Emerging evidence showed that common functional −31G>C polymorphism (rs9904341 G>C) in the promoter region of the survivin gene is involved in the regulation of survivin expression, thus increasing an individual’s susceptibility to gastrointestinal tract (GIT) cancer; but individually published results are inconclusive. The aim of this systematic review and meta-analysis was to derive a more precise estimation of the association between survivin −31G>C polymorphism and GIT cancer risk.A literature search of PubMed, Embase, Web of Science and CBM databases was conducted from inception through July 1st, 2012. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association.Nine case-control studies were included with a total of 2,231 GIT cancer cases and 2,287 healthy controls. The results indicated that survivin −31G>C polymorphism was associated with increased risk of GIT cancer. In the stratified analysis by cancer types, significant associations were observed between survivin −31G>C polymorphism and increased risk of colorectal and gastric cancers. However, the lack of association of survivin −31G>C polymorphism with esophageal cancer risk may be due to a lack of a sufficient number of eligible studies and the influence of different genetic and environmental factors.Results from the current meta-analysis suggests that survivin −31G>C polymorphism might increase the risk of GIT cancer, especially among gastric and colorectal cancers. Gastrointestinal tract (GIT) cancer, especially gastric, esophageal and colorectal cancers, are a global epidemiological health concern Survivin, an inhibitor of apoptosis protein (IAP), is involved in the regulation of apoptosis and in cell cycle control More than 10 common single nucleotide polymorphisms (SNPs) in the promoter region of the survivin gene have been reported, but the −31G>C polymorphism (rs9904341 G>C) is one of the most common variants. The survivin −31G>C polymorphism is a transversion mutation of G to C substitution at position −31 in the promoter region Relevant papers published before July 1st, 2012 were identified through a search in PubMed, Embase, Web of Science and CBM databases using the following terms: (“genetic polymorphism” or “polymorphism” or “SNP” or “gene mutation” or “genetic variants”) and  and . The references used in eligible articles or textbooks were also reviewed to find other potentially sources. Disagreements were resolved through discussion between the authors.Studies included in our meta-analysis have to meet the following criteria: (a) case-control study or cohort study focused on associations between survivin −31G>C polymorphism and GIT cancer susceptibility; (b) all patients diagnosed with GIT cancers should be confirmed by pathological or histological examinations; (c) published data about the size of the odds ratio (OR), and their 95% confidence interval (CI) must be sufficient. Studies were excluded when they were: (a) not a case-control study or a cohort study; (b) duplicates of previous publications; (c) based on incomplete data; (d) meta-analyses, letters, reviews or editorial articles. If more than one study by the same author using the same case series was published, either the studies with the largest sample size or the most recently published study was included. The supporting PRISMA checklist is available as supporting information; see Using a standardized form, data from published studies were extracted independently by two authors. For each study, the following characteristics and numbers were collected: the first author, year of publication, country, language, ethnicity, study design, numbers of subjects, source of cases and controls, pathological type, detecting sample, genotype method, allele and genotype frequencies, and evidence of Hardy-Weinberg equilibrium (HWE) in controls. In case of conflicting evaluations, disagreements were resolved through discussion between the authors.Two authors independently assessed the quality of papers according to modified STROBE quality score systems P-value <0.05 as statistically significant heterogeneity 2I test (ranges from 0 to 100%), which represents the proportion of inter-study variability that can be contributed to heterogeneity rather than by chance P<0.05) or 2I>50% indicated that heterogeneity among studies existed, the random effects model (DerSimonian Laird method) was conducted for meta-analysis. Otherwise, the fixed effects model (Mantel-Haenszel method) was used. To establish the effect of heterogeneity based on the results from the meta-analyses, we also performed subgroup analysis by cancer types, ethnicity, country, source of controls and genotype methods. We tested whether genotype frequencies of controls were in HWE using the 2χ test. Sensitivity was performed by omitting each study in turn to assess the quality and consistency of the results. Begger’s funnel plots were used to detect publication biases. In addition, Egger’s linear regression test which measures funnel plot asymmetry using a natural logarithm scale of OR was also used to evaluate the publication biases P values were two-sided. All analyses were calculated using STATA Version 12.0 software .The strength of the association between survivin −31G>C polymorphism and GIT cancer susceptibility was measured by ORs with 95%CIs under five genetic models, including allele model (C vs. G), dominant model (CC+GC vs. GG), recessive model (CC vs. GG+GC), homozygous model (CC vs. GG), and heterozygous model (CC vs. GC). The statistical significance of the pooled OR was examined by Z test. Between-study variations and heterogeneities were estimated using Cochran’s Q-statistic with a P>0.05). All quality scores of included studies were higher than 20 . The characteristics of the included studies are summarized in According to the inclusion criteria, 9 studies P<0.05), which might be a result of the difference in cancer types, ethnicity, country, source of controls and genotype methods, so random effects model was used. The meta-analysis results showed that survivin −31G>C polymorphism was associated with increased risk of GIT cancers under all genetic models   .P<0.001; dominant model: OR = 1.51, 95%CI: 1.22–1.88, P<0.001; recessive model: OR = 1.58, 95%CI: 1.08–2.32, P = 0.020; homozygous model: OR = 1.84, 95%CI: 1.20–2.82, P = 0.006). Furthermore, we also found significant connections between the CC genotype of survivin −31G>C polymorphism and increased risk of gastric cancer under the recessive and heterozygous genetic models   . HoweverP = 0.022; recessive model: OR = 1.57, 95%CI: 1.12–2.20, P = 0.009; homozygous model: OR = 1.66, 95%CI: 1.09–2.52, P = 0.018; heterozygous model: OR = 1.50, 95%CI: 1.11–2.02, P = 0.008). Also, we found significant associations between the C carrier (CC+GC) of survivin −31G>C polymorphism and increased risk of GIT cancer among Caucasian populations under the dominant model   . Subgrou= 0.044) .Sensitivity analysis was performed to assess the influence of each individual study on the pooled ORs by omission of individual studies. The analysis results suggested that no individual studies significantly affected the pooled ORs under any genetic models of survivin −31G>C polymorphism , indicatP = 0.966; dominant model: t = 0.01, P = 0.997; recessive model: t = 0.07, P = 0.948; homozygous model: t = 0.03, P = 0.974; heterozygous model: t = −0.04, P = 0.971).Publication biases within available research results might not be representative of all research results. Begger’s funnel plot and Egger’s linear regression test were performed to assess the publication biases of included studies. The shapes of the funnel plots did not reveal any evidence of obvious asymmetry under the dominant model . Egger’sSurvivin, a novel identified member in inhibitor of IAP family, is usually described as an apoptosis inhibitors and plays a key role in anti-apoptosis mechanism of cancer metamorphosis Due to the complex functional mechanism and regulatory roles of survivin in tumorigenesis, the relationships between survivin −31G>C polymorphism and GIT cancer susceptibility have been widely studied, however, these results were inconsistent. A clinical and genetic study suggested that the CC genotype of survivin −31G>C polymorphism might increase colorectal cancer risk among Caucasians In interpreting our results of the current meta-analysis, some limitations need to be addressed. Firstly, the sample size is still relatively small and may not provide sufficient statistical power to estimate the correlation between survivin −31G>C polymorphism and GIT cancer risk. Secondly, the selection bias may exist because of the differences in source of controls or detection samples. Thirdly, our meta-analysis was based on unadjusted ORs estimates because not all published presented adjusted ORs and if they did, the ORs were not adjusted by the same potential confounders, such as ethnicity, age, gender, geographic distribution, etc. Nevertheless, it is well acknowledged that many other factors, such as gene-gene or gene-environment interaction may affect the risk of GIT cancer. Furthermore, the present meta-analysis also includes most of the studies from Asian populations, which may not provide strong evidence of heterogeneity by ethnicity. Finally, although all cases and controls of each study were well defined with similar inclusion criteria, there may be other potential factors that were not taken into account that may have influenced our results.In spite of these limitations, our meta-analysis still has some advantages. The specific aim of this study is to update the previous meta-analyses and focus on the correlation between survivin −31G>C polymorphism and GIT cancer risk. Unlike previous meta-analyses, we find that survivin 31G>C polymorphism is associated with increased risk of gastric and colorectal cancers. It is worthwhile to mention that we have established an effective and efficient searching strategy based on computer-assisted program and manual search to find all possible and eligible studies. Through this search strategy, the quality of studies included in this meta-analysis satisfied our selection criteria. Furthermore, explicit methods for study selection, data extraction, and data analysis were well designed before initiating the calculations. Last but not least, there were no evidences of publication bias in this meta-analysis and the sensitivity analysis indicated that the results are statistically robust.In summary, this meta-analysis suggests that survivin 31G>C polymorphism may be a risk factor for developing GIT cancer, especially among gastric and colorectal cancers. However, further studies are necessary in order to warrant and validate the associations between survivin gene polymorphisms, other gene polymorphisms and GIT cancer risk.Supplement S1PRISMA Checklist.(DOC)Click here for additional data file.Supplement S2Modified STROBE quality score systems.(DOC)Click here for additional data file.


