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Aim: A systematic review and a meta-analysis were conducted in order to investigate the potential association of Fc [gamma] receptor (Fc [gamma]R) polymorphisms with susceptibility to aggressive and chronic periodontal disease. Materials and Methods: A database search yielded a total of 17 studies involving 1685 cases and 1570 controls. Three polymorphisms were included in the meta-analysis: Fc [gamma]RIIA H131R (rs1801274), Fc [gamma]RIIIA F158V (rs396991) and Fc [gamma]RIIIB NA1/NA2. Random-effect models were used in the analysis. Odds ratios (ORs) along with their 95% confidence intervals (CIs) were computed to compare the distribution of alleles and genotypes between cases and controls. Results and Conclusions: The Fc [gamma]RIIIB NA1/NA2 polymorphism was associated with both aggressive (per-allele OR 2.005, 95% CI: 1.044, 3.851) and chronic periodontitis (recessive contrast NA2NA2 versus NA1NA1+NA1NA2 OR 1.397, 95% CI: 1.039, 1.878). The analysis showed weak evidence for association between the Fc [gamma]RIIA H131R polymorphism and aggressive periodontitis in Asians (R versus H allele OR 1.579, 95% CI: 1.025, 2.432). On the contrary, no relationship was identified between Fc [gamma]RIIIA F158V and periodontal disease. Accumulating evidence from basic research makes the suggested association between Fc [gamma]RIIIB NA1/NA2 polymorphism and periodontitis biologically plausible. Further research, however, is needed in order to assess possible gene-gene or gene-environment interactions (i.e. with smoking). [ABSTRACT FROM AUTHOR]

AIM: We conducted a systematic review and a meta-analysis, in order to investigate the potential association of cytokine gene polymorphisms with either aggressive or chronic periodontal disease. MATERIAL AND METHODS: A comprehensive literature search was performed. We retrieved a total of 53 studies summarizing information about 4178 cases and 4590 controls. Six polymorphisms were included in our meta-analysis which are the following: IL-1A G[4845]T, IL-1A C[-889]T, IL-1B C[3953/4]T, IL-1B T[-511]C, IL-6 G[-174]C and TNFA G[-308]A. Random effect methods were used for the analysis. We calculated the specific odds ratios along with their 95% confidence intervals to compare the distribution of alleles and genotypes between cases and controls. RESULTS AND CONCLUSIONS: Using random effect methods we found statistically significant association of IL-1A C[-889]T and IL-1B C[3953/4]T polymorphisms with chronic periodontal disease without any evidence of publication bias or significant statistical heterogeneity. A weak positive association was also found concerning IL-1B T[-511]C and chronic periodontal disease. No association was found for all the cytokines examined as far as the aggressive form of the disease is concerned. Future studies may contribute to the investigation of the potential multigenetic predisposition of the disease and reinforce our findings. [ABSTRACT FROM AUTHOR]

