetic models. In summary, our meta-analysis indicated that the LPL D9N polymorphism was associated with an increased risk of CAD, whereas the S447X and HindIII polymorphisms showed protective effects. There was no association observed between the N291S and PvuII polymorphisms and CAD risk.Lipoprotein lipase (LPL) is widely linked to lipid and lipoprotein metabolism, but its effects on coronary artery disease (CAD) are not clearly elucidated. The aim of the present study was to clarify the association between  LPL gene variants directly affect abnormal lipid and lipoprotein metabolism and its influence on the risk of CAD [Coronary artery disease (CAD) is a complex multifactorial disease and a leading cause of morbidity and mortality worldwide . Althougk of CAD . HoweverLPL is a glycoprotein containing 448 amino acids, which is synthesized and secreted by various tissues, such as adipose tissue, myocardium, and skeletal muscle . As an iLPL gene maps to chromosome 8p22, and over 100 various mutations have been identified [LPL gene have been reported to be associated with CAD susceptibility [LPL variants, such as the S447X (rs328) polymorphism, which lead to the transition of Serine (S) to a stop codon (X) at codon position 447, result in reduced TG levels and an overall favorable lipid profile [The entified ,12. Sevetibility . Howevertibility . Similartibility ,14. Howetibility . Meanwhi profile . In addi profile , while o profile ,25.LPL gene polymorphisms  and CAD, we performed this meta-analysis by pooling all eligible studies to calculate the estimate of overall CAD risk.To confirm the correlation existed between the We performed the present study according to the MOOSE  guidelines for meta-analysis of observational studies (Supplementary Table S1) . The litLPL gene polymorphisms  and CAD susceptibility; (2) total CAD cases were documented by angiographic evidence of at least 50% stenosis of one major coronary vessel, myocardial infarction, angina, a history of prior angioplasty, or coronary artery bypass surgery; (3) the data in the reference were sufficient for the present estimation, such as the total number of cases and controls, distribution of genotypes or other relevant information; and (4) the language was limited to English. Studies were excluded if they met any of the following criteria: (1) non-English record; (2) abstracts, letters to the editor, reviews, case-only studies, meta-analysis, and animal studies; and (3) study with useless or insufficient data and multiple publications that reported the same or overlapping population information.The following criteria were applied for reference selection: (1) studies on the evaluation of the Data abstraction was independently performed by two investigators (W.-Q.M. and X.-Q.H.), and disagreements about study selection were discussed and resolved by a third investigator (N.-F.L.). The following information was extracted from each included article: author, publication date, ethnicity, total number of cases and controls, country, sources of controls, genotyping methods, genotype frequency in cases and controls, and Hardy–Weinberg equilibrium (HWE) in the controls.The Newcastle–Ottawa scale (NOS) was applied in the quality assessment . The valLPL gene polymorphisms and CAD susceptibility. The dominant, recessive, and allele genetic models were applied to assess the correlation between the LPL HindIII, PvuII, and S477X gene polymorphisms and CAD risk. Only the dominant genetic model was applied for N291S and D9N, due to the low number of minor homozygotes. The Cochrane Q-test and index (I2) were calculated to evaluate the heterogeneity within studies. P-value < 0.1 in the Q-test or I2 > 50% indicated significant heterogeneity. According to the strength of heterogeneity among studies, the fixed- or random-effects model was applied to calculate the OR and the corresponding 95% CI. The Z-test was used to determine the significance of overall ORs. Subgroup analyses, which were based on ethnicity (Asians and Caucasians) and sample size , were applied to detect sources of heterogeneity. In addition, the influence of sample sizes on the overall risk estimation was assessed by a cumulative meta-analysis [Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were applied to estimate the strength of association between the analysis . A sensiA total of 958 articles were acquired after initial searching. Among them, 712 duplicate articles were excluded, and 160 articles were excluded for ineligibility after screening the titles and abstracts. In addition, 41 articles were excluded because of insufficient data, reviews, meta-analyses, or conference abstracts. Finally, 45 articles containing 80 eligible studies were included in this meta-analysis ,29–57. TLPL HindIII polymorphism with susceptibility to CAD. Twenty-seven studies, involving 6959 cases and 9400 controls, focused on the relationship between the LPL S447X polymorphism and susceptibility to CAD. Eleven studies, including 9272 cases and 15,074 controls, focused on the relationship between the LPL N291S polymorphism and susceptibility to CAD. Eight studies, involving 2583 cases and 2525 controls, focused on the relationship between the LPL D9N polymorphism and susceptibility to CAD, and the remaining 16 studies, involving 7831 cases and 5966 controls, concerned the LPL PvuII polymorphism. The countries in which these studies occurred included the U.S.A., U.K., France, Brazil, China, Finland, and others. HWE had been applied for all polymorphisms in the controls. The quality of these enrolled studies was evaluated using the NOS quality scale (Supplementary Table S3).The characteristics of the studies included in the meta-analysis are shown in Supplementary Table S2. Among 80 eligible studies, 18 studies, containing 5532 cases and 4813 controls, correlated the LPL HindIII polymorphism in all tested genetic models  with some evidence of interstudy heterogeneity  with low interstudy heterogeneity . No signLPL PvuII polymorphism and CAD susceptibility in any genetic model  .The Funnel plot and Egger’s regression test were applied to assess the publication bias of the included studies. The results indicated that the distribution of the included studies on the funnel plot appeared roughly symmetrical . The resLPL gene could influence lipid transport and metabolism and could consequently modulate an individual’s susceptibility to atherosclerosis. However, it is difficult to draw a definite conclusion for whether LPL is a proatherosclerotic or antiatherosclerotic factor, since the effects of LPL partly depend on its locations and activity [LPL gene expression has been shown to play an opposite role [Genetic variations in the activity . The enzactivity ,59. Seveactivity ,60. Incrite role ,62.LPL gene polymorphisms on CAD incidence. In our study, all of the results revealed that three LPL gene variants  were associated with CAD susceptibility. When Asians or Caucasians were analyzed independently, the heterogeneity of the population tended to be weaker, and the subgroup analysis indicated that S447X polymorphism decreased CAD risk in Caucasians. On the other hand, the stratified analysis by ethnicity for the S447X polymorphism was successfully applied to relieve the heterogeneity bias in the polymorphism