RsaI/PstI polymorphism and risk of esophageal cancer (EC) in mainland Chinese populations. A systematic search of PubMed, EMBASE, Web of Science, CBM, CNKI and VIP databases for publications on the CYP2E1 RsaI/PstI polymorphism and risk of EC was performed. and the genotype data were analyzed in a meta-analysis. Odds ratios (ORs) with relevant 95% confidence intervals (CIs) were estimated to assess the association. Sensitivity analysis, test of heterogeneity and assessment of publication bias were performed. The search yielded 17 studies including 18 trails involving 1,663 cases and 2,603 controls. The meta-analyses showed a significant association between the CYP2E1 RsaI/PstI polymorphism and risk of EC in the mainland Chinese population . An increased cancer risk in all genetic models was identified following stratification by ethnicity, source of controls and tumor type. In conclusion, in all genetic models, the association between the CYP2E1 RsaI/PstI polymorphism and risk of EC in the mainland Chinese population was significant. This meta-analysis suggests that the CYP2E1 RsaI/PstI polymorphism is a risk factor for EC, and the c2 allele is a factor that lowers the possibility of EC in the mainland Chinese population and this association did not change due to ethnic differences in genetic backgrounds and the environment.The aim of this study was to explore the cytochrome P450 2E1 (CYP2E1)  Esophageal cancer (EC) ranks as the eighth most common malignancy and the sixth most common cancer-related cause of mortality worldwide, which is characterized by a high incidence and a striking worldwide geographic variation. In fact there exists a so-called ‘Asian esophageal cancer belt’, an area that stretches from the Caucasian mountains across Northern Iran, Afghanistan, Kazakhstan, Uzbekistan and Turkmenistan, into northern China, and China, Iran and Japan have the highest rate of EC in the world –3. TheseHowever, the cause and pathogenesis of EC remains unclear. Histopathologically, EC is classified into two main types: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). A higher incidence rate of EAC occurs in Western countries, while ESCC occurs more often in Oriental countries, particularly in Mainland China ,2,6. TheRsaI/PstI polymorphisms in the promoter gene region are believed to affect the transcriptional activity of the gene, and occur as a wild-type homozygous genotype (c1/c1), a heterozygous genotype (c1/c2) and a variant homozygous rare genotype (c2/c2), and the frequency of the variant c1 allele was observed to be much higher in patients with esophageal diseases than that of healthy individuals , a member of the CYP450 superfamily and an ethanol-inducible enzyme, is involved in the metabolic activation of numerous low molecular weight compounds, including N-nitrosamines, aniline, vinyl chloride and urethane –14. RsaIividuals –17.RsaI/PstI polymorphism was conducted in 1996, but the result failed to reveal a significant association. The second study in Japan also failed to identify a significant difference between healthy controls and patients with EC , China National Knowledge Infrastructure (CNKI) and the Chinese scientific periodical database of VIP information (VIP). Terms used in the search were as follows: i) esophag* and oesophag*; ii) cancer, carcinoma, adenocarcinoma, neoplasm, neoplasia and neoplastic; iii) cytochrome p450 2E1, cytochrome p450II1, CYP2E1, CYPIIE1; iv) polymorphism; v) China and Chinese, without restrictions. In addition, we also reviewed the reference lists of retrieved manuscripts and recent reviews.Strictly following the proposed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)  guidelinRsaI/PstI polymorphism and risk of EC was investigated; iii) diagnosis of ESCC and EAC were either histologically, pathologically or cytologically confirmed; and iv) the odds ratios (ORs) and the corresponding 95% confidence intervals (CIs), or the number of events required to calculate them were reported. Two investigators independently evaluated the eligibility of all studies retrieved from the databases on the basis of the predetermined selection criteria. Disagreements were resolved by discussion or in consultation with a third investigator.We included any study that met with the following criteria: i) case-control study design; ii) association between CYP2E1 Two reviewers independently extracted data for the study characteristics by using a standardized data-collection form. Data were recorded as follows: first author’s last name, year of publication, place of origin, study period and duration of follow-up, characteristics of cancer cases, source of controls, matching criteria, number of cases and controls, number of different genotypes in cases and controls, Hardy-Weinberg equilibrium (HWE) and minor allele frequency in controls. Any disagreements were resolved by consensus.2 statistic, which yields results ranging from 0 to 100%   to generate forest plots to determine whether there was a statistical association between cases and controls and to assess heterogeneity of the included studies. HWE was tested by a Chi-square test at a significance level of P<0.05. Heterogeneity was quantifiably evaluated using the Chi-square based Cochran’s Q statistic  and the geneity) . If hetegeneity) .RsaI/PstI polymorphism and risk of EC, including a total of 1,663 cases and 2,603 controls . In the stratified analysis by tumor type, the results were similar to the control source; the ESCC type showed no association in c2/c2 vs. c1/c1 and c2/c2 vs. c1/c1+c1/c2 (both P>0.05).PstI/RsaI polymorphism   ,19,23,29 P<0.05) . In addi P<0.05) .Funnel plot based on c2/c2 vs. c1/c1 (the genetic model was pooled using a fixed-effects model) was chosen to assess publication bias. The symmetrical shape of the funnel plots  implied EC is an increasingly common cancer with a poor prognosis, which is likely to be caused by multi-factors, including environmental risk and genetic factors ,7–9. In Unlike other factors, the positive association between family history of EC risk is consistent with previous studies, which suggests a genetic susceptibility in EC pathogenesis –50. A meRsaI/PstI polymorphisms in the promoter gene region are reported to affect the transcriptional activity of the gene. Numerous large-sample and unbiased epidemiological studies of CYP2E1 RsaI/PstI polymorphisms could confirm it as a predisposition gene for EC risk, particularly in China .Our meta-analysis summarized all the available data on the association between the CYP2E1 et al  and c2/c2 vs. c1/c1+c1/c2  genetic models, and this could be since the HB studies have certain biases for such controls and may only represent a sample of an ill-defined reference population, and may not be representative of the general population; or it may be that numerous subjects in the PB controls were susceptible individuals. Therefore, the use of proper and representative PB control subjects is important to reduce biases in such genetic studies.RsaI/PstI polymorphism is clearly associated with EC risk in Chinese individuals.The sensitivity of the frequency distributions of genotypes in the controls were inconsistent with HWE, and the stability of results by deleting one study each time suggested that they were not substantially altered and the results were stable. Hence, the heterogeneity of the studies did not substantially lower the statistical validity of the study and the CYP2E1 Compared with the previous meta-analysis , this meRsaI/PstI polymorphism plays an important role in EC development for mainland Chinese individuals. It also suggests that the c2 allele significantly decreases the susceptibility to EC. For future study, studies with larger sample sizes, stricter selection of patients, well-matched PB controls and clearly reported cancer types are required. In addition, the potential gene-gene and gene-environment interactions of the CYP2E1 RsaI/PstI polymorphism and EC should be further investigated.In conclusion, evidence from the included studies suggests that the CYP2E1


PLA2G7 994G-T transversion leads to V279F substitution within the lipoprotein-associated phospholipase-A2 (Lp-PLA2) and to absence of enzyme activity in plasma. This variant offers a unique natural experiment to assess the role of Lp-PLA2 in the pathogenesis of coronary artery disease (CAD) in humans. Given conflicting results from mostly small studies, a large two-stage case-control study was warranted.The Asia-specific PLA2G7 V279F genotypes were initially compared in 2890 male cases diagnosed with CAD before age 60 with 3128 male controls without CAD at age 50 and above and subsequently in a second independent male dataset of 877 CAD cases and 1230 controls. In the first dataset, the prevalence of the 279F null allele was 11.5% in cases and 12.8% in controls. After adjustment for age, body mass index, diabetes, smoking, glucose and lipid levels, the OR (95% CI) for CAD for this allele was 0.80 . The results were very similar in the second dataset, despite lower power, with an allele frequency of 11.2% in cases and 12.5% in controls, leading to a combined OR of 0.80 (0.69–0.92), p = 0.002. The magnitude and direction of this genetic effect were fully consistent with large epidemiological studies on plasma Lp-PLA2 activity and CAD risk.2 activity due to carriage of PLA2G7 279F allele protects from CAD in Korean men. These results provide evidence for a causal relationship between Lp-PLA2 and CAD, and support pharmacological inhibition of this enzyme as an innovative way to prevent CAD.Natural deficiency in Lp-PLA In a recent meta-analysis incorporating 79036 participants from 32 prospective studies the risk of developing cardiovascular diseases was increased by 11% for each standard deviation (SD) unit increase in Lp-PLA2 activity, after correction for other cardiovascular risk factors Elevated levels of lipoprotein-associated phospholipase A2 activity in Japanese subjects identified a non-functional (null) V279F allele within the Lp-PLA2–encoding gene PLA2G7, due to a G to T transversion in exon 9 at position 994 2 to the pathogenesis of CAD, and as such shall complement epidemiological studies and contribute to our understanding of the causality of Lp-PLA2 in atherogenesis in humans. Other common variants within PLA2G7 have been reported, and have minimal, if any effects on Lp-PLA2 activity as compared to the V279F. In particular, the most well characterized of those, A379V confers only a 7.2% difference in Lp-PLA2 activity between AA and VV homozygotesA study of Lp-PLACDKN2A/B locus which has been robustly associated with CAD in European PLA2G7 V279F variant was subsequently tested within a second, independent group of 877 cases and 1230 controls (Study 2).Several reports have been published on the association between the V279F allele and CAD in Asians. An early study in Japanese subjects showed an increased risk for myocardial infarction (MI) and stroke in carriers of 279F variantA total of 2890 CAD cases and 3128 non-CAD controls were included in Study 1 . Given tPLA2G7 279F null allele  frequency was significantly higher among CAD cases, and in the subgroup with MI (−6). Conversely, the PLA2G7 279F allele was associated with a reduced CAD risk of 0.80 , and the effect tended to be gene-dosage dependent, with an OR 0.79 (0.64–0.98) and 0.69 (0.33–1.44) for carriers of one and two copies of the 279F allele, respectively. The protective effect of the null allele was slightly more pronounced for CAD cases with MI .Logistic regression analysis was performed to adjust for differences in various cardiovascular risk factors between the cases and the controls . SmokingPLA2G7 V279F variant was subsequently examined in Study 2, an independent dataset. The clinical characteristics of the participants in this study were very similar to the ones observed in Study 1  and MI (11.3%) compared to controls (12.5%). In the s (12.5%). The assOne potential limitation of