Background: Previous studies had limited power to assess the associations of circulating insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) with clinically relevant prostate cancer as a primary endpoint, and the association of genetically predicted IGF-I with aggressive prostate cancer is not known. We aimed to investigate the associations of IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 concentrations with overall, aggressive and early-onset prostate cancer., Methods: Prospective analysis of biomarkers using the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset (up to 20 studies, 17 009 prostate cancer cases, including 2332 aggressive cases). Odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression. For IGF-I, two-sample Mendelian randomization (MR) analysis was undertaken using instruments identified using UK Biobank (158 444 men) and outcome data from PRACTICAL (up to 85 554 cases, including 15 167 aggressive cases). Additionally, we used colocalization to rule out confounding by linkage disequilibrium., Results: In observational analyses, IGF-I was positively associated with risks of overall (OR per 1 SD = 1.09: 95% CI 1.07, 1.11), aggressive (1.09: 1.03, 1.16) and possibly early-onset disease (1.11: 1.00, 1.24); associations were similar in MR analyses (OR per 1 SD = 1.07: 1.00, 1.15; 1.10: 1.01, 1.20; and 1.13; 0.98, 1.30, respectively). Colocalization also indicated a shared signal for IGF-I and prostate cancer (PP4: 99%). Men with higher IGF-II (1.06: 1.02, 1.11) and IGFBP-3 (1.08: 1.04, 1.11) had higher risks of overall prostate cancer, whereas higher IGFBP-1 was associated with a lower risk (0.95: 0.91, 0.99); these associations were attenuated following adjustment for IGF-I., Conclusions: These findings support the role of IGF-I in the development of prostate cancer, including for aggressive disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Previous studies had limited power to assess the associations of testosterone with aggressive disease as a primary endpoint. Further, the association of genetically predicted testosterone with aggressive disease is not known. We investigated the associations of calculated free and measured total testosterone and sex hormone-binding globulin (SHBG) with aggressive, overall and early-onset prostate cancer. In blood-based analyses, odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression from prospective analysis of biomarker concentrations in the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group (up to 25 studies, 14 944 cases and 36 752 controls, including 1870 aggressive prostate cancers). In Mendelian randomisation (MR) analyses, using instruments identified using UK Biobank (up to 194 453 men) and outcome data from PRACTICAL (up to 79 148 cases and 61 106 controls, including 15 167 aggressive cancers), ORs were estimated using the inverse-variance weighted method. Free testosterone was associated with aggressive disease in MR analyses (OR per 1 SD = 1.23, 95% CI = 1.08-1.40). In blood-based analyses there was no association with aggressive disease overall, but there was heterogeneity by age at blood collection (OR for men aged <60 years 1.14, CI = 1.02-1.28; P het  = .0003: inverse association for older ages). Associations for free testosterone were positive for overall prostate cancer (MR: 1.20, 1.08-1.34; blood-based: 1.03, 1.01-1.05) and early-onset prostate cancer (MR: 1.37, 1.09-1.73; blood-based: 1.08, 0.98-1.19). SHBG and total testosterone were inversely associated with overall prostate cancer in blood-based analyses, with null associations in MR analysis. Our results support free testosterone, rather than total testosterone, in the development of prostate cancer, including aggressive subgroups., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Obesity is considered a chronic inflammatory state characterized by continued secretion of adipokines and cytokines. Experimental and epidemiological evidence indicates that circulating adipokines may be associated with the development of obesity-related cancers, but it is unclear if these associations are causal or confounded. We examined potential causal associations of specific adipokines (adiponectin, leptin, soluble leptin receptor [sOB-R] and plasminogen activator inhibitor-1 [PAI-1]) with five obesity-related cancers (colorectal, pancreatic, renal cell carcinoma [RCC], ovarian and endometrial) using Mendelian randomization (MR) methods. We used summary-level data from large genetic consortia for 114 530 cancer cases and 245 284 controls. We constructed genetic instruments using 18 genetic variants for adiponectin, 2 for leptin and 4 for both sOB-R and PAI-1 (P value for inclusion<5 × 10 -8 ). Causal estimates were obtained using two-sample MR methods. In the inverse-variance weighted models, we found an inverse association between adiponectin and risk of colorectal cancer (odds ratio per 1 μg/mL increment in adiponectin concentration: 0.90 [95% confidence interval = 0.84-0.97]; P = .01); but, evidence of horizontal pleiotropy was detected and the association was not present when this was taken into consideration. No association was found for adiponectin and risks of pancreatic cancer, RCC, ovarian cancer and endometrial cancer. Leptin, sOB-R and PAI-1 were also similarly unrelated to risk of obesity-related cancers. Despite the large sample size, our MR analyses do not support causal effects of circulating adiponectin, leptin, sOB-R and PAI-1 concentrations on the development of five obesity-related cancers., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.)

