Kalthoum Tizaoui

Association between vitamin D receptor polymorphisms and multiple sclerosis: systematic review and meta-analysis of case–control studies

Vitamin D receptor (VDR) polymorphisms have been studied as potential contributors to multiple sclerosis (MS). However, published studies differ with respect to study design and the significance of the effects detected. The aim of this study was to quantify the magnitude of the risk associated with the TaqI, BsmI, ApaI and FokI VDR polymorphisms in MS using a meta-analysis approach. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we conducted a systematic search and meta-analysis of the literature. Subgroup analyses were performed to detect potential sources of heterogeneity from the selected study characteristics. The stability of the summary risk was evaluated using sensitivity analyses. The meta-analysis included a total of 3300 cases and 3194 controls from 13 case–control studies. There were no significant associations found between TaqI and BsmI polymorphisms and MS risk. The association between the ApaI polymorphism and MS risk was significant in the homozygous and codominant models (P=0.013 and P=0.031, respectively), suggesting that the AA ApaI genotype might be a significant MS risk factor. Publication year and age significantly affected the association between TaqI polymorphisms and MS (P=0.014 and P=0.010, respectively), which indicates a protective effect of the major T allele. The AA ApaI and FF FokI genotypes are significant risk factors for MS. The association between the TaqI polymorphism and MS risk is significantly affected by study characteristics.

Contribution of VDR polymorphisms to type 1 diabetes susceptibility: Systematic review of case–control studies and meta-analysis

Vitamin D receptor (VDR) polymorphisms have been inconsistently investigated in type 1 diabetes (T1D). However, the results are inconsistent and inconclusive. The current study aimed to investigate the role of TaqI, BsmI, ApaI and FokI VDR polymorphisms in T1D disease. Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, a systematic search and meta-analysis of the literature, since 1998 until december 2013, was conducted. Subgroup analyses were performed to detect potential sources of heterogeneity from selected study characteristics. Meta-analyses yielded a non-significant association of TaqI polymorphism with T1D [OR=1.014 (0.783-1.312); P=0.918] in the recessive model. The BsmI polymorphism was not associated with T1D [OR=1.44 (0.944-1.386); P=0.171] in the dominant model. Also, ApaI polymorphism was not associated with T1D risk [OR=0.996 (0.859-1.155); P=0.960] in the homozygous model. The FokI polymorphism was not associated with T1D risk [OR=0.968 (0.743-1.263); P=0.813] in dominant model. Stratification according to study characteristics showed that publication year, age, gender, estimated vitamin D levels and latitude moderated significantly association between VDR polymorphisms and T1D disease. Meta-analysis on haplotypes revealed that BAT might be a significant risk factor for T1D [OR=1.331 (0.957-1.850; P=0.089]. However, the bAT was found to be a significant protective factor [OR=0.639 (0.460-0.887); P=0.007]. As conclusion, individual VDR polymorphisms seemed not to be associated with T1D risk. However, haplotypes contributed significantly to disease susceptibility. Study characteristics moderated the association between VDR polymorphisms and T1D. These results suggested that, in T1D pathogenesis, VDR polymorphisms interact with each other and with environmental factors.

Interleukin-17A and -17F genes polymorphisms in lung cancer

Interleukin-17 (IL-17) is a proinflammatory cytokines produced by T helper 17 (Th17) cells, which plays an important role in both innate and adaptive immune systems. Genetic variants in the IL-17 genes may influence the immunopathogenesis of many cancers. In our study, we investigated the association of three single-nucleotide polymorphisms (SNPs: -152 G/A, 7488 A/G and 7383 A/G) in the IL-17A and IL-17F genes with lung cancer risk, in the Tunisian population. The genotypic and allelic distributions of IL-17A and IL-17F genes polymorphisms were analyzed by Polymerase Chain-Reaction (PCR) and Restriction Fragment Length Polymorphism (RFLP) for 239 patients and 258 healthy controls. Our results revealed a statistically significant association between IL-17F 7488G allele and increased lung cancer risk (P=0.028). Stratification analysis indicated that IL-17F 7488G allele enhances the risk of lung cancer development among men and oldest age subject groups (P<0.05). Patients with IL-17F 7488G allele were also more likely to be diagnosed at advanced stage (P=0.04), or with metastatic lung cancer (P=0.035). Furthermore, no significant association between IL-17F 7383 A/G, IL-17 -152G/A polymorphisms and lung cancer risk was observed (P>0.05). However, we reported contradictory findings on the association of IL-17 -152 G/A polymorphisms with lung cancer risk. In addition, we suggested the existence of a biological interaction between IL-17A, but not IL-17F polymorphisms and smoking. Our findings suggest that IL-17F 7488G allele is associated with increased lung cancer risk in the Tunisian population.