this study is the fact that not all cases and controls were collected from the same sites. In order to assess heterogeneity between sites, we examined the prevalence of the 279F allele in each site individually. The allele frequency was very consistent between sites, ranging from 11.3% to 11.8% for CAD cases and from 12.6% to 13% in controls , withoutPLA2G7 V279F variant and CAD, we provide consistent evidence that this null allele offers a significant protection against CAD, in particular myocardial infarction, in Korean males.In this study, the largest to date to explore the association between the et al2 activity/mass corresponded to ∼1.5–2.0 SD, depending on the studies included in the meta-analysis, and each SD was associated with an 11% reduction in risk of CAD. This is fully consistent with the estimate of 20% reduction obtained empirically here. The convergence and consistency of the present genetic results with the epidemiological data on Lp-PLA2 activity and CAD risk supports a causative role for Lp-PLA2 in the generation of CAD.The present data shows that carriage of one copy of the 279F null allele was associated with a 20% reduction in risk for CAD. Our finding is consistent with the expected reduction in CAD risk, when considered in light of prior reports showing that each allele is associated with a ∼50% reduction in plasma Lp-PLA2 activity 2 as a way to prevent CAD. Pharmacological inhibition of the enzyme using darapladib averages 80%, and therefore the effect may be more pronounced than the effect of heterozygous carriage of the null allele. While this offers promise for inhibition, it remains challenging to extrapolate the effect of a genetic defect, established since the time of conception, to a pharmacological intervention of limited duration, usually initiated during adult life. As an illustration, for a similar amplitude, reduction of LDL-cholesterol levels associated with a genetic variant in PCSK9 appears to provide a stronger protection against CAD than would statins Taken together, these findings support the use of pharmacological agents that would inhibit Lp-PLAPLA2G7 V279F and the 9p21 variants were originally typed in 1130 female cases (diagnosed before age 65) and 1680 controls  from Study 1. No association was observed between V279F mutation and the risk of CAD in this dataset . However, for reasons which were unclear as the 9p21 locus has been equally associated with CAD in males and females, The present study has some limitations. First, we only report here data from men. The PLA2G7 279F reported here is quite accurate. Next, in the present study, cases and controls were not all collected from the same centers. The genetic homogeneity of the South Korean population, 2 levels in plasma were not measured in the present study. However, given the large, unambiguous body of published observations, The present study is based on a cross-sectional, age-discordant case-control design. Because relatively younger CAD cases (who may have a higher genetic burden than older cases) were compared with older controls, one cannot exclude the possibility that the benefits of carrying the 279F allele may have been over-estimated here. This possibility, however, is unlikely, as similar ORs were observed in Study 2 which was not age-restricted. Another limitation of the study is that controls did not have any coronary angiogram performed on them, and some of them may have clinically asymptomatic CAD, which may have led to under-estimation of the effect of the variants tested here. Conversely, the angiographic case definition for CAD in non-MI individuals was relatively lenient, and there is a possibility of over-diagnosis of CAD. Still, the overall amplitude of the effect of the positive control 9p21 locus marker in the present study  due to technical reasons, see below]  Cases and controls from Study 2 were all recruited from the Cardiovascular Genomic Center at Yonsei University Medical Center Written informed consent was obtained from each study participant, and the study protocol was approved by the ethics committee or institutional review board in each of the participating centers .PLA2G7 RS16874954 and C__26505812_10 for 9p21 locus RS10757274). Thermal cycle conditions were as follows: 50°C for 2 min, 95°C for 10 min followed by 45 cycles of 95°C for 15 s and 60°C for 1 min. PCR was performed using a Dual 384-Well GeneAmp PCR System 9700 (ABI) and the endpoint fluorescent readings were performed on an ABI PRISM 7900 HT Sequence Detection System. Duplicate samples (n = 212 for V279F and n = 322 for 9p21) and negative controls were included to ensure genotyping accuracy. The genotyping error rate was 0.2%.Genomic DNA was prepared from peripheral blood samples using the Puregene DNA purification kit . SNPs were genotyped using the TaqMan fluorogenic 5′ nuclease assay . The final volume of polymerase chain reaction (PCR) was 5 µl, containing 10 ng of genomic DNA and 2.5 µl TaqMan Universal PCR Master Mix, with 0.13 µl of 40X Assay Mix (Assay ID C__11915291_20 for vs never smoker), BMI, diabetes and plasma levels of glucose, triglycerides, HDL-cholesterol and LDL-cholesterol. As a large fraction of CAD cases were taking statins, LDL-cholesterol levels were corrected as recommended by Tobin Hardy-Weinberg equilibrium was confirmed for both markers using standard approaches. For Studies 1 and 2, the clinical characteristics were compared between CAD patients and control subjects using the chi-square test for categorical variables and 2-tailed Student t-tests or Wilcoxon test  for continuous variables. The association between genotype and CAD was examined using logistic regression analysis adjusting for age, smoking status  and RS10757274 (9p21) by centers.(DOC)Click here for additional data file.


Recent literature suggests a genetic component for non-arteritic anterior ischemic optic neuropathy (NAION). We examined the association of the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme gene, of the M235T polymorphism of the angiotensinogen gene, and of the A1166C polymorphism of the angiotensin II type 1 receptor gene with NAION.Forty-seven patients with NAION and 76 controls, age- and gender-matched, were recruited and genotyped for renin-angiotensin-aldosterone system (RAAS) genes. Genotypes were determined by polymerase chain reaction and restriction enzyme analysis. NAION and control groups were compared in regard to the prevalence of renin-angiotensin-aldosterone system polymorphisms, and further stratified by age and gender.NAION occurrence was not associated with the M235T polymorphism of the angiotensinogen gene and the A1166C polymorphism of the angiotensin II, type 1 receptor gene. Regarding the angiotensin-converting enzyme insertion/deletion polymorphism, our findings suggest that the II genotype could be a risk factor for NAION in younger male patients when compared to all cases and controls . Furthermore I allele was present in all male patients younger than 55 years, making this allele a likely predisposing factor for NAION in young males.RAAS polymorphisms or other genetic factors on NAION susceptibility.Since NAION may occur when compromised watershed microcirculation is combined with insufficient autoregulation of systematic circulation, polymorphisms of genes involved in systematic circulation, such as the RAAS genes, may be associated with NAION occurrence. Large-scale, multicentered, controlled prospective studies are needed to further explore the effects of  Anterior ischemic optic neuropathy (AION), is a vision loss-threatening disease caused by an infarction of the optic nerve, primarily affecting patients older than 55 years . Over a Anterior ischemic optic neuropathy (AION) occurs in two forms: arteritic and nonarteritic (NAION). The arteritic type is associated with giant-cell arteritis, whereas in NAION cases, hypertension, diabetes mellitus, ischemic heart disease, dyslipidemia, hypercoagulable states, and sleep apnea syndrome have been described as risk factors -6. ReporMTHFR) C677T polymorphism and platelet polymorphisms on the glycoprotein Ib alpha gene ) and 2 drops of IGEPAL CA-630  were added, were gently vortexed and centrifuged at 6500× g for 1 min. The supernatant was removed and the pellet resuspended in 500 μl of lysis buffer and centrifuged at 6500× g for 1 s (wash step). The wash step was repeated for 3–5 times. After the washes the pellet was resuspended in 200 μl of lysis buffer and 15 μl 15% SDS (Sigma-Aldrich Company LTD) and was placed in waterbath at 55 °C for 5 min.Whole blood samples from both patients and controls were used for isolation of peripheral blood leukocytes for genetic analysis. Genomic DNA (hereafter DNA) from each individual was isolated using a standard NaCl extraction procedure. Briefly, in a 1.5 ml tube with 700 μl of peripheral blood, 700 μl of lysis buffer  10 mM KCl, 4 mM MgClFollowing incubation 85 μl of NaCl 6M  were added and centrifuged at 9600× g for 3 min. The supernatant was resuspended at 750 μl of ice-cold 100% ethanol (Sigma-Aldrich Company LTD) to precipitate the DNA. The precipitated DNA was transferred to another 1.5 ml tube with 50 μl of TE .ACE gene was analyzed according to Rigat [ACE insertion/deletion genotype, PCR amplification was performed in a total volume of 25 μl consisting of 150 ng extracted DNA, 0.2 mM Deoxynucleotide Triphosphates , 10 pmol of each primer (Invitrogen), 10× Taq DNA polymerase buffer (Invitrogen), 2 mM MgCl2 (Invitrogen), 5% dimethyl sulfoxide DMSO , and 1.25 units of Taq DNA polymerase (Invitrogen). The forward and reverse primers were, respectively: 5′-CTG GAG ACC ACT CCC ATC CTT CTC-3′ and 5′-GAT GTG GCC ATC ACA TTC GTC AGA T-3′. The thermal cycling was as follows: 10 min denaturation at 94 °C, 30 cycles of 94 °C for 45 s, 58 °C for 30 s, and 72 °C for 45 s, with a final extension at 72 °C for 10 min. The final products, one of 490 bp with the insert  and one of 190 bp without the insert , were separated on 2% agarose gel. The resulting genotypes were DD, ID, and II.The I/D polymorphism in intron 16 of the to Rigat . To deteAGT M235T allele determination, PCR was performed according to a previously described procedure [AGT M235T genotype was determined by PCR amplification in a 25 μl mixture of 150 ng of extracted DNA, 0.2 mM dNTPs (Invitrogen), 5 pmol of each primer , 10x Taq DNA polymerase buffer (Invitrogen), 1.5 mM MgCl2 (Invitrogen), 5% DMSO (Euroclone), and 1 unit of Taq DNA polymerase (Invitrogen). The thermocycling conditions were as follows: at 90 °C for 3 min, 10 cycles at 94 °C for 1 min, at 68 °C for 1 min, and at 72 °C for 1 min, then continued with 30 cycles at 90 °C for 30 s, at 68 °C for 1 min, and at 72 °C for 30 s, with a final extension at 72 °C for 10 min. The PCR products were digested at 37 °C for 6 h with the restriction enzyme Tth111I . Digestion products were separated by 2% agarose gel electrophoresis and visualized by exposure to ultraviolet light after ethidiun bromide (Invitrogen) staining. The lengths of the separated fragments were 165 bp, corresponding to the M235 allele (M), and 141 bp, corresponding to the digested T235 allele (T). The resulting genotypes were MM, MT, and TT.For rocedure . Briefly2 (Invitrogen), and one unit of Taq DNA polymerase (Invitrogen). The forward and reverse primers were: 5′-GCA CCA TGT TTT GAG GTT-3′ and 5′-CGA CTA CTG CTT AGC ATA-3′, respectively. The reaction was performed using the following protocol: denaturation for 5 min at 94 °C, followed by 40 cycles of denaturation , annealing , and extension , and a final 10 min extension at 72 °C. The amplified product was digested for 3 h at 37 °C with the Dde1 (New England Biolabs-NEB) restriction enzyme, electrophoresed in 2% agarose gel, and visualized by staining with ethidium bromide (Invitrogen). Amplification of the A allele resulted in a 546 bp DNA fragment.To determine AT1-receptor A1166C genotypes, PCR amplification was also performed using standard