Naseem Akhter

Meta-analysis reveals PTPN22 1858C/T polymorphism confers susceptibility to rheumatoid arthritis in Caucasian but not in Asian population

Abstract The PTPN22 1858C/T polymorphism is associated with rheumatoid arthritis (RA). However, reports from the Asian populations are conflicting in nature and lacks consensus. The aim of our study was to evaluate the association between the PTPN22 1858C/T polymorphism and RA in Asian and Caucasian subjects by carrying out a meta-analysis of Asian and Caucasian data. A total of 27u2009205 RA cases and 27u2009677 controls were considered in the present meta-analysis involving eight Asian and 35 Caucasian studies. The pooled odds ratios (ORs) were performed for the allele, dominant, and recessive genetic model. No statistically significant association was found between the PTPN22 1858C/T polymorphism and risk of RA in Asian population (allele genetic model: ORu2009=u20091.217, 95% confidence interval (CI)u2009=u20090.99–1.496, p value 0.061; dominant genetic model: ORu2009=u20091.238, 95% CIu2009=u20090.982–1.562, p value 0.071; recessive genetic model: ORu2009=u20091.964, 95% CIu2009=u20090.678–5.693, p value 0.213). A significant association with risk of RA in Caucasian population suggesting that T–– allele does confer susceptibility to RA in this subgroup was observed (allele genetic model: ORu2009=u20091.638, 95% CIu2009=u20091.574–1.705, p value <u20090.0001; dominant genetic model: ORu2009=u20091.67, 95% CIu2009=u20091.598–1.745, p value <u20090.0001; recessive genetic model: ORu2009=u20092.65, 95% CIu2009=u20092.273–3.089, p value <u20090.0001). The PTPN22 1858C/T polymorphism is not associated with RA risk in Asian populations. However, our meta-analysis confirms that the PTPN22 1858C/T polymorphism is associated with RA susceptibility in Caucasians.

A Genetic Association Study of CCL5 -28 C>G (rs2280788) Polymorphism with Risk of Tuberculosis: A Meta-Analysis

Aim The CC chemokine ligand 5 (CCL5), plays a key role in the inflammatory response by recruiting mononuclear cells during tuberculosis (TB) infection. Association studies of CCL5 -28 C>G (rs2280788) polymorphism and TB risk have shown inconsistent and contradictory results among different ethnic populations. The aim of this meta-analysis is to investigate the association between CCL5 -28 C>G polymorphism and TB susceptibility. Methodology We performed quantitative synthesis for published studies based upon association between CCL5 -28 C>G polymorphism and TB risk from PubMed (Medline), EMBASE web databases. The meta-analysis was performed and pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for all genetic models. Results A total of six studies including 1324 TB cases and 1407 controls were involved in this meta-analysis. Variant allele (G vs. C: pu200a=u200a0.257; ORu200a=u200a1.809, 95% CIu200a=u200a0.649 to 5.043), heterozygous (CG vs. CC: pu200a=u200a0.443; ORu200a=u200a1.440, 95% CIu200a=u200a0.567 to 3.658) and homozygous (GG vs. CC: pu200a=u200a0.160; ORu200a=u200a5.140, 95% CIu200a=u200a0.524 to 50.404) carriers did not show increased risk compare with those individual with the CC genotype. Similarly, no associations were found in the dominant (GG+CG vs. CC: pu200a=u200a0.295; ORu200a=u200a1.802, 95% CIu200a=u200a0.599 to 5.412) and recessive (GG vs. CC+CG: pu200a=u200a0.188; ORu200a=u200a3.533, 95% CIu200a=u200a0.541 to 23.085) models. Conclusions Overall findings of this meta-analysis suggest that genetic polymorphism -28 C>G in CCL5 is not associated with increased TB risk. However, future larger studies with group of populations will be needed to analyze the relationship between the CCL5 -28 C>G polymorphism and risk of TB.

Evaluating the association between taqi variant of vitamin D receptor gene and susceptibility to tuberculosis: A meta-analysis

Objectives: Vitamin D has been shown to hamper the growth of Mycobacterium tuberculosis in macrophages. The actions of vitamin D are exerted through a vitamin D receptor (VDR). The genetic variant TaqI of VDR has been implicated in tuberculosis (TB) risk in several case-control studies. However, these studies have shown inconsistent results. Hence, a meta-analysis was conducted to investigate the potential relationship between VDR TaqI polymorphism and risk of developing TB. Materials and Methods: We performed a quantitative synthesis for published studies based upon the relationship between TaqI polymorphism and TB risk from PubMed (Medline) and Embase databases. The meta-analysis was performed and pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for all genetic models. Results: A total of 21 studies including 2,960 TB cases and 3,894 controls were included in this study. The pooled analysis demonstrated no evidence of association between VDR TaqI genotypes and risk of TB in any of the genetic models; variant (t vs T: P = 0.618; OR = 1.051, 95% CI = 0.864-1.278), homozygous (tt vs TT: P = 0.120; OR = 1.336, 95% CI = 0.927-1.924), heterozygous (Tt vs TT: P = 0.925; OR = 0.988, 95% CI = 0.774-1.262), dominant model (tt + Tt vs TT: P = 0.805; OR = 1.032, 95% CI = 0.805-1.322), and recessive model (tt vs TT + Tt: P = 0.180; OR = 1.229, 95% CI = 0.909-1.660). No publication bias was detected during the analysis. Conclusions: Overall findings of this meta-analysis suggest that genetic polymorphism TaqI of VDR gene may not contribute to the risk of TB. However, future larger studies with group of populations are warranted to analyze this relationship.

