MTHFR) C677T polymorphism as an instrumental variable, which affects the plasma Hcy levels. Estimate of its effect on plasma Hcy level was based on a recent genome-wide meta-analysis of 44,147 individuals, while estimate of its effect on MM risk was obtained through meta-analysis of case-control studies with 2,092 cases and 4,954 controls. By combining these two estimates, we found that per one standard-deviation (SD) increase in natural log-transformed plasma Hcy levels conferred a 2.67-fold increase in risk for MM : 1.12–6.38; P = 2.7 × 10−2). Our study suggests that elevated Hcy levels are causally associated with an increased risk of developing MM. Whether Hcy-lowering therapy can prevent MM merits further investigation in long-term randomized controlled trials (RCTs).Observational studies have demonstrated an association between elevated homocysteine (Hcy) level and risk of multiple myeloma (MM). However, it remains unclear whether this relationship is causal. We conducted a Mendelian randomization (MR) study to evaluate whether genetically increased Hcy level influences the risk of MM. We used the methylenetetrahydrofolate reductase ( Multiple myeloma (MM) is a malignant disease characterized by proliferation of clonal plasma cells in the bone marrow and typically accompanied by the secretion of monoclonal immunoglobulins that are detectable in the plasma or urine, causing anemia, pathological fracture, and the clinical symptoms of renal failure. Among other plasma cell dyscrasias, such as Waldenström’s macroglobulinaemia and primary amyloidosis, multiple myeloma is the second most frequent haematological malignancy with an age-adjusted incidence of six per 100,000 per year in the USA and Europe13Homocysteine (Hcy), a sulfur-containing amino acid, is formed in the demethylation of the essential amino acid methionine68910In the absence of evidence from high-quality randomized controlled trials (RCTs), the principles of Mendelian randomization (MR) can be applied to strengthen or refute the causality of biomarkers in disease etiology. MR is a study design in which genetic variants are served as instrumental variables for estimating the unconfounded effect of an exposure  on a disease MTHFR) C677T polymorphism as an instrument variable have been carried out in the past111314MTHFR C677T polymorphism as an instrumental variable.MR analyses using methylenetetrahydrofolate reductase  is an approach that provides the required information size in meta-analyses. Under the premise of not expanding the type I error, we can earlier draw a conclusion using TSA, which can terminate defects of invalid test and save medical resources, compared to the traditional meta-analysis. And using TSA can make our result of meta-analysis be more stable and reliableMTHFR C677T polymorphism and risk of MM. 78 articles were excluded after reading abstract and title. Then, 5 articles were excluded once again due to insufficient data, review or corresponding article. Finally, 9 studies with a total of 2,092 cases and 4,954 controls, were included in our meta-analysis1718192021222324MTHFR C677T polymorphism, and a small part of which were genotyped by Microarray or TaqMan assay. Genotypes distribution in the controls of all included studies were in agreement with HWE (Hardy Weinberg Equilibrium).The process of literature retrieval and exclusion was shown in MTHFR C677T polymorphism and MM susceptibility under allele model . However, no remarkable association was observed between MTHFR C677T polymorphism and MM risk under other four genetic models   , Fig. 2.MTHFR C677T polymorphism is associated with increased risk of MM and further relevant trials are unnecessary , the required information size is 2823 subjects to demonstrate the issue. Until now, the cumulative Z-curve crossed the trial sequential monitoring boundary and the required information size has been reached, confirming that ecessary . The triMM/per T-allele from a meta-analysis of 9 case-control studies and beta hcy/per T-allele from a meta-analysis of genome-wide association studies by van Meurs and colleagues, we observed that each 1-SD increase in natural-log-transformed plasma Hcy level was associated with a 2.67-fold increased risk of MM   . Using tvs. CT + CC, t = 1.53, P = 0.169).The leave-one-out sensitivity analysis showed that no single study qualitatively altered the pooled ORs, indicating the reliability and stability of our results. Begg’s funnel plot and Egger’s test were performed to evaluate the potential publication bias of literatures. The shape of the funnel plot showed no evidence of obvious asymmetry . The EggOur MR study demonstrated that a genetic increase in natural log-transformed plasma Hcy by 1 SD was associated with a 2.67-fold increased risk of MM, providing strong evidence in support of a causal role of Hcy on MM susceptibility. Since genetic effects on Hcy levels represent differences that generally persist throughout adult life, the estimate of our MR study reflects an effect of Hcy over the course of a lifetime. Meanwhile, our findings are consistent with previous evidence from observational studies that plasma higher Hcy levels influence risk of MM8MTHFR is a key enzymes of the methylation reaction. MTHFR converts 5,10-methyl-enetetrahydrofolate into 5-methyltetrahydrofolate and this reaction provide a methyl for Hcy into methionine in the catalyzed reaction by methionine synthase (MTR) and MTR requires vitamin B12 as a coenzymeMTHFR C677T reduced by approximately 70% of the mean enzyme activity and the heterozygous mutation of MTHFR C677T reduced by approximately 35% of the mean MTHFR activityMTHFR C677T polymorphism was related to elevated plasma Hcy levels and lower folate level282930As we all know, Hcy, a well-known cardiovascular risk factor, involves in one-carbon methyl group-transfer metabolism343637383940Our research has advantages in itself. Firstly, with the application of Mendelian randomization, the effect estimates are closer to the real situation and we are able to overcome potential confounding and reverse causation that may bias evaluations from observational studies. Secondly, Our MR analysis described the association of a lifetime of exposure to Hcy-increasing allele in the general population, whereas observational studies merely provide insights from intervention for shorter periods in individuals at risk. Lastly, the present data from the largest GWAS meta-analysis for Hcy level  and from the current meta-analysis for MM risk  have enabled us to more precisely examine our study hypothesis than if we used individual-level data from a small study32MTHFR C677T polymorphism since data on other clinical parameters across C677T genotypes are rarely provided from most qualified articles, requiring further confirmation. Thirdly, canalization, the process by which compensatory feedback mechanisms attenuate the phenotypic consequences of genetic variation, has been extensively investigated in the circumstance of MR4445A few limitations of our study should be considered. First of all, MR estimates which utilize instrumental variables accounting for little variance in a trait tend to be biased towards the nullAt last, we have to emphasize this point about the impact of epigenetics on Mendelian randomization as a result of epigenetics gaining recognition as an independent field of study within the last decades. An increasing number of reports suggest that random distribution of epigenetic changes (e.g. gene expression) at conception should be considered on the assumption of MR analysis48In conclusion, our analysis provides a puissant evidence for a causal role of increased plasma Hcy levels in the etiology of MM. These findings may provide a new insight for further investigating the potential pathogenesis of MM and therapeutic target by decreasing the plasm Hcy levels to prevent the onset and progression of MM. Nevertheless, substantial long-term RCTs assessing the effect of Hcy-lowering on the risk of MM should be carried out in future.MTHFR C677T polymorphism with multiple myeloma risk, we performed a meta-analysis of case-control studies. We conducted a comprehensive search in Pubmed, Embase, Web of science databases for all eligible studies  by two authors independently using the following strategies. Key words or terms used for searching were: “methylenetetrahydrofolate reductase” or “MTHFR”, “multiple myeloma”, and “polymorphism” or “variation” or “variant” or “mutation” or “genotype” or “allele” or “SNP”, without any restriction on the language. Reference lists of relevant articles were reviewed manually to look for additional studies. For inclusion, studies had to meet the following criteria: (1) evaluation for the association between MTHFR C677T polymorphism and multiple myeloma; (2) studies were designed as the case-control type; (3) genotype frequencies for both cases and controls were available. Studies were excluded if: (1) no detailed genotype frequency; and (2) case reports, family-based studies, abstracts, editorials and review articles. When multiple literatures reported the same population, only the most recent one with the largest sample sets was selected for this meta-analysis. Two authors selected the articles independently according to the above criteria. Any uncertainty regarding the eligibility was adjudged by further joint inspection of the publications.To estimate the association of the P value). If these were not possible, the authors of the publications were contacted via E-mail for more detailed data.The following data were independently extracted by two investigators from each eligible article according to a fixed protocol: first author’s name, publication year, country and ethnicity of population, genotyping methods, source of control, number of cases and controls, genotype distributions in cases and controls and the HWE in controls  with their 95% confidence intervals (95% CIs) were calculated to evaluate the strength of the association between MTHFR C677T polymorphism and multiple myeloma risk based on different genetic models: allele model (T vs. C), homozygous model (TT vs. CC), heterozygous model (CT vs. CC), dominant model (TT + CT vs. CC), and recessive model (TT vs. CT + CC). Statistical heterogeneity between eligible studies was evaluated by using the Cochran’s Q statistic and I2 testP < 0.1 and I2 exceeding 50% indicated substantial heterogeneity across studies, then a random-effects model was chosen to perform meta-analysis, otherwise, the fixed-effects model was selected. Begg’s funnel plot and Egger’s regression test were used to search for publication bias and a P value > 0.05 suggested no significant publication bias have been detectedHardy-Weinberg equilibrium (HWE) of genotypes distribution in the control group was checked by the χP value is sufficiently small to show the anticipated effect and whether the trial should be terminated early. In the same manner, trial sequential monitoring boundaries can be applied to meta-analyses1654552) required information size, since the heterogeneity adjustment with I2 underestimates the required information sizeMeta-analyses may result in type I errors owing to an increased risk of random error when sparse data are analysed and due to repeated significance testing when a cumulative meta-analysis is updated with new trials5253http://www.ctu.dk/tsa/) and provided the 95% confidence intervals adjusted for sparse data or repetitive testing, which we describe as the TSA adjusted 95% confidence intervals.When the cumulative Z-curve crosses the trial sequential monitoring boundary, a sufficient level of evidence may have been reached and further trials are unnecessary. If the Z-curve does not cross any of the boundaries and the required information size has not been reached, evidence to reach a conclusion is insufficientMM/Hcy) as log OR MM/Hcy = /beta Hcy/per T-allele, as in previous studies59MM/Hcy is the (log) increase of multiple myeloma risk by SD unit increase in the natural log-transformed plasma Hcy (MR estimate). Log ORMM/per T-allele is the (log) increase in multiple myeloma risk per allele (gene-multiple myeloma association). Beta Hcy/per T-allele is the number of SD differences in the natural log-transformed plasma Hcy levels per allele  (gene-Hcy association). The standard error of the MR estimate was derived using the Delta methodhttp://spark.rstudio.com/sb452/power/)MTHFR C677T polymorphism is R2 = 0.01. All P values were two sided. All above statistical analyses were performed using STATA software version 12.0 .We calculated a MR estimate of the effect of the plasma Hcy levels on the risk of multiple myeloma .