analysis within Caucasians, suggesting that ethnicity may potentially be the source of the heterogeneity. In addition, it is worth noting that the P value of the Egger’s regression test for the S447X polymorphism was less than 0.05, which indicated that publication bias likely existed; however, the funnel plot appeared roughly symmetrical, and the sensitivity analysis indicated the stability of the results. Consequently, future studies are warranted to validate our conclusion.Although numerous studies have investigated the correlation between LPL and CAD risk in the past several decades, no definite conclusions have been reached regarding gene polymorphisms. This meta-analysis has combined and reanalyzed individual participant data from 80 eligible studies of the effect of Although several relevant meta-analyses have been published, our study had certain specific advantages . CompareSeveral limitations in our study should also be addressed. First, some genetic models displayed high heterogeneity, although subgroup analysis was performed to detect the sources of this heterogeneity. Second, the ethnic distribution of included studies was primarily Asians and Caucasians. Racial bias may exist, and the conclusions may not be applicable to other races. Third, we searched and collected articles in English from four comprehensive electronic databases, including PubMed, Web of Science, EMBASE, and Cochrane database. Several publications related to this topic written in other languages might have been ignored. Thus, publication bias likely existed. However, the articles included in these four databases are more authoritative and more convenient for readers compared with the original literature.LPL D9N polymorphism was associated with the increased risk of CAD, whereas the LPL HindIII and S447X polymorphisms showed protective effects against CAD. No associations were observed between the LPL N291S and PvuII polymorphisms and susceptibility to CAD.In summary, this updated meta-analysis suggested that the


VEGFA polymorphisms in glioma development. A comprehensive literature search conducted in PubMed, Embase, the Cochrane Library, and OVID databases through February 25, 2017 yielded 4 eligible studies consisting of 2,275 cases and 2,475 controls. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated under allele contrast, dominant, recessive, homozygous, and heterozygous models. In general, minor alleles of polymorphisms rs3025039, rs2010963, and rs3025030 were associated with increased glioma risk. In contrast, a significant correlation was found between the minor allele of polymorphism rs3024994 and decreased susceptibility to glioma. Moreover, statistically significant associations with glioma risk were observed for polymorphisms rs1413711 and rs3025035 in the meta-analysis although positive associations were not observed in any of the included studies individually. No significant correlations with glioma susceptibility were identified for polymorphisms rs3025010 or rs833069 except in the recessive model. Finally, stratified analysis on the basis of genotyping method and Hardy-Weinberg equilibrium (HWE) in controls revealed no significant difference between subgroups. Our results indicated that several VEGFA polymorphisms might be risk factors for glioma in Chinese. More studies with larger sample sizes using different ethnicities are needed to provide additional evidence.Several single nucleotide polymorphisms (SNPs) in the vascular endothelial growth factor A (VEGFA) gene have been previously reported to be associated with glioma susceptibility, but individual studies have demonstrated inconclusive results. In the current study, a meta-analysis was performed to derive a more precise estimation of the involvement of  Glioma is the most common type of primary central nervous system tumors and has an invariable fatal outcome and dismal prognosis , 2. DespThe etiology of glioma is still poorly understood. To date, exposure to ionizing radiation is the only clearly known environmental risk factor, which accounts for only a few cases . In receVEGFA gene have been described. Recent studies have examined the associations of specific SNPs in the VEGFA gene with glioma risk, but the significance of these findings remains unclear.Angiogenesis is a critical process in the development of human glioma, which promotes survival, malignancy, and growth of tumor cells. The vascular endothelial growth factor A (VEGFA) gene, which is located on chromosome 6p12 and consists of 9 exons, is one of the most predominant mediators of pathologic angiogenesis. First, endothelial cells are stimulated by VEGF to proliferate and to migrate . Third, VEGFA polymorphisms and glioma susceptibility.Due to insufficient population sizes, the statistical power of each study was relatively low, and evidence of the risk associated with each polymorphism was inconclusive. To increase statistical power, we conducted a systematic review and meta-analysis of published studies investigating the associations between rs3025039, 4 case-control studies with 2275 cases and 2475 controls; rs2010963, 3 case-control studies with 2115 cases and 2155 controls; rs3024994, 2 case-control studies with 1235 cases and 1275 controls; rs1413711, 2 case-control studies with 1235 cases and 1275 controls; rs833069, 2 case-control studies with 1235 cases and 1275 controls; rs3025010, 2 case-control studies with 1235 cases and 1275 controls; rs3025030, 2 case-control studies with 1235 cases and 1275 controls; and rs3025035, 2 case-control studies with 1235 cases and 1275 controls , recessive , and homozygous models  ; dominant ; recessive ; homozygous ; and heterozygous  , dominant , and homozygous models . Polymorphism rs3025030 was significantly associated with glioma susceptibility in the recessive  and homozygous models . Moreover, significant impacts of polymorphisms rs1413711 and rs3025035 on glioma susceptibility were observed although neither of the included studies showed any positive associations , recessive , and homozygous models ; for rs3025035, allele contrast  and dominant models . However, no significant associations were identified for polymorphisms rs3025010 or rs833069, except in the recessive model, and glioma susceptibility  Figure . A signi) Figure . The minrs3025039. A significant association between VEGFA polymorphism rs3025039 and glioma susceptibility was identified in HWE group under the allele contrast , recessive , and homozygous models   in controls was only performed on rs3025039 polymorphism and glioma susceptibility in both matrix assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) groups .P values from the Egger's and the Begg's tests are listed in Table rs3025039 in the recessive model. However, analysis with the trim and fill method demonstrated that the results of our study did not significantly change after adjusting for publication bias.No obvious asymmetry was observed in any of the Begg's funnel plots, which indicates that publication bias was generally not influencing the results Figure . All P vVEGFA SNPs to the risk of glioma and observed several positive associations at 6 SNPs. The minor alleles of polymorphisms rs3025039, rs2010963, and rs3025030 were associated with increased glioma risk. In contrast, a significant