procedures . PCR ampDigestion of the C allele resulted in a 435 bp DNA fragment. The resulting genotypes were AA, AC, and CC. All samples were run in duplicates with positive and negative for each genotype sample as controls and blanks.2 test. Statistical analysis was performed using the statXact program. All p values were two-tailed and were considered statistically significant at p<0.05. Confidence intervals (CIs) were calculated at the 95% level. Odds ratios (ORs) were defined as the odds ratio of patients with NAION divided by the odds of the control groups, and were calculated to provide an estimate of the relative risk of RAAS polymorphisms associated with NAION.The gene counting method estimated allele frequencies at the individual loci. The agreement of genotype frequencies with Hardy–Weinberg equilibrium expectations was tested using the χForty-seven patients (29 men and 18 women) and 76 controls (47 men and 29 women) were recruited for the study. The patients’ ages ranged from 49 to 85 years, with a mean age of 66.2 years. The age range of the controls was from 48 to 75 years, with a mean age of 65.6 years. Most cases were older than 55 years, and only eight patients were younger (six men and two women). In the control group, 11 individuals (eight men and three women) were under 55 years of age. Epidemiological and other relevant clinical data are shown in The polymorphisms were in Hardy–Weinberg equilibrium in the study population and the control group. The genotype and allele distributions are shown in Despite these negative results, when correlations were made according to age and gender , some noRegarding age, the II genotype frequency was higher in the younger age group ≤50 years (50%), compared to the cases (14.9%), the whole controls (15.8%), and the subgroup of controls ≤55 years (18.1%). This difference was statistically significant when patients at or below 55 years were compared to all cases and the controls, while there was no significant difference in comparison to the controls at or below 55 years .Regarding gender, no significant difference was found when male cases were compared to male controls. When comparisons were made according to age and gender simultaneously, there was a significant difference in the frequency of the II genotype in male cases at or below 55 years (66.6%) in comparison to all male cases and the male controls .ACE gene was more frequently present in patients, compared to controls (72.3% in cases versus 60.5% in controls), especially in younger patients under 55 years of age (87.5% in patients at ≤55 years versus 72.7% in controls at ≤55 years), but without statistical significance. Following an age-gender approach, comparison of male patients under 55 years to all male cases showed that the I allele was present in all six younger male patients (100%).Allele I of the AGT gene and the A1166C the polymorphism of the AT1-receptor gene, any correlation between gender and age groups disclosed no statistically significant difference in allele and genotype distributions. As a result, no association of these two polymorphisms with NAION occurrence was identified.Regarding the M235T polymorphism of the ACE I/D polymorphism, suggesting that the II genotype is a risk factor for NAION in younger patients, especially men, and that the I allele is likely a predisposing factor for NAION in younger males, but not in younger females (≤55 years). We did not find any association between the M235T AGT polymorphism, the A1166C AT1-receptor polymorphism, and NAION occurrenceA finding that surfaced from our study concerned the Although apoplectic onset, disc swelling, hyperemia, and splinter hemorrhages support infarction as the precipitating event in NAION, the precise mechanism of optic nerve ischemia has not been absolutely clarified, and the contribution of the various known vascular risk factors is not entirely known. The optic nerve disc has a unique vasculature with contributions from the short posterior ciliary arteries, the pial circulation, and the retinal circulation , with anRAAS and vasculoprotective genes, may, like the NOS genes, have a role in NAION occurrence, although results conflict [Recent literature indicates that NAION is associated with nocturnal arterial hypotension, which may produce hypoperfusion of the optic nerve head microvasculature . NAION dconflict ,28.RAAS genes have been shown to affect blood pressure phenotypes [ACE I/D polymorphism appears to influence ACE expression and blood pressure, with the D allele and DD genotype being associated with high blood pressure, while the II genotype and the I allele are associated with lower blood pressure [AGT is also associated with increased blood pressure [AT1-receptor gene [The rennin-angiotensin-aldosterone system plays a central role in blood pressure regulation, and enotypes ,30. The pressure ,32. The pressure ,34, whertor gene ,36. Furttor gene , the moltor gene , and thetor gene , suggesttor gene ,41. As ator gene .RAAS polymorphisms play a role in NAION onset. The suspected influence on the I allele and II genotype in ages below 55 years is intriguing and may support the hypothesis that hypoperfusion and low pressure are possible underlying causes of NAION in this age group [RAAS genes [Our results do not indicate that certain ge group . A possiAS genes ,42.The small number of patients younger than 55 years made the comparisons less conclusive, and the small number of younger women did not permit any comparisons between younger and older women or between younger men and women. The strength of our study is its use of an homogenous population affected only with limited immigration the last century.RAAS polymorphisms and other genetic factors on NAION susceptibility.In summary, our study, despite some negative results and other limitations, uncovered interesting findings on blood-pressure gene polymorphisms and NAION susceptibility. It is, to our knowledge, the first study to attempt gender- and age-related analysis of these patients. Large-scale, multicentered, controlled prospective studies are needed to further explore the effects of


A genetic liability for anxiety-related personality traits in healthy subjects has been associated with the functional serotonin transporter promoter polymorphism (5-HTTLPR), although the data are somewhat conflicting. Moreover, only one study has investigated the functional significance of the 5-HTTLPR/rs25531 haplotypes in relation to anxiety traits in healthy subjects. We tested whether the 5-HTTLPR polymorphism and the 5-HTTLPR/rs25531 haplotypes are linked to Harm Avoidance (HA) using an association study (STUDY I) and a meta-analytic approach (STUDY II).STUDY I: A total of 287 unrelated Italian volunteers were screened for DSM-IV Axis I disorders and genotyped for the 5-HTTLPR and rs25531 (A/G) polymorphisms. Different functional haplotype combinations were also analyzed. STUDY II: A total of 44 studies were chosen for a meta-analysis of the putative association between 5-HTTLPR and anxiety-related personality traits.STUDY I: In the whole sample of 287 volunteers, we found that the SS genotype and S'S' haplotypes were associated with higher scores on HA. However, because the screening assessed by Mini-International Neuropsychiatric Interview (M.I.N.I.) showed the presence of 55 volunteers affected by depression or anxiety disorders, we analyzed the two groups  separately. The data obtained did indeed confirm that in the "healthy" group, the significant effects of the SS genotype and S'S' haplotypes were lost, but they remained in the "disordered" group. STUDY II: The results of the 5-HTTLPR meta-analysis with anxiety-related traits in the whole sample confirmed the association of the SS genotype with higher anxiety-related traits scores in Caucasoids; however, when we analyzed only those studies that used structured psychiatric screening, no association was found.This study demonstrates the relevance to perform analyses on personality traits only in DSM-IV axis I disorder-free subjects. Furthermore, we did not find an association between functional serotonin transporter gene polymorphisms and anxiety traits in healthy subjects screened through a structured psychiatric interview. Personality traits can be defined as individual qualities or characteristics that influence cognitions, emotions, and behaviors and lead to adaptive or maladaptive responses. Human personality is a multidimensional structure that is affected by both environmental and genetic factors. According to the literature, individual variation of the heritable component is estimated to account for 30-40% of the variance in personality traits . To dateFunctional studies of the activity of the SLC6A4 promoter in transfected cell lines, postmortem human brains, and lymphoblasts have confirmed that the L allele is associated with higher levels of transcriptional activity and influences the rate of serotonin uptake more than the S variant -8 but alA) or low  transcriptional efficacy [Recently it has been critically discussed that the analysis of 5-HTTLPR is incomplete, because other polymorphisms have been found in the proximity of the Ins/Del locus, such as rs25531, rs25532, rs2020933, and a 17-bp variable tandem repeat in the second intron (STin2) ,12,13. Iefficacy ,14.The inventories mostly used in biological studies of personality are the NEO-Personality Inventory  and the Since the first paper of Lesch  was publIt is important to emphasize that these contrasting results may be explained by the inclusion of studies that recruited participants from psychiatric populations. Both Schinka and Sen's meta-analyses ,24 incluOn the basis of these conflicting evidences we performed the following analyses: 1) STUDY I: an association study between the 5-HTTLPR and rs25531 and the relative estimated/phased haplotypes with anxiety personality traits measured using the self-rated TCI scale. The analyses were carried out in the whole sample of controls as well as in subjects without any DSM-IV axis I disorders screened by structured interviews; 2) STUDY II: meta-analyses of 5-HTTLPR and HA or N in controls and in screened samples.STUDY 1: A new association study of 5-HTTLPR and 5-HTTLPR/rs25531 with HAA total of 287 unrelated volunteers  were recruited through a variety of sources, such as universities, newspaper advertisements, and elderly associations. The study protocol was approved by the Ethics Committee of Fatebenefratelli Hospital , and written informed consent was obtained from all the subjects. The subjects were screened for DSM-IV Axis I disorders through the Mini-International Neuropsychiatric Interview (M.I.N.I.)  and screASA, SGSG, LGSA, and LGLG as S'S'; LA SA and LALG as L'S'; and LALA as L'L') were described in a study by Bonvicini [GLG or SGSG haplotypes in the genotyping analyses.Isolation of DNA, genotyping of 5-HTTLPR and rs25531, as well as the classification of estimated phased haplotypes . The p-values have been corrected for multiple comparisons. All analyses were conducted using SPSS statistical software version 12.0 .The association study showed a power > 80% by using the Quanto program version 1.2.4 with the following parameters: 5-HTTLPR S and S'S' minor allele frequencies (MAFs) of 15% and 21%, respectively, in a population of European origin; p ≤ 0.05; OR ≥ 1.6; log additive mode of inheritance; and population risk ≥ 10%.2 = 0.05; p = 0.82). The results indicated a trend toward an association between 5-HTTLPR and anxiety-related scale for genotypes (p = 0.06), and a significant effect was found when we considered the L allele as dominant (p = 0.02). Concerning the analysis of the 5-HTTLPR/rs25531 the ANCOVA results showed an effect using a dominant L model  of LL, LS, and SS were 0.37 (43.42 +/- 17.14), 0.48 (42.55 +/- 17.96) and 0.15 (48.57 +/- 20.18), respectively  subjects without lifetime DSM-IV Axis I disorders  and 58 subjects (20%) with these disorders (the "disordered" group). In the "disordered" group, 38 subjects had MDD, 2 had Panic Disorder, 22 had Generalized Anxiety Disorder, 6 had Dysthymia, 1 had Bipolar Disorder, 1 experienced alcohol abuse and 1 experienced substance abuse . Because the literature has largely shown that people affected by unipolar major depression and anxiety disorders present homogeneous patterns of personality traits compared to other subjects -28,33-36Thus, to evaluate whether the results from the participants excluded by M.I.N.I. had influenced the previous analyses, we performed ANCOVA using the HA score as the dependent variable, groups , genotypes, and sex as independent variables, and age as a covariate for both 5-HTTLPR and estimated/phased haplotypes. The results indicated that, the disordered group showed significantly higher HA scores than healthy subjects . No association was found between 5-HTTLPR polymorphism and anxiety traits , whereas a significant interaction was observed between the 5-HTTLPR genotype and groups . The same pattern was obtained when the SS genotype was compared to allele L carriers . Concerning the 5-HTTLPR/rs25531, a significant interaction was detected with the dominant L model . In all analyses, no significant gender effect or interaction was obtained.In the sample of subjects with no DSM-IV axis I disorders , we performed an ANCOVA analysis to test the possible association between polymorphisms and HA. There was no significant association between HA and either the 5-HTTLPR or the 5-HTTLPR/rs25531 haplotypes  for all the available studies of the association between the serotonin transporter and anxiety personality traits conducted in healthy adults, using the following search terms: serotonin transporter polymorphism, serotonin transporter gene, 5-HTTLPR, Neuroticism, Harm Avoidance, anxiety, and personality. Once articles had been collected, bibliographies were manually searched for additional eligible studies.All association studies that have measured anxiety traits using any version of NEO  or the TCI (or TPQ) in male and/or female participants of any ethnic origin were included. Only data from controls were included from studies in which psychiatric patients and control data were compared. Data that appeared in more than one published study were included only once in the analyses. Papers not written in English  were exchttp://www.genemapping.cn). In cases where all or part of this information was not available in the publication, the authors were contacted by email.We recorded the number of participants, the mean of N and/or HA trait scores, and the standard deviation for each of the three genotype groups  in each study included in our analysis. Furthermore, we extracted data regarding the male/female ratio, the mean age, the ethnic compositions of the sample, and the structured clinical interview used for screening. Genotype frequencies were used to calculate the HWE .ds) using inverse variance methods to generate a summary d and 95% confidence interval (CI). We analyzed a possible association by both comparing LL genotype versus carriers of the S allele and SS genotype versus carriers of the L allele. The significance of the pooled effect sizes was determined by the Z-test and the between-study heterogeneity was assessed using a χ2 test of goodness of fit and I2 statistic [p value was set at 0.05. In a fixed effects model, the fundamental assumption is that a single true effect size underlies all study results and that observed estimates vary only as a function of chance. The error term in a fixed effects model represents only within-study variation, and between-study variation is ignored. Where the results showed a significant effect in the presence of significant between-study heterogeneity, a random effects model was utilized, with ds pooled using the DerSimonian and Laird methods [Firstly, data were analyzed with the fixed effects model in order to combine individual study effect sizes  were found in the S allele carriers group. When the analysis was run again using the random effects method, the significant effect just described was no longer significant. No evidence for an association between the 5-HTTLPR genotype and N (p = 0.09) as well as no overall effect (p = 0.11) was shown.Because of ethnic differences in the 5-HTTLPR genotype distribution, the studies on Asian and Caucasoid populations were independently analyzed. When we conducted a comparison analysis between the LL genotype and S allele carriers in the Caucasoid population Figure , no asso2 [2 = 0%).When we tested the L allele carriers versus the SS genotype in the same ethnic population Figure , no asso2  = 0.01, In the Asian population, no association was observed between the LL genotype and carriers of the S allele, using either TCI  or NEO . After clustering of the L allele carriers versus the SS genotype, there was no significant evidence of an association between 5-HTTLPR and either HA or N . We did not find between-study heterogeneity in any groups.Because of the bias inherent in a mix of healthy subjects with depressed or anxious people, we carried out a meta-analysis including only the studies with structured psychiatric interview screening ,73,75,88The present study demonstrates the relevance of employing more stringent inclusion/exclusion criteria in association studies on healthy subjects. Our results show the influence of mistakes in the selection of subjects, underscoring the importance of the use of a structured psychiatric interview when people are enrolled as control subjects for this type of study. When we performed analyses on the whole sample of 287 volunteers, effects on the susceptibility to HA were found for both the SS genotype and the S'S' haplotypes. However, because the screening performed by M.I.N.I. revealed the presence of depression or anxiety disorders in 55 volunteers (the "disordered" group), we verified the possible influence of the variable "groups"  on the genotypes. The results evidenced a significant interaction between genotypes and groups ; thus, we conducted the analyses separately for these groups. The data confirmed that in the "healthy" group, the effects of the SS genotype and the S'S' haplotypes were lost, but they remained in the "disordered" group. In addition, we conducted a meta-analysis involving approximately 18,000 controls of Caucasoid and Asian descent and considering anxiety traits measured by TPQ/TCI or NEO. Similarly, an association was observed between S allele in homozygosity and higher scores for anxiety-related traits, but when we analyzed only the studies that used structured psychiatric screening, no association was found.Moreover, another important finding from both STUDY I and STUDY II is the absence of a role of the serotonin transporter gene in anxiety personality traits in healthy subjects.To date, five meta-analyses have been conducted on the involvement of the functional 5-HTTLPR polymorphism with anxiety personality traits -24. SchiIt is well known that anxiety traits are strongly linked to depression and anxiety disorders ,33-36,89G haplotype has lower transcriptional efficacy as well as the S allele. Therefore, in STUDY I we conducted association analyses for 5-HTTLPR/rs25531 to investigate the influence of rs25531. The results showed the association with HA in the "disordered group". In light of these data, we speculate that the genotyping of both the functional polymorphisms (5-HTTLPR and rs25531) and the haplotypes analysis should be taken into account in relation to anxiety-related personality traits.In our recent paper , we haveFinally, in STUDY II, because the S allele is much more prevalent in Asians than in Caucasians ,49,58, sThis study supports the following conclusions: 1. A lack of structured psychiatric screening of subjects may produce an important bias in genetic association studies on personality traits using controls. The symptomatology of depressive and anxiety disorders might interfere with anxiety-related traits in possible associations with the serotonin transporter and the higher frequency of the S allele observed in depressed and anxiety disorder patients; 2. The SLC6A4 gene is not involved in anxiety-related traits measured by TCI and NEO in psychiatrically healthy subjects.The authors declare that they have no competing interests.AM conceived of the study, participated in its design and the coordination and acquisition of data, performed the statistical analyses, and co-wrote the manuscript; CB participated in the design of the study, performed the statistical analyses and carried out all genetic analyses; CS participated in the design and coordination of the study and co-wrote the manuscript; RS performed the statistical analyses and helped draft the manuscript; MG conceived of the study, participated in its design and coordination, and helped draft the manuscript and critically reviewed it for intellectual content. All the authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-244X/11/50/prepub


To assess the association of polymorphism rs198977 in the human kallikrein-2 gene (KLK2) and risk of prostate cancer (PCa).Two investigators independently searched the PubMed, Elsevier, EMBASE, Web of Science, Wiley Online Library and Chinese National Knowledge Infrastructure (CNKI). Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) for rs198977 and PCa were calculated in a fixed-effects model (the Mantel-Haenszel method) and a random-effects model (the DerSimonian and Laird method) when appropriate.Six studies met the inclusion criteria in this meta-analysis, which included 5859 PCa cases and 4867 controls. Overall, rs198977 was associated with the PCa risk . When stratified by ethnicity, significant association was observed in Caucasian samples under both allele comparison  and dominant model . In the overall analysis, a comparably significant increase in the frequency of allele T for rs198977 was detected between cases and controls in Caucasian.This meta-analysis suggests that rs198977 of KLK2 was associated with susceptibility of PCa in Caucasian and the allele T might increase the risk of PCa in Caucasian. Prostate cancer (PCa) is the most commonly diagnosed visceral malignancy accounting for more than one-third of all incident cancers and is the second-leading cause of cancer deaths in men in the United States and the western world et al. have demonstrated that KLK2 variants correlate with hK2 serum levels et al. showed that hK2 mRNA expression was significantly higher in PCa tissue compared with benign tissue There is considerable evidence for a genetic basis underlying risks for PCa All of these observations strongly implicate KLK2 as a plausible candidate gene involved in PCa susceptibility. During this decade, a number of studies have assessed the association between polymorphism rs198977 in KLK2 and risk of PCa in different populations; however, the results are inconsistent and inconclusive Published reports assessing the association between polymorphism of KLK2 and risk of PCa were collected through a comprehensive search of six databases, including PubMed, Elsevier, EMBASE, Web of Science, Wiley Online Library and Chinese National Knowledge Infrastructure (CNKI). The search terms were as follows:  AND (‘prostate cancer’). Searching was completed on Nov 1, 2012. Publication date and publication language were not restricted in our search. Meanwhile, reference lists were examined manually to further identify potentially relevant studies. Unpublished reports were not considered. If more than one article was published by the same author using the same case series, the one investigating the most individuals was selected.Abstracts of all citations and retrieved studies were reviewed. Studies meeting the following criteria were included: (1) Using a case–control design; (2) Detecting the relationship between the polymorphism rs198977 and PCa; (3) Providing available genotype data of rs198977. Studies were excluded if