Whether dietary β-carotene and vitamin A intake protect against lung cancer risk is not clear. Therefore, we performed this meta-analysis to investigate the association between them. The related articles were searched using the databases PubMed and the Web of Knowledge up to May 2015. We used the random-effect model to estimate the relative risk (RR) and their 95% CI. Small-study effect was assessed using Egger’s test. In total, 19 studies comprising 10,261 lung cancer cases met the inclusion criteria. The pooled RR and their 95% CI was 0.855 (0.739–0.989) for higher category of dietary vitamin A intake and lung cancer risk, especially among Asian populations and in the cohort studies. Evidence from 18 studies suggested that higher category of dietary β-carotene intake could reduce lung cancer risk (0.768 (0.675–0.874)).The associations were also significant in American and Asian populations. In conclusions, higher category of dietary β-carotene and vitamin A intakes could reduce the risk of lung cancer. However, the dose-response analysis was not performed due to the limited data in each individual study. Due to this limitation, further studies with detailed dose, cases and person-years for β-carotene and vitamin A of each category are wanted to assess this dose-response association. Lung cancer is a leading cause of cancer mortality worldwide  and the Two recent meta-analyses had been performed to evaluate the relationship between vitamin C  and vitaA comprehensive literature search was performed from 1990 to May 2015 on PubMed and the Web of Knowledge. The following keywords were used in the search: “vitamin A” or “β-carotene” combined with “lung cancer” or “lung carcinoma” without any restrictions. Moreover, the references of the included studies were also reviewed and identify additional studies which were not captured by our computer searches.The studies were considered if they fulfilled the following inclusion criteria: (1) they were observational studies; (2) reported dietary vitamin A or retinol or β-carotene intake; (3) the ending outcome was lung cancer; (4) multivariate-adjusted relative risks (RR) or odds ratio (OR) with 95% confidence intervals (CI) were provided. We excluded the studies if they were: (1) abstracts and (2) overlapped publications.The following data of included studies was extracted: first author’s last name, study design, publication years, country where the study was performed, number of cases, sample size, sex, the histological type of lung cancer, variables adjusted for in the analysis, the category of RR and their 95% CI for dietary vitamin A and β-carotene intake, respectively. We only extracted the results of dietary vitamin A and β-carotene intake if the total intake were available. From each study, the multivariable adjustment RR and 95% CI were extracted. Otherwise, the crude RR was useful.I2, and I2 values of 0%–25%, 25%–50%, 50%–75% and >75% represent no, low, moderate and high heterogeneity , but not in the European populations. Furthermore, when we stratified studies by sex and histological type, the associations were significant only in females and in squamous cell carcinoma. Moderate of heterogeneities were found both in vitamin A and β-carotene intake and lung cancer risk. Therefore, we used meta-regression with publication years, study design, sex, geographic locations, number of cases and source of controls to explore the potential heterogeneity founded in the analyses. However, the results from meta-regression showed no significant finding in the above-mentioned analyses.p = 0.464) or vitamin A intake (p = 0.182).Sensitivity analysis showed that the pooled results were not changed while excluded one study at a time. The Egger’s test did not find any significant small-study effect for lung cancer risk with dietary β-carotene intake (versus lowest category was significantly associated with reduced lung cancer risk. When we performed the subgroup analyses, the associations were significant among American and Asian populations.Findings from our study indicated that the highest category of dietary vitamin A intake could reduce the lung cancer risk compared with lowest vitamin A category, especially in prospective studies and Asian populations. The pooled results suggested that highest category of β-carotene intake Two previous clinical trials had reported that high-dose β-carotene supplementation among smokers and/or asbestos exposed workers could increase the lung cancer risk when compared with the placebo group without any vitamins supplementation ,35. The Vitamin A and β-carotene had been reported associated with some cancers ,40,41,42P-value was all greater than 0.05 for meta-regression analysis and the heterogeneity were presence in some subgroup analyses (In our study, significant between-study heterogeneities were found in several analyses. Munafo and Flint  had repoanalyses . Lung caOur meta-analysis had some advantages. First, a highlight of our analysis was that higher category of dietary vitamin A and β-carotene intake could significantly reduce lung cancer risk. Second, the current study included many more cases and participants, and this could obtain a more precise result between dietary β-carotene and vitamin A intake and lung cancer risk. Third, small-study effect was not detected in our study.There were some limitations that should be concerned in our study. First, case-control study may cause the recall or selection bias, and this can improve the potential heterogeneity. Several case-control studies were included in this study. In our results, the association was not significant in case-control studies. However, an inverse association was found between dietary β-carotene intake and lung cancer risk. Although cohort studies can allow a much greater possibility of reaching reasonable conclusions, the case-control study is an important method. Second, the dose-response analysis between dietary β-carotene and vitamin A intake and lung cancer risk was not conducted due to the limited data in each individual study. Further studies with providing dose, cases and person-years for β-carotene and vitamin A are wanted to assess this dose-response association. Third, for the subgroups of geographic locations, significant association was found only among American and Asian populations, but not in the European populations. In addition, only three studies were conducted in Europe. Therefore, the results from our study are more applicable to American and Asian populations. More studies are wanted to assess this association in other countries. Fourth, moderate between-study heterogeneities were found in whole result and some subgroup analyses, but the meta-regression cannot explain the heterogeneity. Thus, other unknown confounders, such as the possible interaction between genetic and environment variables, may be potential contributors to this heterogeneity.Findings from this study indicated that dietary vitamin A and β-carotene intake could reduce lung cancer risk. However, dose-response analysis was not performed due to the limited data in each individual article. Due to this limitation, further studies with detailed dose, cases and person-years for each category are wanted to assess this dose-response association.