The emergence of Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 made imperative the need for diagnostic tests that can identify the infection. Although Nucleic Acid Test (NAT) is considered to be the gold standard, serological tests based on antibodies could be very helpful. However, individual studies are usually inconclusive, thus, a comparison of different tests is needed. We performed a systematic review and meta-analysis in PubMed, medRxiv and bioRxiv. We used the bivariate method for meta-analysis of diagnostic tests pooling sensitivities and specificities. We evaluated IgM and IgG tests based on Enzyme-linked immunosorbent assay (ELISA), Chemiluminescence Enzyme Immunoassays (CLIA), Fluorescence Immunoassays (FIA), and the Lateral Flow Immunoassays (LFIA). We identified 38 studies containing data from 7848 individuals. Tests using the S antigen are more sensitive than N antigen-based tests. IgG tests perform better compared to IgM ones and show better sensitivity when the samples were taken longer after the onset of symptoms. Moreover, a combined IgG/IgM test seems to be a better choice in terms of sensitivity than measuring either antibody alone. All methods yield high specificity with some of them (ELISA and LFIA) reaching levels around 99%. ELISA- and CLIA-based methods perform better in terms of sensitivity (90%-94%) followed by LFIA and FIA with sensitivities ranging from 80% to 89%. ELISA tests could be a safer choice at this stage of the pandemic. LFIA tests are more attractive for large seroprevalence studies but show lower sensitivity, and this should be taken into account when designing and performing seroprevalence studies.

Purpose: The relationship of allergic diseases, such as asthma, hay fever, and eczema, with cancer is under debate. Observational studies have reported conflicting findings, but such studies are susceptible to confounding and reverse causation. Understanding the potential role of allergy in carcinogenesis may shed new light on the biological mechanisms underpinning intrinsic immunity and cancer., Methods: We conducted a Mendelian randomization study, using germline genetic variants as instrumental variables, to determine the causal relevance of allergic disease and on two most common malignancies: breast cancer and prostate cancer. We used the summary statistics from the largest ever genome-wide association studies conducted on allergic disease (n case  = 180,129), asthma (n case  = 14,085), breast (n case  = 122,977), and prostate cancer (n case  = 79,148) and calculated odds ratios (ORs) and 95% confidence intervals (CIs) of cancer for allergic disease., Results: We did not observe any evidence to support a causal association between allergic disease and risk of breast cancer overall [OR 1.00 (95% CI 0.96-1.04), p = 0.95] or by subtype (estrogen receptor (ER)+ [0.99 (0.95-1.04), p = 0.71], ER- [1.05 (0.99-1.10), p = 0.11]). We also did not find any evidence for an association with prostate cancer [1.00 (0.94-1.05), p = 0.93] or advanced subtype [0.97 (0.90-1.05), p = 0.46]. Sensitivity analyses did not reveal directional pleiotropy., Conclusion: Our study does not support a causal effect of allergic disease on the risk of breast or prostate cancer. Future studies may be conducted to focus on understanding the causal role of allergic disease in cancer prognosis or drug responses (e.g., immunotherapy).