correlation was found between the minor allele of polymorphism rs3024994 and decreased susceptibility to glioma. Finally, polymorphisms rs1413711 and rs3025035 significantly influenced glioma risk, although no positive associations were observed for any of the included studies. These results demonstrate that VEGFA polymorphisms may be associated with glioma risk.In the present study, we assessed the contribution of 8 rs2010963 and rs3025039 are located in the 5′-untranslated (5’-UTR) and 3’-untranslated (3′-UTR) regions of the VEGFA gene, respectively. Renner et al. first identified the VEGFA rs3025039 polymorphism and found that the T allele led to significantly lower plasma VEGFA levels in healthy young men [rs2010963 led to a higher production of the VEGFA precursor and VEGFA in several cell lines [Tumor cells require angiogenesis to deliver nutrients and oxygen to support their rapid growth and high metabolism. VEGFA is an important pro-angiogenic factor for tumor progression because it promotes endothelial cell proliferation and remodels the extracellular matrix in blood vessels . Elevateoung men . A functVEGFA polymorphisms as markers of disease susceptibility [rs3024994 and rs3025030 polymorphisms, which are located in intronic regions, were reported to lead to changes in potential binding sites of transcription factors. Such base pair changes may result in aberrant VEGFA expression and ultimately tumorigenesis [The genetic variants within conventional regulatory regions, such as the 5′- and 3′-UTRs, have been the focus in most previous studies evaluating risk associations; however, accumulating evidence highlights the importance of intronic tibility , 32. Varigenesis .VEGFA polymorphisms rs1413711 and rs3025035 revealed any statistically significant positive correlations associated with glioma risk. Yet pooled analysis demonstrated that both polymorphisms might be related to glioma risk in Chinese. This discrepancy may result from the limited sample size of individual studies. Pooling of cases through meta-analysis however potentially reveals positive associations by narrowing the 95% CI. The polymorphisms rs1413711 and rs3025035 are also located in intronic regions of the VEGFA gene; however, no functional assay has been performed to investigate whether these polymorphisms influence VEGFA expression or function to date. Therefore, larger, preferably population-based case-control studies, as well as mechanistic studies involving variants of VEGFA on glioma progression, are warranted to validate our findings and to further investigate their roles in the development of glioma.No individual eligible studies focused on VEGFA SNPs and glioma risk compared to individual studies was evaluated. Moreover, we also revealed some positive associations that were not observed in previous work. However, the present study also has several limitations that should be taken into account when interpreting the findings. First, our analysis was limited to articles published in English and individuals of Chinese descent. Language bias may therefore exist, and it remains unclear whether these results can be generalized to other populations. Second, significant publication bias was observed in the analysis of glioma risk and VEGFA rs3025039 in the recessive model. The trim and fill method was carried out to adjust the pooled results. Finally, although subgroup analysis was performed based on genotyping method and HWE in controls, we did not design further analyses to investigate associations between VEGFA SNPs and glioma subtype because of limited data.A sufficient number of cases and controls were pooled from different studies and a more accurate estimation of the associations between VEGFA gene might be important in promoting the development of glioma in Chinese. Subsequent studies with larger sample sizes using different ethnicities are needed to evaluate the association between VEGFA gene polymorphisms and various types of glioma.In conclusion, the statistical data presented in this study suggest that variants of the Data analyzed in this meta-analysis were provided by multiple case-control studies systematically identified by searching PubMed, Embase, the Cochrane Library, and OVID databases up to February 25, 2017. The standardized search strategy included the use of MeSH terms  or key words related to polymorphism (polymorphism or polymorphisms or variation or variations or variant or variants or mutation or mutations or genotype or genotypes), the disease (glioma or gliomas or glioblastoma or glioblastomas or astrocytoma or astrocytomas or oligodendroglioma or oligodendrogliomas), or the gene .Inclusion criteria for studies were the following: (1) a case-control or cohort study, (2) contain sufficient data for the evaluation of VEGF polymorphism on glioma risk, (3) published in English, and (4) performed in humans.Two reviewers (P. Z. and A. C.) independently selected studies and extracted the following data from each study: first author's surname, publication year, ethnicity, glioma types, numbers of cases and controls, and the genotype distributions of cases and controls. Any disagreements were resolved by discussion with a third investigator (Q. Q.).http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp), the quality of the eligible studies was separately evaluated by two investigators (P. Z. and A. C.). Any disagreements were resolved by consensus through discussion.According to the Newcastle-Ottawa Scale and Agency for Healthcare Research and Quality , dominant (BB + AB vs AA), recessive (BB vs AB + AA), homozygous (BB vs AA), and heterozygous models (AB vs AA). Between-study heterogeneity was assessed by the I2 statistic and Q test with P < 0.05 and I2 > 50% indicating evidence of heterogeneity. The fixed-effect (Mantel-Haenszel method) or random-effects model (DerSimonian-Laird method) was used to calculate the pooled effect estimates in the presence or absence of heterogeneity. Sensitivity analysis was conducted by sequentially excluding each study to assess the stability of the results. The Begg's and the Egger's tests were performed to assess publication bias. All tests were two-tailed, and P-values < 0.05 were considered statistically significant.We used STATA software 11.0  for all statistical analyses. The pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated to evaluate the strength of associations between