Tumor suppressor gene p53 plays an important role in the maintenance of the genomic integrity, and mutation in the gene may alter an individual’s susceptibility to various carcinomas. P53 Arg72Pro or codon 72 polymorphism has been indicated to increase the risk of developing certain cancers such as bladder cancer and cervical cancer. Human papillomavirus (HPV) infection has been shown as a risk factor for certain cancers such as cervical cancer and oral cancer as well, and the HPV oncoprotein E6 may induce the degradation of p53 function. However, the association between p53 Arg72Pro polymorphism and the risk of oral cancer with HPV infection remains inconclusive. Therefore, this meta-analysis involving 5,614 participants was performed to investigate the relations among the p53 Arg72Pro polymorphism, HPV infection, and the risk of developing oral cancer.A search of the literature by PubMed, Embase, Web of Science, and China National Knowledge Infrastructure databases was conducted to identify studies based on the inclusion and exclusion criteria. Odds ratios with 95 % confidence intervals were combined using a random-effect model or a fixed-effect model. The current study was conducted with 13 studies consisting of 2,413 cases and 3,201 controls. Neither overall analysis nor stratified analyses detected any obvious evidence of association between p53 Arg72Pro polymorphism and oral cancer susceptibility in all genetic models. However, a significant association between p53 Arg72Pro polymorphism and the risk of oral cancer with HPV infection was detected in the Arg/Arg vs. Arg/Pro + Pro/Pro model.In the current meta-analysis which used the quantitative data synthesis for the first time, our study demonstrated that p53 Arg72Pro polymorphism together with HPV infection might jointly alter an individual’s susceptibility to the risk of oral cancer. Our results suggested that p53 Arg72Pro polymorphism may partly contribute to the pathogenesis of oral cancer development. The incident rate for oral cancer has been increasing recently. Research studies have suggested that smoking, alcohol consumption, and betel quid chewing are risk factors that predispose individuals to oral cancer –3. NeverMany published studies have reported that oral carcinoma susceptibility is associated with gene polymorphism. In recent years, much attention has been focused on the p53 codon 72 Arg/Pro polymorphism. The p53 tumor suppressor gene is located at human chromosome 17 and encoding a 53-kDa nuclear phosphoprotein which plays a crucial role in cell cycle regulation, maintenance of genomic integrity, apoptosis, and challenge of environmental insults , 9. MutaHPV infection have been proved as an independent risk factor for the development of oral cancer , 14. TheTherefore, whether or not p53 Arg72Pro polymorphism can increase the risk of oral cancer with HPV infection remains unclear. Based on the above reasons, we conducted this evidence-based quantitative meta-analysis to investigate the relationship between p53 polymorphisms and the risk of HPV-related oral cancer.Relevant articles were searched using combinations of search terms “oral”, “oral cavity”, “buccal”, “oropharynx”, “oral cancer”, “oral carcinoma”, “oral squamous cell carcinoma”, “ameloblastoma”, “P53”, “TP53”, “Arg72Pro”, “HPV”, “human papillomavirus”, “polymorphism”, “susceptibility”, and “gene variants”, in PubMed, Embase, Web of Science, and China National Knowledge Infrastructure databases, focusing on articles which were published from their earliest entry points to April 2014.The following inclusion criteria were used for the selection of literature for meta-analysis: (1) published in English; (2) examined case–control studies investigating the association between HPV infection, Arg72Pro polymorphism, and the risk of oral cancer; (3) definite histopathologic diagnosis; and (4) genotype distribution in controls must be in Hardy-Weinberg equilibrium (HWE). Major exclusion criteria included: (1) the unpublished reports and abstracts; (2) when duplicated studies published by the same author, only the most recent publication study was chosen.All the eligible articles were independently reviewed and extracted by two reviewers (YL and WY) according to the selection criteria listed above. Disagreement was resolved by the third independent investigator (JH). The following data were extracted from the each study: the first author, year of publication, country, ethnicity, genotyping methods, source of the controls, and genotype numbers from the cases and controls.2 statistic were evaluated to investigate the between-study heterogeneity [p < 0.05 was considered statistically significant) [The STATA version 11.0 software  was used to conduct the statistical analyses. The combined odds ratio (OR) with a corresponding 95 % confidence interval (CI) was estimated to evaluate the relationship among p53 Arg72Pro polymorphisms, HPV infection, and the risk of oral cancer. For control groups, the goodness-of-fit test (Chi-square test or Fisher exact test) was used to test the deviations from HWE. The following statistical models were used in the meta-analysis: the allelic model , the codominant model (homozygote comparison: Arg/Arg vs. Pro/Pro), the dominant model (Arg/Arg + Arg/Pro vs. Pro/Pro), and the recessive model (Arg/Arg vs. Arg/Pro + Pro/Pro). Statistics Q and Iogeneity , 23. Eitogeneity , 25. Addificant) , 27.As shown in Fig. P = 0.000, 0.002, 0.013, 0.023 for the allelic genetic model, the homozygote comparison model, the dominant model and the recessive model, respectively Table A total of 13 studies were included in the meta-analysis to examine the association between p53 Arg72Pro polymorphism and the risk of oral cancer. There was no evidence of a significant association in any genetic model   model . Additionally, Egger’s tests did not reveal any obvious evidence of publication bias either Table .Since the identification of the p53 codon 72 polymorphism, many studies have been devoted to explore the genetic effect of p53 Arg72Pro polymorphism on susceptibility of oral cancer. However, the evidence regarding the role of single nucleotide polymorphism of p53 Arg72Pro gene as a genetic marker for the risk of oral cancer is inconsistent. This prompted us to undertake the present meta-analysis to explore a more robust estimate of the relationship between p53 Arg72Pro genetic variant and the oral cancer susceptibility. In this study, we found that individuals who have genetic variants (Arg/Pro genotype or Pro/Pro genotype) may not have induced modification of oral cancer risk compared with those who carry wild-type genotype (Arg/Arg genotype). Same SNP may play different roles in the development of cancer in different ethnic populations. Therefore, the relation of p53 Arg72Pro polymorphism with oral cancer susceptibility might be affected by the different ethnic groups. Nevertheless, neither Arg/Arg genotype individuals nor Pro carriers have a significant association with oral carcinoma in the Asian group or the Caucasian group.HPV belongs to a large virus family, the PAPOVA virus family. There are nearly a hundred types of HPV discovered in human . In thisThe small sample size is a major limitation in this study. There were only five research articles investigating the interaction between the infection with HPV and p53 codon 72 polymorphism on the risk of oral carcinoma. Thus, additional studies with larger sample size are needed to further evaluate the impact of HPV infection and p53 Arg72Pro polymorphism on HPV-associated oral cancer susceptibility.For the first time, the current study provided the quantitatively synthesized estimates for the effect of interaction between HPV infection and p53 Arg72Pro polymorphism on the risk of developing oral cancer. This combined effect might together alter an individual’s susceptibility to oral cancer. Our results suggested that p53 Arg72Pro polymorphism may partly contribute to the pathogenesis of oral cancer development. Further well-designed studies with reference to the interactions of gene-gene and gene-environment on p53 codon 72 polymorphism to oral carcinoma susceptibility are required.


B vitamins may correlate with Parkinson’s disease (PD) through regulating homocysteine level. However, there is no comprehensive assessment on the associations between PD and B vitamins. The present study was designed to perform a meta-analytic assessment of the associations between folate, vitamin B6, and vitamin B12 and PD, including the status of B vitamins in PD patients compared with controls, and associations of dietary intakes of B vitamins and risk of PD. A literature search using Medline database obtained 10 eligible studies included in the meta-analyses. Stata 12.0 statistical software was used to perform the meta-analysis. Pooled data revealed that there was no obvious difference in folate level between PD patients and healthy controls, and PD patients had lower level of vitamin B12 than controls. Available data suggested that higher dietary intake of vitamin B6 was associated with a decreased risk of PD (odds ratio (OR) = 0.65, 95% confidence intervals (CI) = ), while no significant association was observed for dietary intake of folate and vitamin B12 and risk of PD. PD patients had lower level of vitamin B12 and similar level of folate compared with controls. Dietary intake of vitamin B6 exhibited preventive effect of developing PD based on the available data. As the number of included studies is limited, more studies are needed to confirm the findings and elucidate the underpinning underlying these associations. Parkinson’s disease (PD) is a geriatric neurodegenerative disorder with increasing global prevalence resulting in tremors, rigidity, and bradykinesia ,2,3. AltAs methionine synthesis from Hcy requires B vitamins as cofactors, high B vitamins intake will decrease plasma Hcy level and may exert preventive effects of developing PD. However, to the best of our knowledge, there is no comprehensive assessment on the associations between PD and B vitamins. Thus, the present study was designed to comprehensively assess: (i) the B vitamins status in PD patients and controls; and (ii) efficacy of dietary intakes of B vitamins in lowering risk of PD, through meta-analyzing the available literatures. Levodopa is the most effective drug in the symptomatic management of PD and it was found that plasma Hcy levels are elevated in patients treated with levodopa. Thus, the meta-analyses of levodopa treated or untreated PD patients and controls were performed separately.With the following search terms “Parkinson’s disease” and “B vitamins” or “folate” or “folic acid” or “vitamin B6” or “vitamin B12” or “cobalamin”, a literature search was performed in Medline database from inception until February 2015. To avoid missing potentially relevant studies by the search strategy, the reference lists of retrieved articles were also manually screened. A restriction to human studies and references published in English is imposed in the references selection. The review, opinion and editorial references as well as mechanistic studies were not considered. By reviewing titles, abstracts, and a full text of all citations identified with database searches, the potentially relevant references were identified on the basis of the following inclusion criteria.Studies were included if they met the following criteria. The individual studies were examined and determined to be of sound science. For the meta-analysis of the B vitamins levels in PD patients, it was required that the included studies clearly provided the mean and standard deviation (SD) values of B vitamins levels for PD patients and matched controls. For the meta-analysis of the dietary intake of B vitamins and risk of PD, the odds ratios (ORs) or relative risks (RRs) or hazard ratios (HRs) with 95% confidence intervals (CI) of PD risk should be clearly provided.I2 statistic. The random-effect model was used to pool the SMD of B vitamins levels and OR of PD risk. All calculations were done with the Stata 12.0 statistical software .With prespecified data extraction tables, data was extracted from the included studies about the characteristics of study populations, B vitamin levels or PD risk and adjusting factors. The extracted data was used to obtain the corresponding standardized mean difference (SMD) and 95% CI of B vitamins levels in PD patients and controls, or OR and 95% CI of PD risk. Possible statistical heterogeneity between the eligible studies was assessed using the There were three studies included in the meta-analysis of the association between dietary intakes of folate, vitamin B6 and vitamin B12 and risk of PD . AccordiIn the present meta-analysis, the available data indicated no obvious difference in folate level between PD patients and controls, while vitamin B12 level was lower in PD patients than matched controls. Higher dietary intake of vitamin B6 may be associated with a decreased risk of PD, while there is no evidence to support the effects of folate and vitamin B12.Homocysteine has been found to exhibit multiple neurotoxic effects and it is rational to infer that high dietary intakes of B vitamins may lower the risk of PD by decreasing plasma homocysteine levels. The present meta-analysis on the available studies suggested that there was no significant association between dietary intake of folate and vitamin B12 and risk of PD, while high dietary intakes of vitamin B6 was associated with decreased risk of PD. Thus, it is speculated that there may exist an alternative mechanism underlying the protective effects of vitamin B6 for PD. Oxidative stress has been widely accepted to play an important role in the pathogenesis of PD ,5. BesidSeveral limitations of the present study warrant mention. First, the number of eligible studies is limited, especially for the analysis in the B vitamins levels in levodopa untreated PD patients. Second, the B vitamins dietary intakes are based on self-administered diet questionnaire, and the dosages varied in the included studies, which may potentially affect the results, and studies with control of people’s diet are recommended. Third, only studies published in English were included in the analysis.To summarize, available data indicated that that PD patients had lower level of vitamin B12 and similar level of folate compared with controls. High dietary intake of vitamin B6 may be associated with a decreased risk of PD, while no obvious association was observed for dietary intake of folate and vitamin B12 and risk of PD. As the number of included studies is limited, more studies are warranted to confirm the findings and elucidate the mechanisms underlying these associations.