Background: Observational studies have suggested an association between circulating vitamin D concentrations [25(OH)D] and risk of breast and prostate cancer, which was not supported by a recent Mendelian randomization (MR) analysis comprising 15 748 breast and 22 898 prostate-cancer cases. Demonstrating causality has proven challenging and one common limitation of MR studies is insufficient power., Methods: We aimed to determine whether circulating concentrations of vitamin D are causally associated with the risk of breast and prostate cancer, by using summary-level data from the largest ever genome-wide association studies conducted on vitamin D (N = 73 699), breast cancer (Ncase = 122 977) and prostate cancer (Ncase = 79 148). We constructed a stronger instrument using six common genetic variants (compared with the previous four variants) and applied several two-sample MR methods., Results: We found no evidence to support a causal association between 25(OH)D and risk of breast cancer [OR per 25 nmol/L increase, 1.02 (95% confidence interval: 0.97-1.08), P = 0.47], oestrogen receptor (ER)+ [1.00 (0.94-1.07), P = 0.99] or ER- [1.02 (0.90-1.16), P = 0.75] subsets, prostate cancer [1.00 (0.93-1.07), P = 0.99] or the advanced subtype [1.02 (0.90-1.16), P = 0.72] using the inverse-variance-weighted method. Sensitivity analyses did not reveal any sign of directional pleiotropy., Conclusions: Despite its almost five-fold augmented sample size and substantially improved statistical power, our MR analysis does not support a causal effect of circulating 25(OH)D concentrations on breast- or prostate-cancer risk. However, we can still not exclude a modest or non-linear effect of vitamin D. Future studies may be designed to understand the effect of vitamin D in subpopulations with a profound deficiency., (© The Author(s) 2018; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: There are observational data suggesting an inverse association between circulating concentrations of sex hormone binding globulin (SHBG) and risk of postmenopausal breast cancer. However, causality is uncertain and few studies have investigated this association by tumour receptor status. We aimed to investigate these associations under the causal framework of Mendelian randomization (MR)., Methods: We used summary association estimates extracted from published genome-wide association study (GWAS) meta-analyses for SHBG and breast cancer, to perform two-sample MR analyses. Summary statistics were available for 122 977 overall breast cancer cases, of which 69 501 were estrogen receptor positive (ER+ve) and 21 468 were ER-ve, and 105 974 controls. To control for potential horizontal pleiotropy acting via body mass index (BMI), we performed multivariable inverse-variance weighted (IVW) MR as the main analysis, with the robustness of this approach further tested in sensitivity analyses., Results: The multivariable IVW MR analysis indicated a lower risk of overall (odds ratio [OR]: 0.94; 95% confidence interval [CI]: 0.90, 0.98; P: 0.006) and ER+ve (OR: 0.92; 95% CI: 0.87, 0.97; P: 0.003) breast cancer, and a higher risk of ER-ve disease (OR: 1.09; 95% CI: 1.00, 1.18; P: 0.047) per 25 nmol/L higher SHBG levels. Sensitivity analyses were consistent with the findings of the main analysis., Conclusions: We corroborated the previous literature evidence coming from observational studies for a potentially causal inverse association between SHBG concentrations and risk of ER+ve breast cancer, but our findings also suggested a potential novel positive association with ER-ve disease that warrants further investigation, given the low prior probability of being true., (© The Author(s) 2019; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Objective: Mendelian randomisation (MR) is a technique that aims to assess causal effects of exposures on disease outcomes. The paper aims to present the main assumptions that underlie MR, the statistical methods used to estimate causal effects and how to account for potential violations of the key assumptions., Methods: We discuss the key assumptions that should be satisfied in an MR setting. We list the statistical methodologies used in two-sample MR when summary data are available to estimate causal effects (ie, Wald ratio estimator, inverse-variance weighted and maximum likelihood method) and identify/adjust for potential violations of MR assumptions (ie, MR-Egger regression and weighted Median approach). We also present statistical methods and graphical tools used to evaluate the presence of heterogeneity., Results: We use as an illustrative example of a published two-sample MR study, investigating the causal association of body mass index with three psychiatric disorders (ie, bipolar disorder, schizophrenia and major depressive disorder). We highlight the importance of assessing the results of all available methods rather than each method alone. We also demonstrate the impact of heterogeneity in the estimation of the causal effects., Conclusions: MR is a useful tool to assess causality of risk factors in medical research. Assessment of the key assumptions underlying MR is crucial for a valid interpretation of the results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Some subjects are repeatedly exposed to human immunodeficiency virus (HIV), yet they remain uninfected. This suggests the existence of host-resistance mechanisms. The current study synthesizes the evidence regarding the association between interleukin (IL) gene polymorphisms and HIV susceptibility. Medline, Scopus and the Web of Science databases were systematically searched, and a meta-analysis of case-control studies was conducted. Univariate and bivariate methods were used. The literature search identified 42 eligible studies involving 15,727 subjects. Evidence was obtained on eight single-nucleotide polymorphisms (SNPs): IL1A -889 C>T (rs1800587), IL1B +3953/4 C>T (rs1143634), IL4 -589/90 C>T (rs2243250), IL6 -174 G>C (rs1800795), IL10 -592 C>A (rs1800872), IL10-1082 A>G (rs1800896), IL12B -1188 A>C (rs3212227) and IL28B C>T (rs12979860). The IL1B +3953/4 C>T variant appears to increase the risk of HIV acquisition, under the assumption of a recessive genetic model (odds ratio (OR): 4.47, 95% CI: 2.35-8.52). The AA homozygotes of the IL10 -592 C>A SNP had an increased, marginally nonsignificant, risk (OR: 1.39, 95% CI: 0.97-2.01). It reached, however, significance in sub analyses (OR: 1.49, 95% CI: 1.04-2.12). Finally, the well-studied hepatitis C virus (HCV) infection IL28B (rs12979860) CT/TT genotypes were associated with a 27% decrease in HIV infection risk, especially in populations infected with HCV (OR: 0.73, 95% CI: 0.57-0.95). Interleukin signalling is perhaps important in HIV infection and some interleukin genetic variants may affect the risk of HIV acquisition. Approaches targeting specific genes and genome wide association studies should be conducted to decipher the effect of these polymorphisms.