CCR5 59029G/A polymorphism, but relevant findings were controversial. Therefore, we performed this meta-analysis to obtain a conclusion on this issue.Diabetic nephropathy (DN) causes high mortality in patients with diabetes mellitus and imposes heavy burden on individuals and society. In previous studies, various researches have investigated the association of DN with CCR5 59029G/A polymorphism showed significant risk-increasing effects on DN in all analyses under AA vs. GG, AA+GA vs. GG, AA vs. GG+GA, A vs. G and GA vs. GG model contrasts. Besides, a similar result was also obtained in Asian and type 2 diabetes mellitus groups under these five contrasts after subgroup analyses.CCR5 59029G/A polymorphism and DN susceptibility was measured using pooled odds ratios (ORs) with corresponding 95% confidence intervals (95% CIs). Inter-study heterogeneity was inspected with Q test, and sensitivity analysis was conducted to verify the stability of the final outcomes by removing one study each time in turn. Begg’s funnel plot and Egger’s test were utilized to examine publication bias among selected studies.The relevant publications were searched from the electronic databases and other sources. The association intensity between CCR5 59029G/A polymorphism is significantly related to enhanced susceptibility to DN, especially in Asian populations and people with type 2 diabetes mellitus. Diabetic nephropathy (DN), a common microvascular complication of diabetes, is a major cause of chronic kidney diseases, and results in high mortality in diabetic patients , 2. As aCCR5 is polymorphic and located within the gene cluster on chromosome 3p21.3-p24 [Chemokines, inducible proinflammatory cytokines, are regarded as important determinants of early inflammatory responses . The cys21.3-p24 . The pol21.3-p24 , cancers21.3-p24 , tubercu21.3-p24 , atopic 21.3-p24 .CCR5 gene, 59029G/A is frequently-reported to be relevant to the susceptibility to DN, but no consensus has been achieved on this issue yet. To systematically explore the effects of CCR5 59029G/A polymorphism on susceptibility to DN, we carried out this meta-analysis by pooling the previous findings.Among the polymorphisms of CCR5 59029 polymorphism, 11 reports were without available data, 10 were reviews or comments, and the resting 5 article were published in other languages , irrelevant title and abstracts (76), and other reasons (38). Among the 38 literature excluded by other reasons, 12 were for not related to CCR5 59029G/A polymorphism dramatically increased the susceptibility to DN in total analysis under the five genetic comparisons of AA vs. GG, AA+GA vs. GG, AA vs. GG+GA, A vs. G and GA vs. GG . Such situation might be attributed to multiple aspects, such as studies with negative results more likely to be published in local rather than international journals, reports with null findings or small sample sizes having less chance to be published, as well as the interests of sponsors or beneficiaries. Non-parametric “trim and fill’ method was used to adjust publication bias and the results showed that no trimming was performed, the data was unchanged  offering sufficient information on genotype and/or allele frequencies in case and control groups; and (4) using validated genotyping method. Publications were eliminated from the present meta-analysis if any one of the following situations appeared: (1) adopting duplicated data on study participants; (2) animals as study objects; and (3) commentaries, case reports, review articles or conference abstracts. As for reports containing the same group of participants, we selected the one with the largest sample size.All eligible articles must conform to the following criteria: (1) with a case-control design: the individuals in control group were Type 2 Diabetes or Type 1 Diabetes patients without nephropathy, while patients in case group were DN cases; (2) assessing the association between P value for Hardy-Weinberg equilibrium (HWE) in controls. If more than one study was incorporated in one single article, their data were abstracted separately.Data extraction was done independently by two investigators according to the same standard form. The major information included first author’s name, publication year, original country, ethnicity, type of diabetes mellitus, number of cases and controls, genotyping method, genotype and/or allele frequencies in case and control groups, and In this meta-analysis, quality assessment of included studies was conducted using the criteria of Newcastle-Ottawa Scale (NOS). 0-4 scores means the poor quality and the article with 5-9 scores was the good quality study.CCR5 59029G/A polymorphism and DN susceptibility was evaluated through calculating pooled odds ratios (ORs) with their corresponding 95% confidence intervals (95% CIs). Between-study heterogeneity was detected with chi-square-based Q test, with P<0.05 as the significant level. When significant heterogeneity appeared (Pheterogeneity<0.05), the random-effects model was employed to calculate pooled ORs, otherwise, fixed-effects model was used. Sensitivity analysis was performed through sequential omission of each included study to observe alteration in pooled ORs so as to test the stability of the final results. Begg’s funnel plot and Egger’s regression test were both adopted for publication bias examination among included studies. If publication bias was detected, Duval and Tweedie non-parametric “trim and fill’ method was used to adjust publication bias.STATA 12.0 software  was applied to complete all statistical analyses in this study. The strength of the relationship between


Methotrexate (MTX) is widely used and considered a first-line disease modifying anti-rheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA). Many of the relevant genes have been investigated to estimate the association between gene polymorphisms and MTX effectiveness in RA patients, although inconsistent results have been reported. A systematic review and meta-analysis were performed to identify genetic variants associated with MTX efficacy. A total of 30 publications that included 34 genes and 125 SNPs associated with the transporters, enzymes, and metabolites of MTX or the progression of RA were included in the systematic review (SR), and 21 studies were included in 9 meta-analyses. Associations between MTX response in RA patients in MTHFR 1298A > C (rs1801131), ATIC 347C > G (rs2372536), RFC-1 80G > A (rs1051266), SLC19A1 A > G (rs2838956) and SLC19A1 G > A (rs7499) genetic polymorphisms were found, but not observed between the MTHFR 677C > T (rs1801133), TYMS 28 bp VNTR (rs34743033), MTRR 66A > G (rs1801394), and ABCB1 3435C > T (rs1045642). However, for the polymorphisms not being associated following meta-analysis could still be associated if larger cohorts were used, and studies of other polymorphisms are necessary in large cohorts and a rigorous way, which may provide more accurate results for the effect of the gene polymorphisms on the MTX response. Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic synovial joint inflammation, which leads to disability and diminished quality of life1436Although the combined efficacy and continuation rates for MTX are superior to that of other DMARDs8The actual mechanisms of action of low-dose MTX in treating RA are not fully understood. Many of the relevant genes involved in the metabolism of MTX and progression of RA have been investigated to estimate the association between gene polymorphisms and MTX effectiveness in RA patients. However, these studies have produced mixed results because of their small sample size and poor statistical power. A meta-analysis can provide a potential solution to this problem because these evaluations combine the results from several studiesOver the past 10 years, seven meta-analyses12351213For the analyzed studies, the characteristics and detected genes are shown in A total of 34 genes with 125 gene SNPs associated with the transporters, enzymes, and metabolites of MTX or the progression of RA were evaluated to explore the association between the gene polymorphisms and the patient responses to MTX in previous studies .The main