Association between VDR polymorphisms and rheumatoid arthritis disease: Systematic review and updated meta-analysis of case–control studies

BACKGROUND Vitamin D receptor (VDR) polymorphisms have been inconsistently investigated in rheumatoid arthritis (RA). However, published studies demonstrated differences concerning design and effect size. A meta-analysis is necessary to determine the magnitude of the association between VDR polymorphisms and RA risk. OBJECTIVE The aim of the current study was to quantify the magnitude of the association between TaqI, BsmI, and FokI VDR polymorphisms with RA risk. METHODS Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic search and meta-analysis of the literature were conducted. Analyses were performed in the random effects model by using recessive, dominant, codominant, homozygous, and allele contrast models. RESULTS A total of 1703 cases and 2635 controls in 12 case-control studies were included in the meta-analyses. Results indicated a significant association between TaqI polymorphism and RA disease in homozygous, codominant and allele contrast models (P=0.008, P=0.015, P=0.006 and P=0.002, respectively). Association between BsmI polymorphism and RA risk was marginal in the dominant, codominant and allele contrast models (P=0.057, P=0.071, and P=0.069, respectively). Te association between FokI polymorphism and RA risk was significant in the recessive, dominant and allele contrast models (P=0.045, P=0.027, and P=0.013, respectively). Subgroup analysis showed that publication year, ethnicity, age, latitude, and estimated 25(OH)D levels influenced significantly the association between VDR polymorphisms and RA risk. CONCLUSION TaqI and FokI VDR polymorphisms contributed significantly to RA risk. Study characteristics influenced the association between VDR polymorphisms and RA disease.

Vitamin D receptor TaqI and ApaI polymorphisms: A comparative study in patients with Behçet’s disease and Rheumatoid arthritis in Tunisian population

Recent genetic surveys have identified vitamin D receptor (VDR) as a susceptibility gene for several autoimmune diseases. This study was designed to investigate the association of VDR gene polymorphisms with Behçets disease (BD) and Rheumatoid arthritis (RA). A case-control study including 151 BD, 106 RA patients and an appropriate number of healthy control subjects were performed using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) techniques. Association between TaqI polymorphism and BD was marginal under codominant and recessive models (P=0.078 and P=0.058, respectively). After stratification, we found evidence for a significant association between TaqI polymorphism and BD in the elderly subjects (P=0.037). The minor ApaI a allele tended to confer an increased risk for BD susceptibility (P=0.087). BD patients with VDR homozygous AA or aa genotypes were at increased risk for development of erythema nodosum (EN) skin manifestation (P=0.038). No significant association was observed for VDR ApaI and TaqI polymorphisms with RA risk (P>0.05). TaqI and ApaI polymorphisms might be modestly implicated in BD pathogenesis. They could be considered as potential biomarkers in BD rather than susceptibility genes. However, TaqI and ApaI seemed not to be implicated in RA pathogenesis.

Relationship between ABCB1 3435TT genotype and antiepileptic drugs resistance in Epilepsy: updated systematic review and meta-analysis

BackgroundAntiepileptic drugs (AEDs) are effective medications available for epilepsy. However, many patients do not respond to this treatment and become resistant. Genetic polymorphisms may be involved in the variation of AEDs response. Therefore, we conducted an updated systematic review and a meta-analysis to investigate the contribution of the genetic profile on epilepsy drug resistance.MethodsWe proceeded to the selection of eligible studies related to the associations of polymorphisms with resistance to AEDs therapy in epilepsy, published from January 1980 until November 2016, using Pubmed and Cochrane Library databases. The association analysis was based on pooled odds ratios (ORs) and 95% confidence intervals (CIs).ResultsFrom 640 articles, we retained 13 articles to evaluate the relationship between ATP-binding cassette sub-family C member 1 (ABCB1) C3435T polymorphism and AEDs responsiveness in a total of 454 epileptic AEDs-resistant cases and 282 AEDs-responsive cases. We found a significant association with an OR of 1.877, 95% CI 1.213–2.905. Subanalysis by genotype model showed a more significant association between the recessive model of ABCB1 C3435T polymorphism (TT vs. CC) and the risk of AEDs resistance with an OR of 2.375, 95% CI 1.775–3.178 than in the dominant one (CC vs. TT) with an OR of 1.686, 95% CI 0.877–3.242.ConclusionOur results indicate that ABCB1 C3435T polymorphism, especially TT genotype, plays an important role in refractory epilepsy. As genetic screening of this genotype may be useful to predict AEDs response before starting the treatment, further investigations should validate the association.

Multiple sclerosis genetics: Results from meta-analyses of candidate-gene association studies

HighlightsMeta‐analyses contribute to identify true‐positive associated genes in multiple sclerosis.The vast majority of identified multiple sclerosis‐associated loci is located close or inside genes related to the immune system.The number of meta‐analyses in multiple sclerosis is still modest.Performed meta‐analyses have several limitations, resulting in biased results. &NA; As a complex disease, multiple sclerosis (MS) susceptibility implicates many genetic and environmental factors. Usually, individual genetic association studies have several limitations, and results are specific to the population of study. The Meta‐analysis approach has been proposed to resolve these limitations and to increase the power of statistical analyses. In this review, we summarize results from meta‐analyses of candidate genes of MS. Using the keywords: multiple sclerosis, genetic polymorphism and meta‐analysis, we searched electronic databases (PubMed, Embase and Web of Sciences) for published meta‐analyses until May 2017. Meta‐analyses confirmed the association of polymorphisms in fifteen candidate genes with MS disease. However, polymorphisms in fourteen genes showed none significant association. Results outlined the importance of confirmed genes to understand signaling pathways in MS disease and shed light on their utility to develop new drugs targets.