Mendelian randomization (MR) is becoming a popular approach to estimate the causal effect of an exposure on an outcome overcoming limitations of observational epidemiology. The advent of genome-wide association studies and the increasing accumulation of summarized data from large genetic consortia make MR a powerful technique. In this review, we give a primer in MR methodology, describe efficient MR designs and analytical strategies, and focus on methods and practical guidance for conducting an MR study using summary association data. We show that the analysis is straightforward utilizing either the MR-base platform or available packages in R. However, further research is required for the development of specialized methodology to assess MR assumptions.

Multivariate meta-analysis of genetic association studies and genome-wide association studies has received a remarkable attention as it improves the precision of the analysis. Here, we review, summarize and present in a unified framework methods for multivariate meta-analysis of genetic association studies and genome-wide association studies. Starting with the statistical methods used for robust analysis and genetic model selection, we present in brief univariate methods for meta-analysis and we then scrutinize multivariate methodologies. Multivariate models of meta-analysis for a single gene-disease association studies, including models for haplotype association studies, multiple linked polymorphisms and multiple outcomes are discussed. The popular Mendelian randomization approach and special cases of meta-analysis addressing issues such as the assumption of the mode of inheritance, deviation from Hardy-Weinberg Equilibrium and gene-environment interactions are also presented. All available methods are enriched with practical applications and methodologies that could be developed in the future are discussed. Links for all available software implementing multivariate meta-analysis methods are also provided.

Apolipoprotein E (ApoE) is potentially a genetic risk factor for the development of left ventricular failure (LVF), the main cause of death in beta-thalassemia homozygotes. In the present study, we synthesize the results of independent studies examining the effect of ApoE on LVF development in thalassemic patients through a meta-analytic approach. However, all studies report more than one outcome, as patients are classified into three groups according to the severity of the symptoms and the genetic polymorphism. Thus, a multivariate meta-analytic method that addresses simultaneously multiple exposures and multiple comparison groups was developed. Four individual studies were included in the meta-analysis involving 613 beta-thalassemic patients and 664 controls. The proposed method that takes into account the correlation of log odds ratios (log(ORs)), revealed a statistically significant overall association (P-value  =  0.009), mainly attributed to the contrast of E4 versus E3 allele for patients with evidence (OR: 2.32, 95% CI: 1.19, 4.53) or patients with clinical and echocardiographic findings (OR: 3.34, 95% CI: 1.78, 6.26) of LVF. This study suggests that E4 is a genetic risk factor for LVF in beta-thalassemia major. The presented multivariate approach can be applied in several fields of research., (© 2017 John Wiley & Sons Ltd/University College London.)