action of MTX is to inhibit the folate pathway and exert antiproliferative and anti-inflammatory effects in RA. An analysis of the MTX metabolic pathway showed that MTX enters target cells through reduced folate carriers , SLC46A1, SLC22A11 and SLCO 1B1) and effluxes from target cells through ATP-binding cassettes (ABCs), predominantly ABCC1-4, ABCB1 and ABCG2. MTX is polyglutamated by the enzyme FPGS, and this type of polyglutamation can be reversed by the enzyme GGH. Polyglutamated MTX (MTX-PG) is retained within the cells and can competitively inhibit the activity of DHFR and reduce dihydrofolate to tetrahydrofolate (THF). THF is the precursor of the biologically active folate cofactor 5-methyl-THF, and this conversion is catalyzed by MTHFR. MTHFR, SHMT and other enzymes in one carbon pool (MS and MTRR) are not directly inhibited by MTX, although their expression level may contribute to the antifolate effects of MTX through subtle alterations in the folate pools9Gene polymorphisms associated with RA progression, including AIF-1, ESR a (ESR1) and ESR b (ESR2), PTPN22, HLA-DRB1 and HLA-DQB1, TGFB1, TLR4, CXCL9 and CXCL10, were also included in the pharmacogenetic marker studies of MTX response in RA patients.The aforementioned genes are commonly used as important candidate gene polymorphisms in studies of RA response to MTX treatment. All of the genes and pathways included in the present SR are summarized in Ten studies were included in the meta-analysis of MTHFR 677C > T (rs1801133), which contained data from a combined total of 579 responders and 677 nonresponders and included six European studies (423 responders and 438 nonresponders) and three South Asian studies (94 responders and 208 nonresponders). The characteristics of these studies are described in When all of the samples were included, the association between the frequency of 3 MTHFR 677C five > T (rs1801133) alleles  and MTX response was not significant in pre allele , dominant , recessive , codominant , and homozygotic model . Moreover, significant between-study heterogeneity was not observed in all of the five models .Stratification by ethnicity did not identify a significant association between the MTHFR 677C > T (rs1801133) 3 allele frequency  and MTX response in the European or South Asian populations in all of the five models .Eight studies were included in the meta-analysis of MTHFR 1298A > C (rs1801131), which contained data from a combined total of 425 responders and 527 nonresponders and included four European studies (270 responders and 288 nonresponders), two East Asian studies (79 responders and 48 nonresponders) and two South Asian studies (76 responders and 191 nonresponders). The characteristics of these studies are described in 2 = 55.0%, χ2 = 15.54, P = 0.030) and East Asian subgroup in pre-allele model  but not in other three models  3 allele frequency  and MTX response status was not significant in pre-allele model , dominant model , recessive model , codominant model , and homozygotic model . Moreover, significant between-study heterogeneity in codominant model (AC vs. AA + CC) was observed (Ie models .Stratification by ethnicity identify a significant association between the MTHFR A1298C (rs1801131) 3 allele frequency and MTX response in the South Asian populations in recessive   and codoFive studies were included in the meta-analysis of ATIC 347C > G (rs2372536), which contained data from a combined total of 458 patients and 398 controls and included two European studies (132 responders and 134 nonresponders), one East Asian study (72 responders and 33 nonresponders) and two South Asian studies (254 responders and 231 nonresponders). The characteristics of these studies are described in When all of the samples were included, a significant association between the ATIC 347C > G (rs2372536) 3 allele frequency  and MTX response status was identified in dominant model   and codoStratification by ethnicity identified a significant association between the ATIC 347C > G (rs2372536) 3 allele frequency  and MTX response status in Europeans in pre-allele model, dominant model , and codominant model  but not in other model and in the South Asian populations .Three studies were included in the meta-analysis of TYMS 28 bp VNTR (rs34743033), which contained data from a combined total of 335 responders and 264 nonresponders. The characteristics of these studies are described in When all of the samples were included, the association between the TYMS 28 bp VNTR (rs34743033) and MTX response status was not significant in pre-allele , dominant , recessive , codominant , and homozygotic model . Moreover, significant between-study heterogeneity was not observed in all of the five models .Two studies were included in the meta-analysis of MTRR 66A > G (rs1801394), which contained data from a combined total of 126 responders and 198 nonresponders. The characteristics of these studies are described in When all of the samples were included, the association between the MTRR 66A > G (rs1801394) allele frequency  and MTX response status was not significant in pre-allele , dominant , recessive model , codominant model , and homozygotic model . Moreover, significant between-study heterogeneity was not observed in all of the five models .Four studies were included in the meta-analysis of RFC-1 80G > A (rs1051266), which contained data from a combined total of 298 responders and 423 nonresponders. The characteristics of these studies are described in When all of the samples were included, the association between the RFC-1 80G > A (rs1051266) allele frequency  and MTX response status was significant in pre-allele , dominant , recessive , and homozygotic model , but not in codominant model . Moreover, significant between-study heterogeneity was not observed in all of the five models –11.Stratification by ethnicity identified a significant association between the RFC-1 80G > A (rs1051266) allele frequency  and MTX response status in Europeans in pre-allele model, recessive Model , and homozygotic Model , and South Asian populations in Pre-allele model , dominant model , and homozygotic model , but not in other models –11.Two studies were included in the meta-analysis of SLC19A1 G > A (rs7499), which contained data from a combined total of 246 responders and 224 nonresponders. The characteristics of these studies are described in When all of the samples were included, the association between the SLC19A1 G > A (rs7499) 3 allele frequency and MTX response status was significant in pre-allele , dominant , recessive , and homozygotic model , but not in the codominant model . Moreover, significant between-study heterogeneity was not observed in all of the five models .Two studies were included in the meta-analysis of SLC19A1 A > G (rs2838956), which contained data from a combined total of 246 responders and 225 nonresponders. The characteristics of these studies are described in .When all of the samples were included, the association between the SLC19A1 A > G (rs2838956) 3 allele frequency  and MTX response status was significant in pre-allele model, recessive model  and homozygotic model , but not in the dominant  and the codominant model . Moreover, significant between-study heterogeneity was not observed in all of the five models .Two studies