one of the following existed: (1) The design was based on family or sibling pairs; (2) The genotype frequency of rs198977 was not reported; (3) The association of rs198977 with susceptibility of PCa  was not detected, or (4) There was insufficient information for extraction of data.All data were extracted independently by two reviewers (lishan wang and weidong zang) according to the inclusion criteria listed above. The results were compared and disagreements were discussed and resolved with consensus. Evaluation was based on title and abstract whenever available. Full text articles of potentially relevant studies were obtained and re-evaluated for inclusion. The following characteristics were collected from each study using an Excel data extraction form: first author, year of publication, country of sample, ethnicity, numbers of cases and controls, main background of samples, and genotyping methods .The statistical analysis was conducted using STATA 11.0 ; P-value <0.05 was considered statistically significant. Hardy-Weinberg equilibrium (HWE) in the controls was tested by the chi-square test for goodness of fit, and a P –value <0.05 was considered as significant disequilibrium. Pooled odds ratio (ORs) were calculated for allele comparison (T vs. C), dominant model (TT+CT vs. CC), and recessive model (TT vs. CC+CT), respectively. The significance of pooled ORs was determined by Z-test and P-value <0.05 was considered as statistically significant.2 -based Q testing and 2I statistics 2-based Q testing and I2 was interpreted as the proportion of total variation contributed by between-study variation. If there was a significant heterogeneity , we selected a random-effects model (the DerSimonian and Laird method) to pool the data. If not, we selected a fixed-effects model (the Mantel-Haenszel method) to pool the data. Heterogeneity was also quantified using the 2I metric  The OR and 95% CI were estimated for each study in a random-effects model or in a fixed-effects model. Heterogeneity among studies was examined with the χA total of 121 papers were retrieved after the first search, and 115 of these were excluded from the analysis for reasons detailed in [17][24]There were six case-control studies When studies were stratified by ethnicity, significant associations were observed in Caucasian group in both allele comparison  and dominant model  ; while nThe influence of a single study on the overall meta-analysis was investigated by omitting one study at a time, and the omission of any study made no significant difference, indicating that our results were statistically reliable.2 -based Q testing = 0.006 and 2I = 67.0%) and recessive model , but no significant heterogeneity was observed under dominant model . Then subgroup analysis was carried out. When studies were stratified by ethnicity, no statistically significant heterogeneity was observed in Caucasian under either allele comparison  or dominant model , but there was significant heterogeneity under recessive model . For Asian, no statistically significant heterogeneity was observed under any model . Results of heterogeneity were shown in For all samples, statistically significant heterogeneity was observed under both allele comparison  . This inHowever, there are still some limitations in this meta-analysis. (1) In six studies included for our analysis, two of them are Asian samples occupied only 6.52% of whole samples, so such results should be interpreted with caution; (2) Because the samples from 5 countries and controls were not uniform, as in most meta-analyses, results should be interpreted with caution; and (3) meta-analysis is retrospective research that is subject to methodological limitations. In order to minimize the bias, we used explicit methods for study selection, data extraction and data analysis. Nevertheless, our results should be interpreted with caution.This meta-analysis suggests that the polymorphism rs198977 of KLK2 was associated with susceptibility of prostate cancer in Caucasian and the allele T might increase the risk of prostate cancer. The pooled ORs in this study suggest that allele T and genotype TT+CT both have modest but definite genetic effect on prostate cancer in Caucasian. Larger and well-designed studies based on different ethnic groups are needed to confirm our results, especially for Asian samples.Checklist S1PRISMA checklist.(DOC)Click here for additional data file.


TGFB1 gene and risk of late radiation-induced injury of normal tissue, but the conclusions remain controversial.Transforming growth factor-beta 1 (TGF-β1) protein may be multifunctional and related to the development of fibrosis, induction of apoptosis, extracellular signaling and inhibition of proliferation in response to radiation-induced DNA damage. Several studies have investigated associations between single nucleotide polymorphisms (SNPs) in the TGFB1  with risk of late radiation-induced injury of normal tissue.We searched three electronic databases  for eligible publications and performed a meta-analysis assessing the association of three commonly studied SNPs in TGFB1. However, we did not find statistical evidence of any significant association with overall risk of late radiotherapy toxicity in the pooled analysis or in further stratified analysis by cancer type, endpoint, ethnicity and sample size.We finally included 28 case-only studies from 16 publications on aforementioned SNPs in TGFB1 and risk of late radiation-induced injury of normal tissue, but this finding needs further confirmation by a single large study.This meta-analysis did not find statistical evidence for an association between SNPs in  Radiotherapy remains a cornerstone of modern cancer management, with curative or palliative potential in roughly half of incident solid tumors, and has the advantage of organ and function preservation in most cases . UnfortuTGFB1. The human TGFB1 gene is located at chromosome 19q13.1 and encodes the transforming growth factor-beta1 (TGF-β1) protein, a versatile pro-fibrotic cytokine that is involved in the development and continuation of post-irradiation injury in various tissues [TGFB1 have been reported to affect TGF-β1 levels in circulating plasma and hence lead to the risk of developing radiation-induced toxicity [-509T>C SNP in the promoter was found to be significantly associated with an increased circulating concentration of TGF-β1 [in vitro and also with fibrosis in lung allografts [TGFB1 represent logical candidates for association studies designed to address late toxicity following radiotherapy. A number of studies have reported associations between various SNPs and radiation-induced injury of normal tissue ,4, among tissues . The TGF tissues . Associa tissues . The TGFtoxicity . For exaf TGF-β1 , whereaslografts . Thus, STGFB1 gene have been reported according to the dbSNP database (http://www.ncbi.nlm.nih.gov/projects/SNP), among which three common SNPs, rs1800469 c.509TC in the 5’near gene, rs1800470 c.29CT encoding Pro10Le and rs1800471 c.74GC encoding Arg25Pro, have been widely studied for associations with risk of late radiotherapy toxicity, but the results are mixed rather than conclusive, partially because of possible weak effects of these SNPs on late radiotherapy toxicity risk or relatively small studies to detect such weak associations. Therefore, we performed a comprehensive meta-analysis that improved statistical power to derive a more precise risk estimate for the associations.To date, at least 638 SNPs in the TGFB1” or “TGFbeta1” or “transforming growth factor beta 1”, “genetic variation” or “polymorphism”, “cancer” or “neoplasm” or “tumor” or “malignancy”, “radiotherapy” or “radiation”, “toxicity” or “adverse effect” . We also manually examined the references of the retrieved articles and relevant reviews for additional relevant eligible studies. We contacted authors directly for crucial rude data that were unavailable in the original publications. We searched three electronic databases  for all relevant publications using the following terms: “TGFB1 SNPs  and late radiotherapy toxicity; written in English or Chinese; sufficient information provided to estimate odds ratios (ORs) and their 95% confidence intervals (CIs). We did not consider abstracts or unpublished reports. We also excluded investigations of TGFB1 SNPs with acute radiotherapy toxicity. Late radiotherapy toxicities occur in months to years after treatment, including fibrosis, atrophy, vascular damage, neural damage as well as a range of endocrine and growth-related effects. Acute effects typically emerge within a few weeks of the completion of a course of fractionated radiotherapy, including skin erythema, dry or moist desquamation of the skin, mucositis, nausea and diarrhea., Additionally, if studies had the same subjects or overlapping data, we only included the latest or the most complete study with the largest sample size in this meta-analysis.We defined the inclusion and exclusion criteria as follows: evaluation of Two authors independently extracted data from each study and reached a consensus on all items, including first author's surname, year of publication, country of origin, ethnicity, cancer type, total number of genotyped cases, genotyping methods, endpoints, scoring system, treatment summary, and numbers of genotypes for each SNP in cases. For studies that included subjects of a different racial descent, we extracted data separately for each ethnic group and categorized these groups as Caucasians, Asian and Mixed (which contained more than one ethnic group). In addition, studies involving different endpoints were divided into multiple single studies for subgroup analyses.TGFB1 SNPs and risk of late radiotherapy toxicity by the pooled ORs with the corresponding 95% CIs for dominant models of rs1800469 (TC/CC vs. TT), rs1800470 (TC/TT vs. CC) and rs1800471 (GC/CC vs. GG). We also performed stratification analyses by cancer type , ethnicity (Caucasian and others), endpoint  and sample size . We performed Chi square-based Q-test to assess between-study heterogeneity and considered it significant if P < 0.10. When the P value of the heterogeneity test was ≥ 0.10, we used the fixed-effects model (Mantel-Haenszel method), assuming no significant heterogeneity of effect size across all studies [P < 0.05 determined by Egger’s test suggested a possible publication bias [P values were two-sided with a significance level of P < 0.05. We evaluated associations between  studies . Otherwi studies . In addiion bias . If publion bias . FinallyTGFB1 SNPs with acute radiotherapy toxicity [We identified a total of 53 relevant publications after initial screening, of which 22 met the inclusion criteria and were subjected for further evaluation. We excluded four publications with conference abstracts or insufficient data to extract ORs and 95% CIs (after failure to get a response from the authors) -18. We atoxicity ,20. Finatoxicity ,21-35 wiTC/CC vs. TT: OR = 0.73, 95% CI = 0.45-1.19, P = 0.206) or in the stratified analysis by ethnicity, cancer type, endpoint, and sample size. For rs1800470, we included a total of 1,669 cases from nine publications, and we also did not find any statistical evidence of significant associations of the SNP with late radiotherapy toxicity risk in both the pooled analyses  and further subgroup analyses . Because we included only a limited number of publications for this SNP, we did not conduct further stratified analysis.For the rs1800469 SNP, we obtained genotyping data for 2,926 cases from 15 studies. We found no association between the rs1800469 SNP and late radiotherapy toxicity risk, either in the overall pooled meta-analysis , we used the random-effects model that generated wider CIs. For rs1800471, we did not find evidence of heterogeneity among studies (P = 0.912) and then used the fixed-effects model. The leave-one-out sensitivity analysis indicated that no single study changed the pooled ORs qualitatively (data