Bone mineral density is known to be a heritable, polygenic trait whereas genetic variants contributing to lean mass variation remain largely unknown. We estimated the shared SNP heritability and performed a bivariate GWAS meta-analysis of total-body lean mass (TB-LM) and total-body less head bone mineral density (TBLH-BMD) regions in 10,414 children. The estimated SNP heritability is 43% (95% CI: 34-52%) for TBLH-BMD, and 39% (95% CI: 30-48%) for TB-LM, with a shared genetic component of 43% (95% CI: 29-56%). We identify variants with pleiotropic effects in eight loci, including seven established bone mineral density loci: WNT4, GALNT3, MEPE, CPED1/WNT16, TNFSF11, RIN3, and PPP6R3/LRP5. Variants in the TOM1L2/SREBF1 locus exert opposing effects TB-LM and TBLH-BMD, and have a stronger association with the former trait. We show that SREBF1 is expressed in murine and human osteoblasts, as well as in human muscle tissue. This is the first bivariate GWAS meta-analysis to demonstrate genetic factors with pleiotropic effects on bone mineral density and lean mass.Bone mineral density and lean skeletal mass are heritable traits. Here, Medina-Gomez and colleagues perform bivariate GWAS analyses of total body lean mass and bone mass density in children, and show genetic loci with pleiotropic effects on both traits.

Motivation: In the context of genome-wide association studies (GWAS), there is a variety of statistical techniques in order to conduct the analysis, but, in most cases, the underlying genetic model is usually unknown. Under these circumstances, the classical Cochran-Armitage trend test (CATT) is suboptimal. Robust procedures that maximize the power and preserve the nominal type I error rate are preferable. Moreover, performing a meta-analysis using robust procedures is of great interest and has never been addressed in the past. The primary goal of this work is to implement several robust methods for analysis and meta-analysis in the statistical package Stata and subsequently to make the software available to the scientific community., Results: The CATT under a recessive, additive and dominant model of inheritance as well as robust methods based on the Maximum Efficiency Robust Test statistic, the MAX statistic and the MIN2 were implemented in Stata. Concerning MAX and MIN2, we calculated their asymptotic null distributions relying on numerical integration resulting in a great gain in computational time without losing accuracy. All the aforementioned approaches were employed in a fixed or a random effects meta-analysis setting using summary data with weights equal to the reciprocal of the combined cases and controls. Overall, this is the first complete effort to implement procedures for analysis and meta-analysis in GWAS using Stata., Availability and Implementation: A Stata program and a web-server are freely available for academic users at http://www.compgen.org/tools/GWAR., Contact: pbagos@compgen.org., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com)

Objective: The aim of this study was to investigate the potential association of FZD3 polymorphisms with schizophrenia., Methods: A systematic review and a meta-analysis were carried out comprising of nine genetic association studies, with both a population-based and a family-based design, and three genome-wide association studies. A total of 1601 family trios, 39 922 schizophrenic patients, and 61 287 healthy individuals were involved in the analysis and six polymorphisms were examined: rs2241802, rs2323019, rs352203, rs3757888, rs880481, and rs960914. A summary-based method for pooling genetic association studies under both family-based and population-based designs was used. Odds ratios along with their 95% confidence intervals were computed to compare the contrast of alleles in patients and controls., Results: The results indicate a potentially weaker effect of FZD3 polymorphisms on schizophrenia than that suggested originally and possibly limited to Chinese populations. No relationship was identified between all examined polymorphisms and schizophrenia, except for rs352203, which plays a protective role against schizophrenia. However, this effect was mainly attributed to studies including Chinese patients. In the Chinese population, evidence for an elevated risk for schizophrenia linked to the rs2323019 polymorphism was also identified., Conclusion: Given the different linkage disequilibrium patterns observed in Chinese populations, schizophrenia may be related to some other polymorphisms of gene FZD3 that are in stronger linkage disequilibrium to Chinese than to the other populations studied.