were included in the meta-analysis of ABCB1 3435C > T (rs1045642), which contained data from a combined total of 177 responders and 161 nonresponders. The characteristics of these studies are described in .2 = 86.9%, χ2 = 7.63, P = 0.006), dominant , recessive  and homozygotic model   allele frequency and MTX response status was not significant in pre-allele , dominant , recessive , codominant model , and homozygotic model . Moreover, significant between-study heterogeneity was observed in pre-allele (I= 0.006) .The Begg’s funnel, presented in The Begg’s funnel, presented in The Begg’s funnel, presented in The Begg’s funnel, presented in The pathogenesis of RA is not well understood, and there are considerable challenges in the design of effective medicines to cure RA. MTX is still the gold standard drug for RA and plays antiproliferative and anti-inflammatory roles in RA therapy11et al.312Methylenetetrahydrofolate reductase (MTHFR) is the best studied gene in the MTX cellular pathway and encodes a protein with several important roles, including the conversion of the prominent circulatory form of folate, 5, 10-methylenetetrahydrofolate required for purine and thymidine synthesis, to 5-methyl tetrahydrofolate, which acts as a carbon donor for the re-methylation of homocysteine to methionine by methionone synthaseet al.15202122ATIC is an important gene in the adenosine pathway, which is involved in the de novo synthesis of purine and converts aminoimidazole carboxamide adenosine ribonucleotide (AICAR) into formyl-AICAR and has been mapped to chromosome 2q35. MTX is polyglutamylated to form MTX polyglutamates after entering cells and directly inhibits ATIC, which leads to an intracellular accumulation of AICAR, and causing the release of adenosine into the extracellular space. The adenosine released diminishes the adherence of neutrophils and inhibits the function of natural killer cells, monocytes/macrophages and T-lymphocytes, thus producing potent anti-inflammatory effectset al.et al.et al.1924TYMS is a key enzyme in de novo thymidylate synthesis, and it is directly inhibited by MTX-PG. The TYMS gene has a tandem repeat polymorphism (two or three repeats of a 28 bp unit) in the enhancer region in the 5′-UTR. Lima A. in vivo methylation. It was reported that the MTRR 66A > G gene polymorphism might affect the activity of the enzyme and the pharmacological effects of MTX, and MTR AG and MTRR G allele seems association with the poor response of MTX in RA patientsMTR and MTRR participate in folate metabolism and are also involved in the metabolism of adenosine. MTRR is an auxiliary factor of MTR and catalyzes the regeneration of the methylcoamine, maintains sufficient activation of MTR, and is indirectly involved in the process of Solute carriers  and ABCs  are two groups of MTX transporters that influence cellular MTX uptake and efflux. The RFC-1 80G > A (rs1051266), SLC19A1 G > A (rs7499), SLC19A1 A > G (rs2838956), and ABCB1 3435C > T (rs1045642) polymorphisms were included in the present meta-analysis.et al.et al.130311et al.For RFC-1 80G > A rs1051266), RFC-1 is a constitutively expressed folate transport protein that has high affinity for MTX and is involved in transport of folate and MTX into the cell; the 80G > A variant maps within exon 2 of the RFC1 gene on chromosome 21 and encodes a substitution of histidine for the arginine at amino acid position 27. Ghodke-Puranik Y 66, RFC-1The present meta-analysis of SLC19A1 A > G (rs2838956) found significant associations between the SLC19A1 A > G (rs2838956) 3 allele frequency  and MTX response status in pre-allele recessive (A vs. G) and homozygotic model (AA vs. GG). For the SLC19A1 G > A (rs7499) gene polymorphism, this meta-analysis showed a significant association between the frequency of 3 alleles  and MTX response status in in pre-allele, dominant, recessive and homozygotic model when all 480 patients were included in the present study. However, because of the small sample size, the association between SLC19A1 (rs2838956 and rs7499) and the response to MTX in RA patients require further verification.et al.et al.Furthermore, the ABCB1 3435C > T (rs1045642) polymorphism, Takatori R In addition to the above MTX transporter genes, an increased likelihood of non-response has been reported to be associated with SLC22A11 rs11231809 T carriers; ABCC1 rs246240 G carriers; ABCC1 rs3784864 G carriers; the CGG haplotype for ABCC1 rs35592, rs2074087 and rs3784864; and the CGG haplotype for ABCC1 rs35592, rs246240 and rs3784864et al.Many RA progression genes have been included in research investigating the association between gene polymorphisms and MTX response. SNPs in AIF-1The lack of a significant association in this meta-analysis may represent a true result, but the possibility of a false-negative finding requires consideration. Certain limitations of our meta-analysis warrant consideration. First, the possibility of publication bias is always a concern. Although our analysis did not observe clear evidence of such a bias, it should be recognized that publication bias is difficult to exclude with certainty, especially when the number of incorporated studies is small. Second, publication bias could have distorted our meta-analysis because of the small number of included studies. We included 10, 8, 5, 3, and 4 studies in the meta-analysis of the MTHFR (677C > T (rs1801133) and 1298A > C (rs1801131)), ATIC 347C > G (rs2372536), TYMS 28 bp VNTR (rs34743033), and RFC-1 80G > A (rs1051266) polymorphisms, respectively, and 2 studies in the meta-analysis of the MTRR 66A > G (rs1801394), SLC19A1 (G > A (rs7499) and A > G (rs2838956)), and ABCB1 3435C > T (rs1045642) polymorphisms. Third, heterogeneity and confounding factors may have affected the meta-analysis. Variables such as sex, rheumatoid factor status, disease duration, and even the baseline DAS28 all have the potential to influence this analysis.Even though the genetic researches showed inconsisit results in the previous researches and meta-analysis, the genetics still seem to be a powerful supplemental method of the experssion and the biomarker studies in the future research into MTX response and the combination of the above research techniques should be helpful to understanding the MTX efficacy. Given the small effect size still a choke point of the polymorphisms associated research, genotyped these and other polymorphisms within the candidate genes in large sample size study are required. Furthermore, the ethnic group, sex, rheumatoid factor status, disease duration, MTX dose, treatment duration, MTX with or without the combination of the folic acid and even the baseline disease activity of the cohorts might greatly influence the correlation of genetic polymorphisms and the MTX efficacy, so the standardized research and treatment protocal is needed to improve the quality of the genetics researches.Taken together, this SR and meta-analysis demonstrated associations between MTX response in RA patients in MTHFR 1298A > C (rs1801131), ATIC 347C > G (rs2372536), RFC-1 80G > A (rs1051266), SLC19A1 A > G (rs2838956) and SLC19A1 G > A (rs7499) genetic polymorphisms, but not in the MTHFR 677C > T (rs1801133), TYMS 28 bp VNTR (rs34743033), MTRR 66A > G (rs1801394), and ABCB1 3435C > T (rs1045642) genetic