not shown).Because substantial heterogeneities were observed among studies for the associations between the two SNPs  and late radiotherapy toxicity  and late radiotherapy toxicity risk. Egger’s test provided further statistical evidence indicating that no publication bias existed in this meta-analysis . The shapes of the funnel plots seemed symmetrical, indicating that there was no obvious publication bias for associations between the TGFB1 SNPs and the risk of late radiotherapy toxicity. We found that none of the three SNPs  was significantly associated with late toxicity risk in the pooled analysis. Similarly, in the subgroup analysis, we found no statistical association between the SNPs and late toxicity risk in any of the subgroups. Our meta-analysis comprehensively explored the associations between TGF-β1 is a multifunctional cytokine associated with proliferation, differentiation, and deposition of extracellular matrix proteins in irradiated cells . ConsideTGFB1 SNPs and risk of late radiotherapy toxicity [TGFB1 SNPs are among the most extensively studied SNPs in terms of sensitivity of normal tissues to radiobiology, it is difficult to draw any definite conclusions [TGFB1 SNP rs1800469 genotype, as well as treatment-related outcome data, and clinically-assessed fibrosis (measured at least two years after therapy) in 2782 participants from 11 patient cohorts, but their meta-analysis did not confirm previous reports of associations between fibrosis or overall toxicity and the rs1800469 SNP in breast cancer patients [To date, two reported meta-analyses have focused on associations between toxicity ,7. Andretoxicity . In bothclusions . Later opatients .Notably, the results of the present meta-analysis require some caution in the interpretation, because of several limitations in the present and published meta-analyses. First, some data were excluded from the analyses, because of unavailable original data, which could cause some bias in the estimates. In addition, although there is no obvious evidence of publication bias observed in the meta-analysis, the power of the funnel plot to test the asymmetry with less than thirty publications is relatively low. Furthermore, most of the data on publication bias is retrospective rather than prospective, including our present analysis. Reporting publication bias from prospective studies is needed. Second, in the process of quality assessment and data extraction from the original literature, we found some studies that had overly small sample sizes, which may have resulted in false-positive or false-negative results for each study. Third, it has been reported that treatment-related factors, such as with or without chemotherapy or chemotherapy sequential may influence the outcome. However, due to the retrospective nature of the studies included in the meta-analysis, we could not obtain the needed information for assessing the effect of confounding factors on the outcome. Fourth, all included studies were of case-only design, which may have selection biases, implementation biases, and confounding bias, due to the nature of hospital-based studies. Fifth, radiotherapy toxicity is a complex phenotype involving many different pathological mechanisms, and these different processes may lead to various clinical end-points. Despite a recognized need for a standardized approach for reporting radiation toxicity, a variety of scoring systems have been used, and the toxicity remains generally under-reported. Sixth, according to the stratified analysis, we observed that the source of homogeneity may come from different cancer type, endpoint, ethnicity and sample size of each study. The results of subgroup analysis demonstrated that there was some variability among studies for the same endpoint. A possible explanation for this variability may be related to other unmeasured differences in the current analysis, such as the side effects scoring system or the time between radiotherapy and when the presence/absence of side effects occurred. Seventh, in most publications that were included in the meta-analysis, although the side effects and the corresponding risk factors were described, the information about the time between radiotherapy and when the presence/absence of side effects was often missing which could have contributed to the bias in estimating the true association and thus the influence on the outcome. Finally, some of the findings in subgroups may have been underestimated, because there was only one trail available.TGFB1 may not contribute to risk of late radiation-induced injury of normal tissue. Because the subjects from studies included in this meta-analysis are still nor large enough, well-designed prospective studies with larger sample sizes and more detailed information on confounding factors are required to validate these findings. In conclusion, the present meta-analysis suggests that SNPs in Checklist S1PRISMA checklist.(DOC)Click here for additional data file.


The impact of pre-existing diabetes on the development of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) in critically ill patients remains unclear. We performed a meta-analysis of cohort studies to evaluate the risk of ALI/ARDS in critically ill patients with and without pre-existing diabetes.We searched PubMed and Embase from the inception to September 2013 for cohort studies assessing the effect of pre-existing diabetes on ALI/ARDS occurrence. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using random- or fixed-effect models when appropriate.studies with a total of 12,794 participants and 2,937 cases of pre-existing diabetes, and 2,457 cases of ALI/ARDS were included in the meta-analysis. A fixed-effects model meta-analysis showed that pre-existing diabetes was associated with a reduced risk of ALI/ARDS , with low heterogeneity among the studies . However, the asymmetric funnel plot and Egger's test (p = 0.007) suggested publication bias may exist.Seven cohort Our meta-analysis suggests that pre-existing diabetes was associated with a decreased risk of ALI/ARDS in critically ill adult patients. However, the result should be interpreted with caution because of the potential bias and confounding in the included studies. Acute lung injury (ALI) is a syndrome characterized by hypoxemia, noncardiogenic pulmonary edema, low lung compliance and widespread capillary leakage. When accompanied by more severe hypoxemia (PaO2/FiO2<200 mmHg), it is called acute respiratory distress syndrome (ARDS) Diabetes also is a global health priority. The prevalence of diabetes is expected to dramatically increase by the year 2025 The impact of pre-existing diabetes on the development of ALI/ARDS remains unclear in critically ill patients, especially those with one or more predisposing conditions such as sepsis/septic shock, pneumonia, trauma, and aspiration. To our knowledge, the quality and consistency of epidemiological evidence on the topic have not been systematically investigated, which is an important gap in our understanding of the effect of pre-existing diabetes on the development of ALI/ARDS. With recently accumulating evidence, therefore, we performed a meta-analysis of cohort studies to evaluate the risk of ALI/ARDS in critically ill patients with and without pre-existing diabetes.We performed this meta-analysis in accordance with the Meta-analysis of Observational Studies in Epidemiology(MOOSE) statement The following inclusive selection criteria were applied: (a) study design: cohort study; (b) study population: critically ill adult patients, it meaned ICU or emergency patients with ALI/ARDS predisposing risk factors, including sepsis, septic shock, pancreatitis, pneumonia, aspiration, trauma, or high-risk surgery; (c) comparison intervention: with and without pre-existing diabetes; and (d) outcome measure: the development of ALI/ARDS. In the case of duplicate data publication , we only included the most informative article or complete study to avoid duplication of information.A standardized data collection form was used to extract the following information from each included article: first author, publication year, sample size, number of diabetes cases, number of ALI/ARDS cases, population characteristics, type of study design, definition of ALI/ARDS, and odds ratios (ORs) with the corresponding 95% confidence intervals (CIs) on multivariable analysis. The supplementary files were also examined for data extraction. Where necessary, we contacted authors of included studies for additional information.We assessed the methodological quality of each study on 8 items used in the Newcastle-Ottawa Scales (NOS) Two investigators (WJ Gu and YD Wan) independently conducted the study selection, data extraction and quality assessment, a third investigator (TW Sun) was consulted to resolve any discrepancies.p<0.1) and quantified with the I2 statistic, which describes the variation of effect size that is attributable to heterogeneity across studies 2I value greater than 50% indicates significant heterogeneity. The value of the 2I statistic was used to select the appropriate pooling method: fixed-effects models were used for 2I< 50% and random-effects models for 2I≥50% prior subgroup analyses according to study design (prospective vs. retrospective), predisposing conditions (sepsis/septic shock vs. >1 predisposing conditions), study center (single-center vs. multicenter), and sample size(≤1000 vs. >1000). We also investigated the influence of a single study on the overall pooled estimate by omitting one study in each turn. Potential publication bias was detected by Begg's funnel plots and Egger's regression test p value <0.05 was judged as statistically significant, except where otherwise specified. All statistical analyses were performed using STATA, version 11.0 (Stata Corp).OR was used as a common measure of the association between pre-existing diabetes and the development of ALI/ARDS across studies. Heterogeneity was tested using the Cochran Q statistic  on the basis of the title/abstract and full text (see the detail in The main characteristics of the seven included cohort studies are shown in p<0.001), with low heterogeneity among the studies . Further exclusion of any single study did not materially alter the overall combined OR, with a range of from 0.55  to 0.68 . p = 0.007) suggested that publication bias may exist. Also, there was asymmetry in the lower segments of the funnel plot in which small negative trials were missing , the definition of diabetes, severity of the illness, and the adjusted confounding factor were not strictly described in some trials. These factors may result in heterogeneity and have a potential impact on our results. Second, the critically ill patients was really a broad population, in our study, most studies described it as ICU patients with one or more ALI/ARDS predisposing risk factors, including sepsis, septic shock, pancreatitis, pneumonia, aspiration, trauma, or high-risk surgery, etc. So whether the conclusion was suitable for the unselected ICU population remain questionable. Third, both the asymmetric funnel plot and Egger's test suggested publication bias may exist. Small negative trials were missing, potentially resulting in overstatement of the treatment effect. Furthermore, we are unable to assess the impact of pre-existing diabetes on other clinically meaningful end points, such as mortality attributed to ALI/ARDS, because of sparse and inconsistent reporting across studies.In summary, this meta-analysis of seven cohort studies suggests that pre-existing diabetes decreased the risk of ALI/ARDS in critically ill adult patients; however, the result should be interpreted with caution because of the potential bias and confounding in the included studies.Checklist S1PRISMA Checklist.(DOC)Click here for additional data file.File S1Methodological quality assessment (risk of bias) of included studies by Newcastle-Ottawa Scales.(DOC)Click here for additional data file.