Aim. To pool the data currently available to determine the association between calcium channel blockers (CCBs) and risk of Parkinson's disease (PD). Methods. Literature search in PubMed, EBSCO, and Cochrane library was undertaken through March 2014, looking for observational studies evaluating the association between CCBs use and PD. Pooled relative risk (RR) estimates and 95% confidence intervals (CIs) were calculated using random-effects model. Subgroup analyses, sensitivity Analysis, and cumulative meta-analysis were also performed. Results. Six studies were included in our meta-analysis according to the selection criteria, including three cohort studies and three case-control studies involving 27,67,990 subjects including 11,941 PD cases. We found CCBs use was associated with significant decreased risk of PD, compared with not using CCBs ); a significant heterogeneity was found between studies . Both the classes of CCB, that is, dihydropyridine calcium channel blockers (DiCCB)  P = 0.032) and non-DiCCB  P = 0.013), were found to be reducing the risk of PD. Conclusion. In our analysis, we found that CCBs use was associated with a Significantly decreased risk of PD compared with non-CCB use. Approximately 1% of the population over 60 years of age suffers from Parkinson's disease (PD) which is a second most common chronic progressive neurodegenerative disorder in the elderly after Alzheimer's disease . PatholoRecent interest in antihypertensive drugs, especially CCBs, has been triggered by the belief that these medications, which inhibit nitric oxide, tumor necrosis factor-alpha, and interleukin-1 beta synthesis, thus reduce oxidative stress and the inflammatory response, which might be neuroprotective . ExperimSeveral observational studies have been conducted to examine the association between CCBs use and PD risk and have generated mixed results. Until now, no definite conclusion on this topic has been established. In the present meta-analysis, we examined the CCB use in relation to risk of PD.Two authors independently performed the literature search by using MedLine (PubMed), EBSCO, and the Cochrane library databases up to March 2014. Search terms include “ OR antihypertensive agents) OR calcium antagonists) OR dihydropyridine calcium channel blockers) AND parkinson disease” with limits of humans and English language. Titles and abstracts of the resulting articles had been examined to exclude irrelevant studies. Full texts of remaining articles were read to extract information on the topic of interest. Bibliographies and citation sections of retrieved articles had been reviewed for additional pertinent studies.The studies considered in this meta-analysis were all observational (cohort or case-control) studies that evaluated exposure to CCBs and risk of PD. Articles were excluded if they were reviews, letters to the editor without original data, editorials, case reports, or clinical trials. When there were multiple publications from the same population, only data from the most recent report were included in the meta-analysis and the remaining was excluded. Any discrepancies were addressed by a joint reevaluation of the original article.Two authors independently reviewed the primary studies to assess the appropriateness for inclusion in the present meta-analysis and data which has been extracted. The following information was extracted from each study: (i) first author's last name, year of publication, and country of the population studied; (ii) study design; (iii) number of subjects and number of PD cases; (iv) effect estimates and 95% confidence intervals (CIs); (v) assessment of CCB exposure; (vi) PD assessment; and (vii) control for confounding factors by matching or adjustments, if applicable. We extracted the effect estimates that reflected the greatest degree of control for potential confounder.Two authors using the Newcastle-Ottawa Scale (NOS)  assessedQ and I2 statistics; for the Q statistic, a P value <0.10 and for I2, a value >50% was considered statistically significant for heterogeneity [P < 0.05 was considered statistically significant, except otherwise specified.Because the risk of PD is low, the risk ratio (RR) in prospective cohort studies mathematically approximates the odds ratio , therefoogeneity . The priogeneity , 13, whiThe primary outcome in this meta-analysis was reported as RR with 95% CI of developing PD in CCB users. Subgroup analyses were performed according to (i) dihydropyridine calcium channel blockers (DiCCBs) versus non-DiCCBs; (ii) individual type of CCB; (iii) dose; (iv) duration; (v) study design (cohort and case-control); (vi) gender; and (vii) age group to examine the impact of these factors on the association. To evaluate the stability of our results, we also performed a one-way sensitivity analysis. The present work was performed in this meta-analysis as per the guidelines for the meta-analysis PRISMA .A total of 626 articles were identified during the initial search . After sSix relevant studies were identified, including three cohort –17 and tThree cohort studies involve –17 Tabl 27,48,57Three population-based case-control studies –20 Tabl involvinP = 0.031; I2 54.6%), random-effects model was chosen over a fixed effects model. We found CCB use was associated significantly with decreased risk of PD compared with not using CCB ). The multivariable adjusted RRs of use of CCB and risk of PD for each study and grouped data of all studies are shown in P = 0.68) indicating little or no publication bias in our analysis.As a significant heterogeneity was found (P = 0.032) and non-DiCCB  P = 0.013), were found to be reducing the risk of PD. We found a significant reduced risk of PD in females 0.67  P = 0.243, in contrary to males 0.85  P < 0.001.Both the classes of CCB, that is, DiCCB  P = 0.080 and Becker et al. [P = 0.07.To test the robustness of our findings, we also performed a sensitivity analysis. To do this, the overall effect size was calculated by removing one study at a time. This analysis showed no significance variation when excluding the Pasternak et al.  study 0.r et al.  study 0.P < 0.001) compared to studies having medium quality [P = 0.272) (P < 0.001).Subgroup of studies having high quality , 19 pres quality –18, 20 (= 0.272) . StudiesIn the past decade, the role of CCBs in reduction of PD has been understood increasingly. With the present pooled analysis of 6 observational studies, a 19% reduction in PD risk among CCBs users as compared to nonusers was observed. CCBs are one of the most important antihypertensive drugs. The present analysis demonstrated the potential neuroprotective role of CCBs in reducing the risk of PD.α-synuclein deposition, dysfunction of protein turnover, and mitochondrial dysfunction leading to neuronal loss via excitotoxicity, calcium overload, and apoptosis [α-synuclein aggregation include posttranslational modifications, oxidative stress, and raised intracellular calcium ion [ In vitro culture models showed that transient increases of intracellular calcium induce cytoplasmic α-synuclein aggregates [α-synuclein aggregation. By blocking the influx of calcium, CCBs can prevent or stop the progression of PD [+2 in the cell. An array of CCBs are approved by USFDA to treat hypertension which could be tried to lessen the increase in intracellular Ca+2 seen in aged neurons in patients at high risk of developing PD based on family history.The etiopathogenesis of PD is complex. It involves poptosis . Factorscium ion , 23. In gregates . In addion of PD . Kang eton of PD . This prEvidence on association between hypertension and risk of PD is conflicting. Prospective studies –29 showe In vitro and few in vivo studies have shown the role of agents modulating the RAS such as angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) [1 receptor stimulates the NF-B signal transduction pathway which facilitates the synthesis of inflammatory mediators, which cause inflammation and later cell death. Thus ARBs and ACEIs act by modulating the oxidative stress and inflammation at the level of dopaminergic neurons in substansia nigra and basal ganglia. This makes them potential future targets to prevent or to stop progression of PD [Other antihypertensive drugs were also studied as potential agents to prevent or to stop progression of PD.s (ARBs) . Angioteon of PD .P = 0.243) as compared to men 0.85 . These results are well coincided with the results published by Becker et al. [In our subgroup analysis, we found more pronounced reduced risk in women among CCBs users 0.67 (0.55–0.81, r et al. . Our stur et al. –17 as cor et al. –20. The r et al.  providedSubgroup analysis revealed that use of nondihydropyridine CCBs was reported in only two studies , 19. We A word of caution is necessary in interpretation of the analysis because sensitivity analysis by excluding study by Pasternak et al.  or BeckeSeveral limitations of our study need to be addressed. Our analysis was restricted to articles in English language, which may have led to somewhat biased results. All the studies included were observational studies with different follow-up periods, and no standard definition of CCBs usage was there. The specific role of individual drugs and doses was also not possible because of nonreporting in the studies.Our analysis suggests that CCBs may have protective role in PD. However, future prospective studies with larger sample size are required to understand the effect of individual CCBs at various dose and duration of use.