polymorphisms. However, for the polymorphisms not being associated following meta-analysis (e.g. those in MTHFR 677C > T (rs1801133) could still be associated if larger cohorts were used, and studies of other polymorphisms are necessary in large cohorts and a rigorous way, which may provide more accurate results for the effect of the gene polymorphisms on the MTX treatment response.The methodology for this study was based on the Preferred Reporting Items for SRs and Meta-Analyses (PRISMA) statementAll studies investigating the relationship between a genetic variant and MTX treatment response in RA published before February 2016 were identified using computer-based searches of the PubMed database and Embase database (OvidSP) using the following combination of keywords: ‘methotrexate[Title/Abstract] AND (polymorphism[Title/Abstract] OR polymorphisms[Title/Abstract] OR genetic[Title/Abstract])) AND  OR “rheumatoid arthritis”[All Fields] OR (“rheumatoid”[All Fields] AND “arthritis”[All Fields]))’. Details of the search flow are provided in The following inclusion criteria have been used: 1) evaluation of the associations between the gene polymorphism (or nucleotide tandem repeat)and the efficacy of MTX treatment in adult patients with RA; (2) detailed genotype data could be acquired to calculate the odds ratios (ORs) and 95% confidence intervals (CIs); (3) per-reviewed publications in English or Chinese. Exclusion criteria include (1) duplication of previous publications; (2) comment, review, editorial and conference abstract; (3) inability to ascertain the number of null and wild genotypes or alleles; (4) studies not conforming to Hardy-Weinberg equilibrium; (5)studies with no SNP site or no gene sequence; (6)non-English or Chinese publications. Each study was screened in duplicate by two independent reviewers (QQ and HJ) per the guidelines of the Human Genomic Epidemiology (HuGE) Review Handbook. Of note, for studies of MTX efficacy, all measures of disease activity were accepted, which mainly included the 44-joint count Disease Activity Score (DAS44) or the 28-joint count DAS (DAS28) or Physician’s global assessment of disease (VAS score) and the ACR 20% or ACR 50% improvement response criteria (ACR20 or ACR50) evaluatiReferences were screened and data were extracted independently by 2 authors (QQ and HJ) using a predetermined data collection template. To resolve discrepancies on the inclusion of studies and interpretation of data, a third investigator (XC) was consulted, and consensus was reached by discussion. The following data were recorded: first author’s last name, year of publication, location of study, inclusion and exclusion criteria, sample size, MTX dose, SNP analysis results, treatment duration, demographic details of patients, follow-up period, and outcomes.2 statistic. Differences in the pooled ORs were compared using a Z test. Potential publication bias was assessed with the Egger’s test and represented graphically with Begg’s funnel plots of the natural log of the OR versus its standard error. A two-sided P value of less than 0.05 was considered significant for all analyses. All statistical meta-analyses were completed with STATA Hardy–Weinberg equilibrium (HWE) was accessed for each study by Chi-square test in response groups, and P < 0.05 was considered a significant departure from HWE. Studies that did not use a categorical outcome for response or did not publish necessary genotype counts per response category were excluded, if these data could not be obtained directly from the authors. The gene SNPs detected in more than two studies were included in the meta-analysis. Genotype frequencies for the MTHFR (677C > T rs1801133) and 1298A > C (rs1801131)), ATIC 347C > G (rs2372536), TYMS 28 bp VNTR rs34743033), MTRR 66A > G (rs1801394), RFC-1 80G > A (rs1051266), SLC19A1 (G > A (rs7499) and A > G (rs2838956)), and ABCB1 3435C > T rs1045642) polymorphisms were determined. In this process pre-allele, dominant, recessive, codominant, and homozygotic model were performed and allowed for the inclusion of a maximum number of studies12033, MTRR3 and 129642 polymHow to cite this article: Qiu, Q. et al. Polymorphisms and Pharmacogenomics for the Clinical Efficacy of Methotrexate in Patients with Rheumatoid Arthritis: A Systematic Review and Meta-analysis. Sci. Rep.7, 44015; doi: 10.1038/srep44015 (2017).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


TLR-9 gene rs187084 polymorphism was associated with an increased risk of KOA. Stratification analyses further validated this finding among old people (age ≥ 55 years). In conclusion, TLR-9 gene rs187084 polymorphism is positively correlated with susceptibility to KOA, especially among old people. Nevertheless, this finding should be confirmed by larger size studies with more ethnic populations.Osteoarthritis (OA) is a complex disease that is induced by many genetic risk variants and other factors. To examine the role of toll-like receptor 9 (TLR-9) in OA patients, we conducted a case–control study involving 215 knee OA (KOA) patients and 215 controls in a Chinese population. Genotyping with a custom-by-design 48-Plex single nucleotide polymorphism Scan™ Kit showed the  Osteoarthritis (OA) is a degenerative joint disease characterized by joint destruction with cartilage loss and occasional gross derangement of joint integrity . Knee osToll-like receptors (TLR) could bind to various damage-associated molecular patterns, which may be associated with autoinflammation and the production of costimulatory signals necessary for adaptive immune reactions . TLR-9 iTLR-9 gene rs187084 polymorphism and associated with T allele or TT genotype of this polymorphism TLR-9 genus (SLE) , and sepus (SLE) , which mus (SLE) . Howeverus (SLE) .TLRs are essential molecules implicated in both innate and adaptive immune responses . Many stTLR-9 gene rs187084 polymorphism and OA risk in a Chinese population from mainland China. The stratified analyses by sex and age in our study were not concerned in previous studies [In a two-stage case–control study with 503 patients and 428 controls, Su et al.  first in studies ,12. We fDespite the finding about the potential relationship between TLR-9 rs187084 polymorphism and KOA risk, the present study still has some limitations that merit careful consideration. First, confounding factors such as smoking habit and weight may affect the results. Second, the sample size is relatively small, which might underpower our work. Third, selection bias is unavoidable in this hospital-based case–control study. Finally, there is no further subgroup analysis due to limited clinical information.TLR-9 gene rs187084 polymorphism is associated with an increased risk of KOA, especially among old people (age ≥ 55 years). Nevertheless, this finding should be further evaluated by well-designed studies with larger sample sizes and ethnically diverse populations.In conclusion,