Several studies have suggested a difference in clinical features of intellectual ability and psychiatric illness in the Prader–Willi syndrome (PWS) with the 15q11-q13 paternal deletion and maternal uniparental disomy (mUPD). Our objective was to appraise evidence on this association through a meta-analysis.The electronic records PubMed and EMBASE from 1956 to 2012 were extracted for meta-analysis. Meta-analyses were performed by using fixed effect model. Mean difference, odds ratio, and 95% confidence interval were calculated.p=0.02] and verbal IQ (VIQ)  but higher performance IQ (PIQ) . In contrast, PWS patients with mUPD are associated with significantly higher risk of psychiatric illness  and higher risk of bipolar disorder .We retrieved a total of 744 PWS cases from 13 studies. These include 423 cases with paternal 15q11-q13 deletions and 318 cases of mUPD. Compare to the PWS cases with mUPD, PWS patients with the paternal 15q11-q13 deletion associated with significantly lower full scale IQ (FSIQ) [mean difference (MD), -2.69; 95%CI, -4.86 to -0.52; Significant different clinical features of cognitive development and psychiatric illness are associated with PWS with different molecular defects. These findings provide support for evidence based practice to evaluate and manage the PWS syndrome with different molecular defects. Prader–Willi syndrome (PWS) is a genomic imprinting disorder caused by deficiency of paternally expressed gene or genes in the chromosome 15q11-13 region . Most paAlthough the majority of clinical features of PWS are well recognized and characterized, the behavioral features associated with PWS has not been fully investigated. The number of new PWS cases, caused by either paternal deletion of 15q11-q13 or mUPD, has been increased significantly in recent years due to available array CGH (comparative genomic hybridization) technique in clinical diagnostic laboratory. The different clinical presentations related to behaviors and mental health have been suggested between individuals with paternal deletion of 15q11-q13 and mUPD ,15, autiThere is, however, no consensus as to whether the difference in the neurodevelopment outcomes between 15q11-q13 paternal deletion and mUPD are evident and clinically significantly. This information, however, is important to counsel family and develop anticipatory care. Therefore, we reviewed published literature on this topic systematically and conducted a meta-analysis to evaluate the level of intellectual disability and frequency of psychiatric illness and their correlations between PWS cases caused by the 15q11-q13 paternal deletion and mUPD.A comprehensive literature search was performed to identify the relevant studies in PubMed, the Cochrane Central Register of Controlled Trials and EMBASE from 1956 to May 31, 2012. Using Medical Subject Headings terms, searches were limited to original studies in human. The keyword of Prader–Willi syndrome was used in combination with deletion or UPD.The Endnote X4 and NoteExpress2 software were used to compile the data for meta-analysis. The PWS cases confirmed molecularly with either paternal deletion or mUPD were included for meta-analysis. We contacted corresponding authors of the studies for additional information as needed. The studies reported more than one of the outcomes of neurodevelopment were included in the metaanalysis: 1) IQ: full scale IQ (FSIQ), verbal IQ (VIQ) and performance IQ (PIQ); 2) psychiatric illness including depressive psychosis, bipolar disorder or other psychotic illness. The studies were excluded for meta-analysis if required data were incomplete. Two reviewers independently screened all studies for those requiring further retrieval (full text or abstract), and then independently reviewed these studies to identify whether they met the inclusion criteria. Disagreements regarding trial eligibility were discussed and resolved by two reviewers.I2 statistics were used to measure heterogeneity of the studies. If the I2 value was less than 50%, a fixed effects meta-analysis was applied. If the I2 value was more than 50%, the random-effects meta-analysis was performed. Potential publication bias was investigated by visual assessment of the funnel plot (plots of effect estimates against sample size). Metaanalyses and funnel plot calculation were performed using Review Manager software version 5.1 . Statistical significance was determined if the 2-sided P value was less than 0.05.We report outcomes using odds rate (OR) with 95% confidence intervals (CIs) for dichotomous data and weighted mean difference (MD) with 95% CI for continuous data. A total of 581 records were identified from the electronic database, 331 records from PubMed, 250 records from EMBASE. Seventy-seven reviews, 24 animal studies, and 71 single case reports were immediately removed. A total of 22 articles were removed due to language barrier and 131 articles without Prader-willi in their title were removed. Ninety three studies were duplicated in two databases. One hundred fifty studies did not meet the inclusion criteria or because of incomplete data in the papers. After these careful filtering, a total of 13 studies ,21,24–33p=0.02)] and results were homogeneously distributed (p=0.57) (Funnel plot for publication bias about FSIQ is presented in (p=0.57) .p<0.00001)] and results were homogeneously distributed (p=0.71)  .p=0.006)] and results were homogeneously distributed (p=0.66)  .p<0.00001)] and results were homogeneously distributed (p=0.41) (Funnel plot for publication bias about psychiatric illness is presented in (p=0.41) .p=0.51)] and results were homogeneously distributed (p=0.13)  .p=0.0002)] and results were homogeneously distributed (p=0.52)  .To our knowledge, this is the first meta-analysis to review the psychiatric illness and intellectual abilities in PWS with different types of molecular defects. Our analysis indicates significant differences of clinical presentation related to the neurodevelopment and psychiatric illness between PWS cases with 15q11-q13 paternal deletion and mUPD. Overall, the PWS with paternal deletion have lower FSIQ score than that of mUPD. More specifically, the verbal IQ but not performance IQ is more affected in the cases with 15q11-q13 deletion. Conversely, the psychosis and bipolar disorders are significantly more prevalent in PWS cases with mUPD than that of 15q11-q13 deletion. These findings not only strengthen the previous impression from small scale studies but also provide new insight that has not reported before.SNORD116 snoRNA cluster [SNORD116 cluster plays a major role in the core features of PWS. However, how the loss of expression non-coding snoRNAs ultimately leads to the clinical presentations of PWS remains unclear. The molecular difference between paternal deletion and mUPD is clear. Summary of the genetic and expression of chromosomal region 15q11, 2-13 are presented in UBE3A and ATP10A are not affected. The non-imprinted genes in the regions are haploinsufficient in paternal deletion cases. In the mUPD cases, the maternally expressed genes are predicted to be two folds of that in paternal deletion cases and one fold higher than that in normal. The non-imprinted genes are not affected. The expression of imprinted gene is expected to be same as paternal deletion cases if the imprinting is complete or 100%. It is reasonable to hypothesize that the differential expression of genes between paternal deletion of 15q11-q13 and mUPD may contribute to the difference in neurocognitive function and prevalence of psychiatric illness. For instance, the higher expression of UBE3A in mUPD cases may play a significant role in psychiatric illness. UBE3A is a maternal and brain-specific imprinting gene in the region [UBE3A encodes ubiquitin protein ligase E3A, functions as an E3 ligase in the ubiquitin proteasome pathway and as a transcriptional coactivator [UBE3A causes Angelman syndrome, a neurodevelopmental disorder with intellectual disability, hypotonia and seizures [UBE3A may be the major player to contribute the ASD in these cases [CYFIP1 in the 15q11.2 region may also play a role in contributing to neurodevelopment and psychiatric illness because of copy number variant of 15q11.2 including CYFIP1 has been associated with schizophrenia [CYFIP1 encodes cytoplasmic FMR1 interacting protein 1, and component of the CYFIP1-EIF4E-FMR1 complex which binds to the mRNA cap and mediates translational repression [The immediate question is what contributes to these differences between cases with paternal deletion and mUPD. Human chromosome 15q11–q13 is a domain subject to regulation of genomic imprinting, an epigenetic process in which the expression of genes is depending upon the parent-of-origin . It is w cluster –39. These region ,41. UBE3ctivator . Loss ofseizures ,44. The seizures . It has se cases ,47. Otheophrenia . CYFIP1 pression .The clinical implication of our finding is significant because it provides a basis to develop evidence based practice guideline for evaluating and managing individuals with PWS. In particular, our findings provide evidence to support more diligent care of PWS with psychiatric illness.Our conclusion from the meta-analysis is convincing and significant. However, several imitations in our study may still be worth for discussion and for improvement in future. First, like all other meta-analysis, because clinic data were collected from different investigators, at different sites, and at different ages, the comparison may be confounded by the variable quality of clinical data. Second, it should be noted that the diagnosis of psychiatric diseases in many reports included in meta-analysis might be made based on self-report but not through a specialized clinical evaluation using DSM IV criteria. These limitations may influence the data quality thereby affect the conclusion. Therefore, more accurate and detailed description about psychiatric symptoms is recommended for further study of PWS to figure out underlying molecular mechanism. Third, although the total number of patients is reasonable, the increase of the sample size may still be desirable in future study. Fourth, the breakpoints for the deletion case are not defined in detail.Our meta-analysis has revealed significant differences in the severity of neurocognitive impairment and the prevalence of psychiatric illness between PWS cases with paternal deletion of 15q11-q13 and mUPD. The PWS with paternal deletion have lower FSIQ and VIQ score than that of mUPD, but PWS with mUPD are more susceptible to psychosis, bipolar disorders than that of paternal deletion. These findings may provide a framework for future study to elucidate the genetic basis of psychiatric illness. Our finding will also provide rationale to develop evidence based practice for evaluating and caring individuals with PWS.Table S1PRISMA 2009 Checklist.(DOC)Click here for additional data file.