XRCC1 gene on clinical outcomes of advanced lung cancer patients treated with platinum-based chemotherapy. This meta-analysis aimed to summarize published findings and provide more reliable association. A total of 53 eligible studies including 7433 patients were included. Patients bearing the favorable TrpTrp and TrpArg genotypes of Arg194Trp were more likely to better response rates to platinum-based chemotherapy compared to those with the unfavorable ArgArg genotype (TrpTrp+TrpArg vs. ArgArg: odds ratio (OR) = 2.02, 95% CI, 1.66–2.45). The GlnGln and GlnArg genotypes of Arg399Gln were significantly associated with the poorer response rates compared to those with the ArgArg genotype . The GlnGln genotype might be more closely associated with shorter survival time and higher risks of death for patients (GlnGln vs. ArgArg: hazard ratio (HR) = 1.14, 95% CI, 0.75–1.75). Our cumulative meta-analyses indicated a distinct apparent trend toward a better response rate for Arg194Trp, but a poorer response rate in Arg399Gln. These findings indicate a predictive role of XRCC1 polymorphisms in clinical outcomes. The use of XRCC1 polymorphisms as predictive factor of clinical outcomes in personalized chemotherapy treatment requires further verification from large well-designed pharmacogenetics studies.Published data have shown inconsistent results about the pharmacogenetics of  Lung cancer, a major serious public health problem, is one of the most common malignant tumors and has become the leading cause of cancer-related deaths in the world23456781The treatment of lung cancer patients is surgery for early stages, whereas chemotherapy regimen is the main conventional therapeutic method for locally advanced stages and metastatic cancers. Currently, the platinum-based chemotherapy is one of the most extensively accepted and used treatments in advanced lung cancer patients, which has been shown to improve overall survival (OS)10111387878XRCC1) gene, located on chromosome 19q13.2, has long been recognized as a central role in BER pathway by interacting with other DNA repair proteins, acting as a “scaffold” in both DNA single-strand break repair and BER activities2122232427XRCC1 gene might modulate DNA repair capacity, and hence markedly influence the anticancer effect of platinum drugs, the efficacy of platinum-based chemotherapy treatment and the prognosis and survival of patients. Although a great number of studies have extensively investigated the pharmacogenetics of XRCC1 genetic variants 194 tryptophan (Trp), exon 6; rs25489, G → A, Arg280 histidine (His), exon 6; rs25487, G → A, Arg399glutanine (Gln), exon 10; rs3213245, C→T, T-77C, 5′-untranslated region (5′-UTR); and rs3213239 (insertion variation GGCC), http://www.ncbi.nlm.nih.gov/projects/SNP) on clinical outcomes of platinum-based chemotherapy in advanced lung cancer patients, the observed results from these studies remain conflicting rather than conclusive671029303132333435363738394041424344454647484950515253545556575859606162636465666768697071727374757677XRCC1 gene polymorphisms and response to platinum-based chemotherapy in lung cancer1415167980XRCC1 genetic polymorphisms on the efficacy and clinical outcomes of advanced lung cancer patients treated with platinum-based chemotherapy.It has been speculated that the single nucleotide polymorphisms (SNPs) or mutations occurring in the DNA repair pathways may alter gene expression and the activity of DNA repair17XRCC1 genetic polymorphisms, rs1799782 (Arg194Trp) and rs25487 (Arg399Gln) were finally enrolled in this meta-analyses. Other XRCC1 genetic polymorphisms were not included because of insufficient numbers of relevant publications on each polymorphism, such as three studies with rs25489 (Arg280His), two studies with rs3213245 (T-77C), one study with rs3213239 (insertion variation GGCC). 24 of the included studies were reported in the Arg194Trp genetic polymorphism, and 45 were reported in the Arg399Gln genetic polymorphism. Seven of the included studies were conducted on Caucasian patients, and 46 were conducted on Asian patients. 22 studies were published in English, and 31 studies were published in Chinese. There were 46 studies reported the objective response rate (ORR), 22 studies reported the OS and hazard ratios (HRs), 20 studies reported the median survival time (MST), four studies reported the median time to progression (TTP), and 11 studies reported the median progression-free survival (PFS)   and 2. TXRCC1 Arg194Trp polymorphism. The results from the meta-analysis suggested that there were statistically significant associations between the XRCC1 Arg194Trp polymorphism and ORR under all the genetic models (TrpTrp versus (vs.) ArgArg: odds ratio (OR) = 2.07, 95% confidence intervals (CIs), 1.67–2.58, P < 0.001; TrpArg vs. ArgArg: OR = 2.11, 95% CI, 1.68–2.65, P < 0.001; TrpTrp+TrpArg vs. ArgArg: OR = 2.02, 95% CI, 1.66–2.45, P < 0.001, 23 eligible studies including 3662 advanced lung cancer patients were qualified for the final analysis for the XRCC1 Arg399Gln polymorphism. In the dominant genetic model, the GlnGln and GlnArg genotypes of XRCC1 Arg399Gln polymorphism were significantly associated with the unfavorable ORR in advanced lung cancer patients treated with platinum-based chemotherapy compared to those with the favorable 399ArgArg genotype , especially in the recent studies published for the past 4 to 5 years . Between 2006 and 2009, a total of 12 studies were published, with a cumulative effect estimate of OR being 0.76 . Between 2010 and 2015, a total of 25 more publications were added cumulatively, resulting in an overall effect estimate of OR being 0.68  may be indicative of poorer response rates, shorter survival time and higher risks of death than the 399ArgArg genotype. Thus, we suggested that the XRCC1 Arg194Trp and Arg399Gln genetic polymorphisms may be predictive factors for treatment response to advanced lung cancer patients treated with platinum-based chemotherapy.In this study, we found, by an extensively quantitative and systematic review of all available published studies, that patients carrying The platinum-based chemotherapy regimens are the standard first-line therapies for advanced lung cancers, and commonly used today. The platinum is an effective chemotherapeutic drug for lung cancer patients. The platinum-based compounds could damage DNA by activating intracellularly to form reactive platinum complexes that covalently bind to DNA to induce intrastrand and interstrand DNA cross-links, as well as DNA-protein cross-links, thereby causing the eventual death of cancer cells141184XRCC1 genetic polymorphisms with sensitivity to platinum-based chemotherapy treatment has attracted much interest and became a research hotpot in individual treatment for lung cancer patients. The XRCC1 genetic polymorphisms have been proved to be associated with an altered DNA repair activity11XRCC1 transcript abundance levels have shown a significant correlation with DDP chemoresistance in NSCLC cell linesXRCC1 genetic polymorphisms might be associated with the clinical outcome of platinum-based chemotherapy treatment in lung cancer patients71034374345545960636469717576XRCC1 genetic polymorphisms contribute to the repair of DNA damage induced by the platinum agents. Previous studies have also reported that the XRCC1 genetic polymorphisms could be potential risk factors for the pathogenesis of lung cancer88899091101493XRCC1 gene might be associated with sensitivity to platinum-based anticancer drugs and have predictive or prognostic values in clinical outcomes for patients with lung cancer. The Arg194Trp and Arg399Gln genetic polymorphisms are the most extensively studied SNPs of XRCC1 gene. These polymorphisms, that lead to the encoded amino acid changes  which might affect the normal function of XRCC1 protein, might alter the efficiency of DNA repair1479XRCC1 function. Although, the Arg280His genetic polymorphism is also an amino acid variant and leads to the Arg to His substitution , the codon 280 is located outside the known functional domains of XRCC1The XRCC1 protein, a limiting factor in the BER pathway, is considered to play key roles in DNA damage repair, and the association of XRCC1 Arg194Trp and Arg399Gln polymorphisms are significantly associated with clinical outcomes in advanced lung cancer patients treated with platinum-based chemotherapy. Our meta-analysis suggested that there were significant associations between the Arg194Trp polymorphism and ORR under all the genetic models; however, there were significant associations between the Arg399Gln polymorphism and ORR only in the dominant genetic model and in the Asian population. It seemed that the Arg194Trp may be a reliable predictive