Update on Asthma Genetics: Results From Meta-Analyses of Candidate Gene Association Studies

Several studies have investigated the risk factors associated with asthma. Both genetic and environmental factors are considered to contribute to asthma susceptibility. Individual genetic association studies usually suffer from small sample size leading to biased results. Meta-analysis is a powerful tool that has the potential to resolve this limitation by increasing the statistical power of analyses. The current review summarizes the recent knowledge concerning genetic factors involved in asthma predisposition based on meta-analyses. Using the keywords: asthma, meta-analysis, polymorphism, we searched Pubmed, Medline, Embase and Google Scholar databases for the associated articles. Genetic polymorphisms in twenty-three genes are associated with asthma risk in meta-analyses. However, polymorphisms in nine genes showed none significant association. These findings are used to assess the genetic risk factors and to understand the molecular pathways related to asthma.

De novo vs. inherited copy number variations in multiple sclerosis susceptibility

The Human Genome Project has identified, along with single nucleotide polymorphisms (SNPs), a range of other DNA sequence variations, including insertions and deletions of nucleotides and translocations of various segments of a chromosome.1 These variations have, collectively, been named copy number variants (CNVs).1 They represent a major source of genomic variation, with nearly 1500 variable regions covering approximately 12% of the human genome.2 A CNV could act directly by affecting gene dosage and gene expression through complex mechanisms. It is thought, therefore, that CNVs in genedosage sensitive genes may have considerable influence on disease susceptibility.2 Among genes overlapped by CNVs, significant enrichments in certain gene ontology categories have been identified, including those related to immune responses and interaction with the environment.3 CNVs have already been associated with several monogenic, syndromic and complex diseases. Candidate gene association studies in multiple sclerosis (MS) have identified multiple common allelic variants. Given the important role of vitamin D in MS, polymorphisms in the vitamin D receptor (VDR) gene have been extensively studied in relation to MS susceptibility. A meta-analysis by Tizaoui et al.4 showed that SNPs in the VDR gene were significantly associated with MS risk. The genetic effects were modest, implicating other genetic variations such as CNVs, which may have larger effects than SNPs. Interestingly, the meta-analysis reported the interaction of VDR polymorphisms with exogenous factors. In fact, as a receptor for vitamin D, VDR expression is, directly and indirectly, dependent on environmental factors. Vitamin D deficiency may increase the incidence of CNVs. Genes involved in vitamin D pathways may be particularly prone to genetic variations. Gene ontology analyses have revealed that CNVs are frequent in genes implicated in immune responses and responses to external biotic stimuli.5 Although investigations of SNPs could provide important information in MS genetics, the results remain partial. In the future, more interest should be given to CNVs in genes related to vitamin D pathways. Recently, CNV associations have been identified for various neurological and developmental diseases.6 As a complex disease, MS is related to any variation in the human genome that alters the expression of MS candidate genes. Taking advantage of studies indicating that DNA rearrangements are frequent, and may play an important role in complex disease susceptibility, Sato and collaborators 7 explored CNVs in MS. The most identified CNVs were 5 to 50 kb deletions at particular T cell receptor (TCR) gamma and alpha loci. These CNVs were observed in peripheral blood T cell subsets only, suggesting that the CNVs were somatically acquired. Furthermore, they found that certain genomic regions within the TRG and/or TRA loci were deleted. These CNVs were specifically present in CD31, CD41 and CD81 T cell subsets, indicating somatic mutations.7 Because the genomic region of the TCR usually undergoes somatic rearrangements in the embryonic thymus, it is important to assess CNVs within the TCR loci. Sample lymphocyte counts or the DNA source may influence rearrangements in the TCR loci.8 Sato et al.7 showed that the deletion-type CNV at the TRG locus involves the entire J gene segment and part of the V gene segment. Such alteration of the genome seems unlikely to occur with physiological rearrangements. These results are consistent with previous data showing that several inherited and de novo CNVs may cause pediatric MS.9 Researchers have reported a single rare CNV harboring the SACS gene. Patients with this CNV shared some features with both MS and the spastic ataxia of CharlevoixSaguenay (ARSACS). It has been reported that SACS mutations cause autosomal-recessive ARSACS disease. This observation suggests that some autoimmune diseases may share CNVs as common risk factors.10 De novo CNVs in the SACS gene region and other genes have been identified in MS.11 Many of Department of Basic Sciences, Medicine Faculty of Tunis, Tunis El Manar University, 15 Rue Djebel Lakdar, Tunis 1007, Tunisia Correspondence: K Tizaoui, E-mail: kalttizaoui@gmail.com Received: 25 October 2017; Revised: 9 December 2017; Accepted: 9 December 2017 Cellular and Molecular Immunology (2018) 15, 812–814 & 2018 CSI and USTC All rights reserved 2042-0226/18

Association of Vitamin D Receptor Gene Polymorphisms with Asthma Risk: Systematic Review and Updated Meta-analysis of Case–Control Studies

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