A plethora of network-based approaches within the Systems Biology universe have been applied, to date, to investigate the underlying molecular mechanisms of various human diseases. In the present study, we perform a bipartite, topological and clustering graph analysis in order to gain a better understanding of the relationships between human genetic diseases and the relationships between the genes that are implicated in them. For this purpose, disease-disease and gene-gene networks were constructed from combined gene-disease association networks. The latter, were created by collecting and integrating data from three diverse resources, each one with different content covering from rare monogenic disorders to common complex diseases. This data pluralism enabled us to uncover important associations between diseases with unrelated phenotypic manifestations but with common genetic origin. For our analysis, the topological attributes and the functional implications of the individual networks were taken into account and are shortly discussed. We believe that some observations of this study could advance our understanding regarding the etiology of a disease with distinct pathological manifestations, and simultaneously provide the springboard for the development of preventive and therapeutic strategies and its underlying genetic mechanisms., (Copyright © 2016 Elsevier B.V. All rights reserved.)

We present here an extension of the classic bivariate random effects meta-analysis for the log-transformed sensitivity and specificity that can be applied for two or more diagnostic tests. The advantage of this method is that a closed-form expression is derived for the calculation of the within-studies covariances. The method allows the direct calculation of sensitivity and specificity, as well as, the diagnostic odds ratio, the area under curve and the parameters of the summary receiver operator's characteristic curve, along with the means for a formal comparison of these quantities for different tests. There is no need for individual patient data or the simultaneous evaluation of both diagnostic tests in all studies. The method is simple and fast; it can be extended for several diagnostic tests and can be fitted in nearly all statistical packages. The method was evaluated in simulations and applied in a meta-analysis for the comparison of anti-cyclic citrullinated peptide antibody and rheumatoid factor for discriminating patients with rheumatoid arthritis, with encouraging results. Simulations suggest that the method is robust and more powerful compared with the standard bivariate approach that ignores the correlation between tests. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

The network-based approaches that were employed in order to depict the relationships between human genetic diseases and their associated genes are described. Towards this direction, monopartite disease-disease and gene-gene networks were constructed from bipartite gene-disease association networks. The latter were created by collecting and integrating data from three diverse resources, each one with different content, covering from rare monogenic disorders to common complex diseases. Moreover, topological and clustering graph analyses were performed. The methodology and the programs presented in this article are related to the research article entitled "Network analysis of genes and their association with diseases" [1].

Co-infection of human immunodeficiency virus (HIV) with hepatitis C virus (HCV) is rather common. In the era of highly active antiretroviral therapy (HAART), viral hepatitis could result in adverse outcomes in HIV+ patients. The current meta-analysis aims to evaluate the impact of HCV on immunological and virological responses after HAART initiation in HIV/HCV co-infected individuals by synthesizing the existing scientific evidence. A comprehensive search of electronic databases was performed. Eligible studies were analysed using univariate and multivariate meta-analytic methods. Totally, 21 studies involving 22533 individuals were eligible. The estimated summary difference in CD4 cell counts increase between HIV and HIV/HCV co-infected subjects after 3-12 months on HAART was 34.86 cells/mm(3) [95% confidence interval (CI): 16.82-52.89]. The difference was more prominent in patients with baseline CD4 counts below 350 cells/mm(3) (38.97, 95% CI: 20.00-57.93) and attenuated 2 years later (13.43, 95% CI: 0.83-26.04). The analysis of ratio measures yielded similar findings. The virological control remained unaffected by the presence of HCV (adjusted Hazard Ratio for co-infected patients vs those with HIV alone: 0.99, 95% CI: 0.91-1.07). The bivariate meta-analytic method confirmed the results of the univariate approaches. This meta-analysis supports the adverse effect of HCV on immune recovery of HIV+ patients initiating HAART, especially of those with initially impaired immunologic status. Although this effect diminishes over time, early administration of HAART in the setting of co-infection seems to be justified., (© 2013 John Wiley & Sons Ltd.)