locus to assess the pharmacogenetics of XRCC1 gene on clinical outcomes of advanced lung cancer patients treated with platinum-based chemotherapy compared with the Arg399Gln based on ORR outcomes. We found that all patients in the enrolled studies examining the Arg194Trp genotypes were Asians, likely because this genetic polymorphism is rare in Caucasians (<6%)167997et al. firstly designed the quality assessment systemXRCC1 gene were not statistically influenced the median PFS in all advanced lung cancer patients with platinum-based chemotherapy treatment , our cumulative meta-analysis was encouraged to sort out the cumulative evidence from time-tendency of clinical outcomes by successively adding published studies to the given results. As for the nt trend . As for  to 0.68 . The triXRCC1 gene polymorphisms and platinum-based chemotherapy in lung cancer patients, these results remain conflicting rather than conclusive1415167980XRCC1 gene polymorphisms with platinum-based chemotherapy treatment for lung cancer through conducting to comprehensive literature search in multiple databases without limiting publication date and language. As a result, our updated meta-analysis enrolled 53 available studies including 7433 advanced lung cancer patients, which were significantly more than the previous published meta-analyses. Therefore, findings from this study could provide more precise and reliable comprehensive assessment than those published meta-analyses on the predictive role of XRCC1 genetic polymorphisms in clinical outcomes of platinum-based chemotherapy treatment for advanced lung cancer patients. Several previous published meta-analyses have been carried out to reveal the potential correlation of Despite our efforts in performing a comprehensive analysis, several limitations of this meta-analysis should be taken into consideration when interpreting the present results. Firstly, the sample sizes of enrolled studies were from 45 to 460, and the small sample size of studies might not generate solid conclusion in some situation. Some of the findings in subgroups may have been undervalued because of there was only one trial available for analyses. Secondly, the significant heterogeneity between studies was found in our pooled analysis, while it is unlikely to alter our main conclusions because our results reflected the most current state of this issue in clinical practice and studies. Stratified analyses by possible confounding factors that could contribute to the ORR and OS of patients, such as gender, age, ethnicities, cancer pathology types, cancer stage, smoking history, specific anti-cancer drugs, chemotherapy regimens, test methods, and toxic effects of various platinum-based therapies or other chemotherapies, could provide additional useful information and be helpful to reduce the heterogeneity. However, few of these studies provided sufficient data by subgroups, thus making such subgroup analyses were impossible to implement in the present study. Furthermore, our analyses mostly used unadjusted estimates, because not all published studies calculate adjusted estimates by possible confounding factors. A more precise analysis with the adjustment estimates could be conducted if more detailed individual data were available. Therefore, in order to make the result more accurate and reliable, future studies are necessary to avoid these pitfalls. Thirdly, among all 53 trials utilized in this meta-analysis, most of studies were conducted in Asians (Chinese and Korean populations), only seven studies in Caucasian populations . Thus, the findings from this meta-analysis might be applicable only to these ethnic populations, while could limit the generalizability to other patient populations. Fourthly, only published studies in English and Chinese were enrolled in this meta-analysis, published studies in other languages, ongoing studies and unpublished data were not collected, which could cause some biases in our estimates.XRCC1 gene in clinical outcomes of platinum-based chemotherapy for advanced lung cancer patients. The XRCC1 Arg194Trp and Arg399Gln polymorphisms are likely to be associated with the ORR, OS and sensitivity to platinum-based chemotherapy for advanced lung cancer patients. The use of XRCC1 gene polymorphisms as predictive factor of clinical outcomes in personalized chemotherapy treatment for lung cancer patients might need to be investigated more carefully in well-designed pharmacogenetics and functional studies with large sample sizes in diverse ethnic populations to ensure a more accurate and robust conclusion in the future.In conclusion, despite the limitations, our meta-analysis indicates a predictive role for the genetic polymorphisms of XRCC1 or X-ray repair cross complementing group 1”, “base excision repair” or “BER”, “SNPs or genetic polymorphisms or variations”, “pharmacogenomics”, “platinum or cisplatin or carboplatin or nedaplatin, lbaplatin, oxaliplatin” and “chemotherapy” from PubMed, MEDINE, Excerpta Medica Database (EMBASE), ISI Web of Science, ScienceDirect, Wiley Online Library, Cochrane Central Register of Controlled Trials, Chinese Biomedical Literature Database (CBM), Wangfang Data, and Chinese National Knowledge Infrastructure (CNKI) databases up to March 30, 2015. No restriction of publication date was applied. Reference lists were screened manually to further identify additional eligible studies. We retrieved all potentially studies to identify the most eligible literatures.We conducted a systematic literature search using the following search terms “lung cancer or tumour or tumor or neoplasm or carcinoma”, “XRCC1 genetic polymorphisms were genotyped; (3). Treatments had platinum-based chemotherapy; (4). Studies had sufficient data to estimate relative risks for prognostic effects of advanced lung cancer ; (4). only full-text studies were included. Studies were excluded if any of the following exclusion criteria applies: (1). Duplicated publications; (2). Abstracts, comments, letters, and review articles; (3). Not reported any clinical outcomes; (4). No sufficient data were reported. (5). The studies with animals or cell lines were reported; (6). The corresponding authors were not provided the valid data or critical information upon our request.The following inclusion criteria for the current meta-analysis were as follows: (1). Patients had pathologically or histologically confirmed advanced lung cancer. (2). Two investigators (Z.R. Yuan and J. Li) independently extracted data from each eligible publications. Discrepancies between investigators were resolved by discussion from the third investigator, or the team’s decision. The following information was collected from the included studies: the first author’s name, year of publication, country, ethnicities (categorized as Asian and Caucasian), number of patients, median age (year), clinical stage, evaluation criterion, genotyping methods, outcomes , and the number of responders and non-responders in different genotypes.The QS of each eligible literature was also evaluated separately by two investigators (Z.R. Yuan and J. Li) using a predefined scale . Based o79819799XRCC1 genetic polymorphisms and response rate of platinum-based chemotherapy for advanced lung cancer patients was estimated by calculating pooled ORs with corresponding to 95% CIs. The significance of the pooled ORs was estimated using the Z-test, and P-value < 0.05 was considered statistically significant. HRs and 95% CIs were estimated for OS, MST, median TTP, median PFS, directly from the raw data of enrolled articles, or indirectly from the Kaplan–Meier (KM) curve of enrolled articles using published methods1021042 index2 index >50% for Q-test indicated the existence of heterogeneity between studiesFive genetic models, including homozygote genetic model , heterozygote comparison (heterozygote vs. wild homozygote), dominant genetic model , recessive genetic model , and allele genetic model  were considered in this meta-analysis. We extracted the ORR, OS, ORs, HRs, MST, PFS, and TTP from all enrolled studies. We evaluated the ORs and 95% CIs for the ORR and no response after platinum-based chemotherapy (complete response (CR) + partial response (PR) vs. progressive disease (PD) + stable disease (SD), using the World Health Organization (WHO) or the Response Evaluation Criteria in Solid Tumors (RECIST) criteria). We conducted the PRISMA checklist as the protocol of this meta-analysis and followed its guideline 101. The How to cite this article: Yuan, Z. et al. Predictive assessment in pharmacogenetics of XRCC1 gene on clinical outcomes of advanced lung cancer patients treated with platinum-based chemotherapy. Sci. Rep.5, 16482; doi: 10.1038/srep16482 (2015).