LSP1 rs3817198 T > C polymorphism and breast cancer risk has been widely investigated, but remains controversial. We therefore undertook a comprehensive meta-analysis to provide a high-quality evaluation of this association. A literature search was performed among Pubmed, EMBASE and Chinese National Knowledge Infrastructure (CNKI) databases prior to July 31, 2016, and the strength of the association between the LSP1 rs3817198 T > C polymorphism and breast cancer risk was assessed based on odds ratio (OR) and 95% confidence interval (95% CI). In total, 12 studies with 50,525 cases and 54,302 controls were included. Pooled risk estimates indicated a significant association between the LSP1 rs3817198 T > C polymorphism and breast cancer risk. Analysis of cases stratified based on ethnicity suggested that the association was significant in both Caucasian and Asian populations. Stratification based on source of controls revealed an association only in population-based studies. These findings indicate the LSP1 rs3817198 T > C polymorphism is associated with increased risk of breast cancer, especially in Caucasian and Asian populations. Large, well-designed studies with different ethnicities are still needed to verify our findings.The association between the  BRCA1, BRCA2, PTEN, TP53, CHEK2, ATM, BRIP1 and PALB2, are associated with high and moderate risk of breast cancer [In 2012, there were approximately 1.7 million newly diagnosed breast cancer patients and 521,900 deaths, accounting for 25% of all new cancer cases and 15% of all cancer-related death in women . Environt cancer . Howevert cancer .LSP1), is located on chromosome 11p15.5. It encodes an F-actin bundling cytoskeletal protein expressed in hematopoietic and endothelial cells [LSP1 gene have been identified, and one of the most common polymorphisms, the LSP1 s3817198 T > C, has been widely studied for its potential association with breast cancer risk. Several publications have reported a significant association of the LSP1 rs3817198 T > C polymorphism with the risk of breast cancer [LSP1 rs3817198 T > C polymorphism was significantly correlated with breast cancer risk. However, only seven studies were available at that time. Since then, some new case-control studies evaluating the association have emerged [LSP1 rs3817198 T > C polymorphism and breast cancer risk.One of these genes, lymphocyte-specific protein 1 , and only 2 were considered low quality .As shown in Figure LSP1 rs3817198 T > C polymorphism and breast cancer risk are listed in Table LSP1 rs3817198 T > C polymorphism and increased breast cancer risk (homozygous model (CC vs. TT): odds ratio (OR) = 1.12, 95% confidence interval (CI) = 1.02–1.24, P = 0.021, Figure P = 0.039). Stratified analysis by ethnicity revealed an increased risk of breast cancer associated with rs3817198 T > C in Caucasian populations : OR = 1.07, 95% CI = 1.01–1.13, P = 0.017; recessive model (CC vs. TC + TT): OR = 1.16, 95% CI = 1.07–1.27, P = 0.001; dominant model (TC +CC vs. TT): OR = 1.10, 95% CI = 1.04–1.16, P = 0.001; as well as comparison of allele frequencies: OR = 1.09, 95% CI = 1.05–1.13, P < 0.001, Figure P = 0.023, Figure LSP1 rs3817198 variant allele (C) was significantly associated with an increased breast cancer risk in population-based studies . Thus, the random-effects model was applied to calculate pooled ORs and 95% CIs. The leave-one-out sensitivity analysis found that no single study had qualitatively altered the pooled ORs, suggesting that our meta-analysis were relatively robust.There were significant heterogeneities detected while evaluating the association between the P = 0.637; heterozygous model: P = 0.156; recessive model: P = 0.191; dominant model: P = 0.194; comparison of allele frequencies: P = 0.268).Egger's test was used to assess publication bias in this meta-analysis. No publication bias was found for any of the five models  investigated the association between the  studies , 18–20 c11 investLSP1 rs3817198 T > C polymorphism and breast cancer risk, and is based on a relatively large sample size. Our results indicate that the LSP1 rs3817198 T > C polymorphism increases susceptibility to breast cancer, especially in Caucasian and Asian populations.Several limitations to our meta-analysis should be noted. First, in the stratification analysis by ethnicity, the numbers of studies among Asian and Africans were relatively small. Therefore, the statistical power might be not sufficient to assess the relationship. Second, the source of controls was not uniformly defined. Some studies adopted population-based controls or hospital-based controls, while other studies had nested controls. Third, our meta-analysis results were based on unadjusted risk estimates. We did not have sufficient data to conduct a more precise analysis with adjustment for age, obesity, smoking, drinking, menopausal status, environmental factors and lifestyle. Nonetheless, our meta-analysis provides a more comprehensive assessment of the association between the LSP1 rs3817198 T > C polymorphism and breast cancer risk, we performed a literature search using Pubmed, EMBASE, and Chinese National Knowledge Infrastructure (CNKI) databases prior to July 31, 2016. The search terms that used were as follows: “Lymphocyte-specific protein 1 or LSP1”, “variant or polymorphism” and “cancer or tumor or carcinoma”. Reference lists of relevant studies and review articles were also screened manually for additional eligible articles. Only articles written in English and Chinese were retrieved for further screening.To retrieve all eligible articles that assessed the association between the LSP1 rs3817198 T > C polymorphism with breast cancer risk; (c) sufficient information for estimating the ORs and 95% CIs; and (d) genotype frequency distributions in the control group in compliance with HWE. The exclusion criteria were: (a) not a case-control study; (b) abstracts, reviews, or comments; (c) lacking sufficient data; (d) replicating data. If several studies shared the same or overlapping subjects, only the most recent study or the study with the largest number of participants or most complete data was selected.Eligible studies had to satisfy all of the following criteria: (a) case-control studies in human populations; (b) investigation of the association of the LSP1 rs3817198 for cases and controls, evidence of HWE, and quality score  [Two authors independently reviewed and extracted the information from the studies and applied the inclusion and exclusion criteria. If any discrepancy was encountered, a consensus was finally reached by consultation and discussion with a third author. The following data were extracted from each eligible study: the surname of the first author, year of publication, country of origin, ethnicity, source of control, number of cases and controls, allele or genotype frequencies of the ore < 9) , 28.LSP1 rs3817198 T > C polymorphism and the risk of breast cancer was assessed by ORs and corresponding 95% CIs under five different genetic models. The models were as follows: homozygous model (CC vs. TT), heterozygous model (TC vs. TT), recessive model (CC vs. TC + TT) and dominant model (TC +CC vs. TT), as well as comparison of allele frequencies (C vs. T). We use the Q-statistic to evaluate between-study heterogeneity. For the Q test, a P value greater than 0.10 indicated a lack of heterogeneity. In the case of no heterogeneity, the fixed-effects model (Mantel-Haenszel method) was applied [I2 test was also used to quantify the heterogeneity among studies [The strength of the association between the  applied . Otherwi applied . In addi studies . We also studies . All sta