Objective: A systematic review and a meta-analysis were conducted, to investigate the possible association of methylene tetrahydrofolate reductase (MTHFR) gene polymorphisms with adverse effects related to methotrexate (MTX)., Methods: A systematic literature search in PubMed retrieved a total of 44 studies (42 unique articles). Two polymorphisms were included in the meta-analysis: C677T and A1298C. Random effect models were used in the analysis. Odds ratios along with their 95% confidence intervals were computed to compare the distribution of alleles and genotypes between cases and controls., Results: The analysis highlighted a significant association of C677T polymorphism with overall MTX toxicity, hepatotoxicity, hematological toxicity, and neurotoxicity. It also revealed an association with MTX toxicity in patients with rheumatoid arthritis. In contrast, a protective effect of C677T MTHFR polymorphism on acute graft-versus-host disease and on patients treated with hematopoietic cell transplantation was found. As for the A1298C polymorphism, a statistically significant association with overall MTX toxicity and a protective role of the polymorphism in rheumatoid arthritis patients was detected., Conclusion: These results indicate the association of MTHFR polymorphisms with MTX toxicity. However, further studies are needed to reveal the underlying biological mechanism of the association.

Many environmental and genetic factors have been implicated in the development of multiple sclerosis. However, the aetiology has not been clarified yet. Therefore, using a meta-analytic approach, we tried to probe the potential association between various cytokine gene polymorphisms and the occurrence of multiple sclerosis. A comprehensive literature search yielded 45 eligible studies, which involved 7379 cases and 8131 controls. Totally, the effect of eight polymorphisms, i.e. IL-1A C[-889]T, IL-1B C[-511]T, IL-1B C[3953]T, IL-4 C[33]T, IL-10 C[-819]T, IL-10 G[-1082]A, tumour necrosis factor-a (TNFA) G[-308]A and TNFA G[-238]A, was evaluated in a random-effects meta-analysis. There was no evidence of statistically significant association between the aforementioned polymorphisms and multiple sclerosis. Publication bias and heterogeneity were absent in most analyses. Within its limitations, the current literature-based meta-analysis does not indicate that specific polymorphic variations of genes encoding pro-inflammatory and anti-inflammatory cytokines affect susceptibility to multiple sclerosis., (© 2011 The Author(s). European Journal of Neurology © 2011 EFNS.)

Polycystic ovary syndrome (PCOS) is a heterogeneous condition with unknown aetiology which is considered to be the most common endocrine disorder in women of reproductive age. In this work we investigated the association of insulin receptor (IotaNSR) and insulin receptor substrates (IRSs) polymorphisms with the risk of developing PCOS. The meta-analysis of eleven studies (889 cases, 1303 controls) yielded a significant association for IRS-1 Gly972Arg (G972R) polymorphism concerning the GR vs. GG genotype (OR: 1.77, 95% CI: 1.28, 2.45), with no between-studies heterogeneity. Concerning IotaNSR His1058 C/T, the meta-analysis of eight studies (795 cases, 576 controls) found no significant evidence for association with PCOS (OR for the TT+CT vs. CC comparison equal to 1.28 with 95% CI: 0.88, 1.85) and a moderate between studies variability (I(2)=44.6%). No evidence for publication bias was found in these meta-analyses. Following a multivariate Mendelian randomization approach, the overall OR was unaffected but the overall mean difference of fasting insulin levels between carriers of GR and RR genotypes in controls was significant (2.18, 95% CI: 0.36, 4.01). These results suggest that IRS-1 Gly972Arg polymorphism is significantly associated with the risk of developing PCOS and that this association is primarily mediated by increasing the levels of fasting insulin. The particular polymorphism is located in a region nearby two phosphorylation sites that interact physically with INSR and PI 3-kinase and there is enough evidence from the literature suggesting that the Arg972 variant is associated with decreased PI 3-kinase activity and impaired insulin-stimulated signaling., (Copyright (c) 2009 Elsevier Inc. All rights reserved.)