P = 0.042), but not in girls. And we observed a significant relationship of the polymorphism with total cholesterol (TC) and high density lipoprotein cholesterol (HDL-C) independent of obesity in boys. The T allele carriers have higher levels of low density lipoprotein cholesterol (LDL-C) in obese boys, and triglyceride (TG), TC and LDL-C in non-obese girls . In the meta-analysis, under dominant model the T allele increased body mass index (BMI) level in boys, while it decreased BMI in girls, and increased the levels of TC both in the overall and subgroups, TG and HDL-C in the overall and boys, and LDL-C in the overall . Our results suggest that the T allele might carry an increased risk of obesity in Chinese boys. The meta-analysis suggests that T allele acts as a risk allele for higher BMI levels in male childhood, while it is a protective allele in female childhood. And the polymorphism is associated with the levels of plasma lipids, which may be modulated by obesity and gender.Hepatic lipase (LIPC) is a key rate-limiting enzyme in lipoprotein catabolism pathways involved in the development of obesity. The C-514T polymorphism in the promoter region is associated with decreased LIPC activity. We performed a case-controlled study (850 obese children and 2119 controls) and evaluated the association between LIPC C-514T polymorphism, obesity and plasma lipid profile in Chinese children and adolescents. Additionally, we conducted a meta-analysis of all results from published studies as well as our own data. A significant association between the polymorphism and obesity is observed in boys ( The hepatic lipase gene (LIPC) is a member of the lipase gene family, in which protein sequence homology with other lipases is 30–75% Since it plays an important role in lipoprotein catabolism pathways The role of LIPC C-514T polymorphism in high density lipoprotein cholesterol (HDL-C) production has been well-established The present study included 2969 unrelated subjects , aged 7–17 years old. The subjects were recruited from a cross-sectional study on metabolic syndrome of children and adolescents conducted in six regions in China  in 2010. The BMI classification reference recommended by the Working Group on Obesity in China in 2004 was applied to serve as the criteria for obesity 2). Clinical parameters included measurement of the concentrations of triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and HDL-C in the plasma.Anthropometric measurements including weight, and height were examined by the trained investigators and the children were asked to be lightly dressed and barefoot. Body mass index was calculated as weight divided by the square of height . After extraction, the DNA samples were diluted to a final concentration of 20 ng/μl and the genotype of the C-514T polymorphism was performed using the Sequenom MassARRAY iPLEX platform –control status. The Hardy–Weinberg equilibrium (HWE) was assessed using the chi-squared goodness-of-fit test. Independent t-tests and chi-squared tests were used for comparisons of means and proportions between cases and controls.The clinical characteristics of continuous values were presented as a mean with S.D., and the polymorphism genotype frequency was presented as a number with percentage according to caseLogistic regression was applied to test the associations of LIPC C-514T polymorphism with obesity adjusted for age and stratified by gender. The trend tests were analyzed by chi-squared test. A multiple linear regression model was applied to estimate the associations of LIPC C-514T polymorphism with plasma TG, TC, LDL-C and HDL-C, and their interactions modified with age and stratified by obesity status and gender. The analysis was performed using a stepwise approach.P < 0.05 was considered statistically significant.All the statistical analysis was performed using SPSS 20.0 for Windows . A two-sided A comprehensive literature search was conducted for relevant publications covering the period up to December 2014, from the sites PubMed, MEDLINE and ISI Web of Knowledge. Search strategies included keywords as ‘LIPC’, or ‘HL’, or ‘hepatic lipase’, and ‘polymorphism’, or ‘variant’, or ‘SNP’, and ‘children’ or ‘adolescents’. The publications were limited to English, and those that examined the relationship between the LIPC C-514T polymorphism and BMI, or plasma lipid levels according to gender in children and adolescents were included in the meta-analysis. The duplicated papers were excluded if the subjects were from the same population, only the research with a wealth of information was included. And the studies were excluded if the indices of outcome were not able to be extracted or estimated from the published paper or by contacting the authors. The following information was extracted from each study, including first author name, publication year, region/ethnicity composition of the population, age, method of genotyping, sample size, genotype frequencies and mean with S.D. or standard error of BMI and serum lipid parameters by genotypes.versus CC). The heterogeneity among the studies was quantified by using an inconsistency index (I2), and confirmed significant with the P-value less than 0.1. A fixed-effect model was applied with no heterogeneity existing, otherwise, the random-effect model was adopted. The publication bias was assessed by Begg’s funnel plot and the Eegg’s linear regression. The P-value for the HWE test was calculated by a goodness-of-fit chi-squared test in the participants for each study. The meta-analysis was conducted using STATA software . A two-sided P < 0.05 was considered statistically significant.The associations of the polymorphism with BMI and lipid parameters were estimated by weighted mean difference (WMD) and its 95% confidence interval (CI) stratified by gender under a dominant model . In contrast with the control group, the case group tended to be younger, and had higher levels of anthropometric indexes , plasma lipid concentrations , while lower HDL-C levels . But the distribution of the genotype between the case and control group did not achieve statistical significance (P = 0.069). After the data were stratified by gender, the polymorphism was associated significantly with obesity in boys , and the trend test showed a significant effect of the polymorphism on obesity (P = 0.038). However, no positive association was observed in girls. A trend was found in the whole subjects and the boy’s subgroup in that the BMI level increased with the number of T allele, however, only marginal significant results were found under the additive model. And neither trend nor statistical significance was observed in the girl’s subgroup (As shown in Tablesubgroup .P < 0.05). Significant associations of the T allele with higher levels of TG, TC and LDL-C were only found in normal weight girls compared with CC homozygote . And significant interaction between the genotype and gender for the TG level was observed in the normal weight individuals, the girls with the T allele had the highest level of TG compared with the other groups  were selected into the meta-analysis for the association of C-514T polymorphism with BMI. Three studies with 4555 subjects (2723 boys and 1832 girls) evaluated the polymorphism about plasma levels of TG and TC, and two studies with 3295 subjects (2089 boys and 1206 girls) evaluated the polymorphism about LDL-C concentration, and five studies with 8034 subjects (4086 boys and 3948 girls) evaluated the polymorphism about HDL-C concentration.TableP = 0.007; I2 = 31.5%, P = 0.211). However, the results in the girl’s subgroup showed an opposite effect trend since the T allele reduced the BMI level . The overall effect was weakened to non-significance due to the opposite direction effect on the subgroups . The results in the girl’s subgroup showed a consistent trend while the differences did not reach a statistically significant level . And a significant increase in effect was also observed in the overall   Fig..P < 0.001 ; WMD = 0.09, 95% CI = 0.01–0.16, P = 0.002 ; WMD = 0.11, 95% CI = 0.07–0.16, P < 0.001 , respectively] , the analysis with LDL-C was conducted using the random-effect model. The T allele significantly increased the LDL-C concentration compared with the CC homozygote in the overall without heterogeneity . Although similar trend effects were also observed in the boy’s and girl’s subgroups, the tendency failed to achieve statistical significance  . And a consistent trend was also observed in the girl’s subgroup while no significance was detected . The result of the overall was similar with that in the boy’s subgroup (WMD = 0.05, 95% CI = 0.03–0.07, P < 0.001; I2 = 22.7%, P = 0.234; Fig.Under the fixed-effect model, the T allele carriers showed an increased HDL-C concentration compared with the CC homozygote in the boy’s subgroup (WMD = 0.07, 95% CI = 0.04–0.09, A sensitivity analysis was conducted by omitting one study at a time and recalculating the pooled WMD for the remaining studies. The results suggest that no individual studies substantially influenced the pooled point estimate Fig..P > 0.05; Fig.Begg’s funnel plot and Eegg’s linear regression test were performed to estimate the potential publication bias of the included studies. As shown in Figureet al. In the present study, we explored the associations between the LIPC C-514T polymorphism, obesity and plasma lipid profiling in a representative sample of Chinese children and adolescents. We found a significant relationship between the LIPC C-514T polymorphism and obesity in boys. The T allele increased the risk of obese boys. No significant association was observed in girls. The meta-analysis yielded similar results in boys in that the T allele increased the risk of obesity. While a significant opposite effect was revealed by the meta-analysis in girls. Several studies have explored the relationship of LIPC C-514T polymorphism and obesity. Most of them failed to detect a positive association LIPC has been reported as a factor involved in the control of energy balance and body fat accumulation, consequently producing an effect on obesity in mice; elevated hepatic lipase activity favours obesity, while its deficiency might protect against obesity et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. We also compared the plasma lipid levels among LIPC C-514T genotypes stratified by gender and obesity status. In the normal weight group, the T allele conferred increased levels of TC and HDL-C in boys and TG, TC and LDL-C in girls. In the obesity group, the T allele associated with increased TC, LDL-C and HDL-C was only found in boys. A great deal of previous studies has examined the association of LIPC C-514T polymorphism with plasma lipid profile, and most of them found significance in HDL-C The interaction between the genotypes and gender was statistically significant for TG only in normal weight subjects. The results indicated that the genotypic effect on the TG level was gender and obesity status dependent which was higher in girls compared with boys, and the presence of obesity abolished the effect on TG for girls. The interaction was not observed in other studies.et al. The study was performed in a children and adolescents population, which made the study avoid the potential confounders that may influence the genotypic effect on plasma lipids with adults, for instance, severe obesity, smoking and alcohol. A meta-analysis was conducted by Isaacs et al. Several limitations of the present study should be taken into consideration. First, after excluding the study of Talmud In conclusion, the genotype distributions of the LIPC C-514T polymorphism were related to obesity status in a gender-specified fashion, male childhood with T allele might have a higher trend to be obese, while the female childhood with the T allele might tend to be defended against obesity. And the T allele confers elevated concentrations of TG, TC, LDL-C and HDL-C which might be modulated by gender and obesity.


