Niki L. Dimou

Cytokine gene polymorphisms in periodontal disease: a meta-analysis of 53 studies including 4178 cases and 4590 controls

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.

Methylene tetrahydrofolate reductase gene polymorphisms and their association with methotrexate toxicity: a meta-analysis.

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.

Fcγ receptor polymorphisms and their association with periodontal disease: a meta-analysis

AIM A systematic review and a meta-analysis were conducted in order to investigate the potential association of Fcgamma receptor (FcgammaR) 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: FcgammaRIIA H131R (rs1801274), FcgammaRIIIA F158V (rs396991) and FcgammaRIIIB 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 FcgammaRIIIB 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 FcgammaRIIA 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 FcgammaRIIIA F158V and periodontal disease. Accumulating evidence from basic research makes the suggested association between FcgammaRIIIB 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).

Circulating vitamin D concentration and risk of seven cancers: Mendelian randomisation study

Objective To determine if circulating concentrations of vitamin D are causally associated with risk of cancer. Design Mendelian randomisation study. Setting Large genetic epidemiology networks (the Genetic Associations and Mechanisms in Oncology (GAME-ON), the Genetic and Epidemiology of Colorectal Cancer Consortium (GECCO), and the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortiums, and the MR-Base platform). Participants 70 563 cases of cancer (22 898 prostate cancer, 15 748 breast cancer, 12 537 lung cancer, 11 488 colorectal cancer, 4369 ovarian cancer, 1896 pancreatic cancer, and 1627 neuroblastoma) and 84 418 controls. Exposures Four single nucleotide polymorphisms (rs2282679, rs10741657, rs12785878 and rs6013897) associated with vitamin D were used to define a multi-polymorphism score for circulating 25-hydroxyvitamin D (25(OH)D) concentrations. Main outcomes measures The primary outcomes were the risk of incident colorectal, breast, prostate, ovarian, lung, and pancreatic cancer and neuroblastoma, which was evaluated with an inverse variance weighted average of the associations with specific polymorphisms and a likelihood based approach. Secondary outcomes based on cancer subtypes by sex, anatomic location, stage, and histology were also examined. Results There was little evidence that the multi-polymorphism score of 25(OH)D was associated with risk of any of the seven cancers or their subtypes. Specifically, the odds ratios per 25 nmol/L increase in genetically determined 25(OH)D concentrations were 0.92 (95% confidence interval 0.76 to 1.10) for colorectal cancer, 1.05 (0.89 to 1.24) for breast cancer, 0.89 (0.77 to 1.02) for prostate cancer, and 1.03 (0.87 to 1.23) for lung cancer. The results were consistent with the two different analytical approaches, and the study was powered to detect relative effect sizes of moderate magnitude (for example, 1.20-1.50 per 25 nmol/L decrease in 25(OH)D for most primary cancer outcomes. The Mendelian randomisation assumptions did not seem to be violated. Conclusions There is little evidence for a linear causal association between circulating vitamin D concentration and risk of various types of cancer, though the existence of causal clinically relevant effects of low magnitude cannot be ruled out. These results, in combination with previous literature, provide evidence that population-wide screening for vitamin D deficiency and subsequent widespread vitamin D supplementation should not currently be recommended as a strategy for primary cancer prevention.

Bivariate genome-wide association meta-analysis of pediatric musculoskeletal traits reveals pleiotropic effects at the SREBF1/TOM1L2 locus

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.Author summaryBone 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.

GWAR: robust analysis and meta-analysis of genome-wide association studies

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.

A meta-analysis of FZD3 gene polymorphisms and their association with schizophrenia.

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.

Apolipoprotein E Polymorphism and Left Ventricular Failure in Beta-Thalassemia: A Multivariate Meta-Analysis: ApoE and LVF in beta-thalassemia

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.

Multivariate Methods for Meta-Analysis of Genetic Association Studies

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.

A Primer in Mendelian Randomization Methodology with a Focus on Utilizing Published Summary Association Data

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.