ADRB2) gene polymorphisms and asthma risk. However, the results are inconsistent. A meta-analysis that focused on the association between asthma and all ADRB2 polymorphisms with at least three case-control studies was thus performed.A number of studies have assessed the relationship between beta-2 adrenergic receptor  in an analysis stratified by ethnicity. For the Gln27Glu polymorphism, a protective association was found in children via recessive model comparison  and homozygote genotype comparison , and in adults via dominant model comparison .Arg16Gly, Gln27Glu, Thr164Ile, and Arg19Cys single nucleotide polymorphisms (SNPs) were identified in 46 case-control studies. The results showed that not all of the SNPs were associated with asthma in the overall population. Significant associations were found for the Arg16Gly polymorphism in the South American population via dominant model comparison (ADRB2 gene polymorphisms were reproducibly associated with a risk of asthma across ethnic groups in the general population.None of the  ADRB2, also known as β2-AR) gene, has been extensively studied.Asthma, which is characterized by variable airway obstruction caused by bronchial hyper-reactivity and airway inflammation, is one of the most common chronic respiratory diseases worldwide. The prevalence of asthma varies worldwide, ranging from 0.2% in China to 21.0% in Australia ADRB2), a member of the G protein-coupled receptor (GPCR) family, is abundantly expressed on bronchial smooth muscle cells, and specifically binds and is activated by a class of ligands known as catecholamines, and epinephrine in particular ADRB2 variants are associated with airway hypersensitivity, asthma severity, and the response to medications ADRB2 gene The β2-AR , and Wangfang databases  was conducted. The search strategy was as follows: “asthma” or “asthmatic” and “β2-adrenergic receptor” or “ADRB2” or “β2-AR” in combination with “polymorphism,” “mutation,” or “variant”. The searches were performed without restrictions with regard to publication date and language. Articles that were not published in English or Chinese were subsequently excluded.OR) with 95% confidence interval (CI). For overlapping studies, the one with the most suitable data was selected. Studies were only excluded if they did not meet these inclusion criteria.Studies that fulfilled the following criteria were incorporated into the meta-analysis: (1) case-control studies that evaluated the association between ADRB2 gene polymorphisms and risk of asthma; (2) the genotype distributions or allele frequency of each study was available or sufficient data could be extracted for calculating the odds ratio  to estimate the risk. In the current study, the aa genotype was a wild-type, while the AA genotype was a mutant. The Q-test and 2I test were used to assess the effect of heterogeneity. Heterogeneity was considered statistically significant when Q-test (P<0.10) or 2I>50%. If heterogeneity was indicated, data were combined according to the random-effects model; when the Q-test (P>0.10) or 2I<50%, the fixed-effect model was used. Stratified analysis was performed by 1000 time permutation HWE P-value, ethnicity and case age to further explore HWE-specific, ethnicity-specific and age-specific effects. Sensitivity analysis was conducted by sequentially excluding one study at a time to examine the effect of each study on the combined result. Potential publication bias was investigated through the funnel plot and further assessed using Egger's test. A cumulative analysis was conducted after sorting by publication date. All statistical analyses of this meta-analysis were performed using the computer software STATA 11.0 .Pearson's chi-square test was performed to evaluate whether the genotype distribution deviated from Hardy-Weinberg equilibrium (HWE) in the control group. Significantly deviating samples were re-assessed by 1000 time Montecarlo permutation analysis using the freely available software at ADRB2 polymorphisms and asthma risk. Thus, 206 relevant records were identified. Of these, 121 were excluded due to the lack of a case-control design. Of the remaining 85 articles, 26 were excluded due to overlapping data. Therefore, 59 articles were identified for further study. Of these 59 articles, four ADRB2 polymorphisms that had been reported in at least three case-control studies. A total of four SNPs met the inclusion criteria: Arg16Gly , Gln27Glu , Thr164Ile , and Arg19Cys . Some of the included studies only focused on the Chinese population, so a meta-analysis of the Chinese population was performed independently. The genotype and allele distribution for the four SNPs are shown in After a comprehensive search of the PubMed, Embase, Web of Science, Wanfang, and CNKI databases, 1154 articles were identified, 948 of which were subsequently excluded because they were not relevant to The HWE for each included study was calculated by chi-square test. The P-value of the genotype distribution in each control group is shown in OR = 1.754, 95% CI = 1.179–2.609, 2I = 16.9%, studies  = 2, case  = 314, control  = 237), but not in the other genetic comparisons or other ethnic groups. In the Chinese population, there was no significant association in any of the genetic model comparisons. The results are shown in For Arg16Gly, there was no significant association in any of the genetic model comparisons in the overall population  to 5. InOR = 0.566, 95% CI = 0.417–0.769, 2I  = 0.0%, studies  = 11, case  = 1693, control  = 1502) and homozygote genotype comparison , and in adults only in the dominant model comparison . In the Chinese population, there was no significant association in any of the genetic model comparisons. The results are shown in For Gln27Glu, no evidence of an association with asthma risk was found in the overall population in any of the genetic model comparisons  to 9. InFor Thr164Ile, only four case-control studies were included, so no stratified analysis was performed. There was no evidence of an association with asthma risk in any of the genetic models in the overall population. The results are shown in For Arg19Cys, only three case-control studies provided genotype distribution data, therefore no stratified analysis was conducted. No significant association was found in the overall population in any of the genetic models. The results are shown in Cumulative analysis of the association between Arg16Gly and Gln27Glu polymorphisms and the risk of asthma was performed after sorting by publication date. As shown in Sensitivity analysis was conducted by sequentially excluding individual studies to estimate the stability of the results. After sequentially excluding each study, statistically similar results were found.t = 2.69, P = 0.011). No evidence of publication bias was found for the Arg16Gly, Thr164Ile, or Arg19Cys polymorphism in any of the genetic model comparisons. The results are shown in Potential publication bias was investigated using the funnel plot and was further assessed using Egger's test. Significant publication bias was detected for the Gln27Glu polymorphism in the dominant model comparison  structure in Chinese and Europeans may explain these differences: the minor allele of the ADRB2 Arg16Gly  in the population of northern and western European ancestry (CEU) was A with a frequency of 0.358, whereas it was G with a frequency of 0.439 among the Han Chinese in Beijing (HCB). The minor allele of the ADRB2 Gln27Glu  was 0.467, whereas it was 0.122 in HCB. Another reason for these differences is that sample size was small for the South American and North American populations, and therefore the current boundary result may have been unable to demonstrate that the Arg16Gly and Gln27Glu polymorphisms are associated with the risk of asthma in these populations. More studies with a larger sample size are needed. In the Chinese population, the results of the current meta-analysis showed that there was no significant association with the risk of asthma with either the Arg16Gly polymorphism or the Gln27Glu polymorphism in any of the genetic model comparisons, supporting Ni Suiqin's P<0.05, but not in the group with P>0.05. For Gln27Glu, a significant association was found in the dominant model comparison in the group with P>0.05. These results therefore need to be interpreted with caution. There are several possible explanations as to why the control group population was not in HWE. First, the population was not characterized by random mating. Second, the locus under consideration exhibited an inconstant fluctuating mutation rate. Third, there was selection for a particular phenotype. Fourth, the population was not sufficiently large or non-random. Fifth, there had been a change in the population structure during the period of study due to migration.In the analysis stratified by HWE according to the P-value for the Arg16Gly and Gln27Glu polymorphisms, a significant association was found in the recessive model comparison and the homozygote genotype comparison for Arg16Gly in the group with No significant association with the risk of asthma was found for the Thr164Ile and Arg19Cys polymorphisms. Thus, the Thr164Ile and Arg19Cys polymorphisms may not be involved in the pathogenesis of asthma. Further research is needed because, as only four case-controls were included in the study, there might not be sufficient statistical evidence to clarify the association between the Thr164Ile and Arg19Cys polymorphisms and the risk of asthma.ADRB2 is located on chromosome 5q31–32, encodes 413 amino acids, and is an intronless gene ADRB2 gene, respectively, can cause changes in the amino acid sequence. The altered amino acid sequence can lead to down-regulation of the β2-AR and may cause the desensitization of related reactions ADRB2 gene; a base change from C to T can lead to a change in amino acid from threonine (Thr) to isoleucine (Ile). The missense polymorphisms of Arg16Gly, Gln27Glu, and Thr164Ile may lead to functional changes in ADRB2. Most of the studies relating to ADRB2 and asthma risk have focused on coding region polymorphisms. In recent years, studies on ADRB2 have not been confined to coding region polymorphisms alone, as more and more studies have begun to pay attention to promoter region polymorphisms. Arg19Cys is located in the 5′ leader region that harbors an open reading frame (ORF) in the promoter region of the ADRB2 gene; a base change from T to C leads to a change in amino acid from arginine (Arg) to cysteine app:addword:cysteine(Cys). Recent in vivo and in vitro research has demonstrated that this change can impede the translation of ADRB2 mRNA, and thus can regulate cellular expression of the receptor ADRB2 alter signal regulation, gene expression, or the function of its product or not.t = 2.69, P = 0.011), but not in the other three genetic model comparisons. In fact, positive results or results with “expected” findings are more likely to be published. Publication bias may lead to a false positive result. We detected significant publication bias for the Gln27Glu polymorphism in the dominant model, so the results need to be interpreted with caution. Fifth, moderate heterogeneity was found in some genetic models for the Arg16Gly polymorphism. Because no information was available other than the factors we performed a stratified analysis, and thus we were unable to use meta-regression to explore other possible sources of between-group heterogeneity. Furthermore, the result of the sensitivity analysis was stable. Therefore, the heterogeneity seemed to have no effect on the results, suggesting their reliability.There are certain inevitable limitations to the current meta-analysis. First, all available literature should be included in the meta-analysis, but we only included literature published in English and Chinese, thus neglecting studies published in other languages. In addition, most of the included studies just focus on Chinese and Asian, which may result in an inability to detect modest association due to lack of power because of underreporting/lower incidence of asthma in these populations. Second, most original literature only provides a generic asthma definition, and does not describe asthma phenotype(s) and environmental factors in detail, so we cannot supply this information. Third, several studies were not included because they did not provide sufficient data for statistical analysis, which may have biased the result. Fourth, publication bias was only detected for the Gln27Glu polymorphism in the dominant model comparison Click here for additional data file.