Superantigen influence in conjunction with cytokine polymorphism potentiates autoimmunity in systemic lupus erythematosus patients

Risk posed by microbial superantigens in triggering or exacerbating SLE in genetically predisposed individuals, thereby altering the response to its treatment strategies, has not been studied. Using streptococcal pyrogenic exotoxin A and staphylococcal enterotoxin B as prototype superantigens, we have demonstrated that they profoundly affect the magnitude of polyclonal T cell response, particularly CD4+ T cells and expression of CD45RA and CD45RO, and cytokine secretion in vitro in SLE patient PBMCs. Also, reduced proportions of FoxP3 expressing CD4+CD25+ T cells were detected in SLE as compared to healthy control PBMCs. Furthermore, polymorphism in IL-10 and TGF-β showed significant association with SLE in our study population. These results indicate that accumulation of superantigen-reactive T cells and cytokine polymorphism may cause disease exacerbation, relapse, or therapeutic resistance in SLE patients. Attempts to contain colonizing and/or superantigen-producing microbial agents in SLE patients in addition to careful monitoring of their therapy may be worthwhile in decreasing disease severity or preventing frequent relapses. The study suggests that superantigen interference in conjunction with cytokine polymorphism may play a role in immune dysregulation, thereby contributing to autoimmunity in SLE. Therefore, changes in T cell phenotypes and cytokine secretion might be good indicators of therapeutic efficacy in these patients.

Interleukin-6-174G > C (rs1800795) polymorphism distribution and its association with rheumatoid arthritis: A case-control study and meta-analysis.

Abstract The association of interleukin-6 (IL-6)-174Gu2009>u2009C (rs1800795) single nucleotide polymorphism (SNP) with the risk of acquiring rheumatoid arthritis (RA) is a relevant issue because of conflicting and consensus lacking reports published in literature. We investigated IL-6-174Gu2009>u2009C promoter polymorphism in 34 RA patients, attending a tertiary care hospital in north India. We also performed a meta-analysis, of the previously published studies reporting this genetic relationship, in overall population, and independently in Asian and Caucasian ethnicities to further elucidate this association. A total of 13 studies, including the current one, involving 3291 RA cases and 3812 controls were analyzed. Out of the 13 studies, 6 were from Asian, 6 from Caucasian and 1 from a mixed population. Our case-control study showed significant association of IL-6-174Gu2009>u2009C SNP with increased RA risk: allelic (ORu2009=u20093.750, 95% CIu2009=u20091.800–7.813, pu2009<u20090.001); dominant (ORu2009=u20092.800, 95% CIu2009=u20091.167–6.721, pu2009=u20090.021); and recessive (ORu2009=u200936.72, 95% CIu2009=u20092.004–672.7, pu2009=u20090.015). The meta-analysis revealed the increased RA risk associated with IL-6-174Gu2009>u2009C SNP in overall population: allelic (ORu2009=u20091.650, 95% CIu2009=u20091.169–2.329, pu2009=u20090.004); homozygous (ORu2009=u20091.380, 95% CIu2009=u20090.906–2.101, pu2009=u20090.133); heterozygous (ORu2009=u20091.559, 95% CIu2009=u20091.001–2.428, pu2009=u20090.049); dominant (ORu2009=u20091.663, 95% CIu2009=u20091.078–2.567, pu2009=u20090.022); and recessive (ORu2009=u20091.366, 95% CIu2009=u20090.964–1.935, pu2009=u20090.079). Subgroup analysis also showed this polymorphism to be associated with increased RA risk in Asian population: allelic (ORu2009=u20093.724, 95% CIu2009=u20091.361–10.190, pu2009=u20090.010); dominant (ORu2009=u20093.823, 95% CIu2009=u20091.320–11.074, pu2009=u20090.013); and recessive (ORu2009=u20094.357, 95% CIu2009=u20091.634–11.623, pu2009=u20090.003), but not in Caucasian population. This meta-analysis shows that IL-6-174Gu2009>u2009C SNP is significantly associated with increased RA risk in overall, and specifically in Asian population.

Tumor necrosis factor (TNF)-α −308G/A (rs1800629) polymorphism distribution in North India and its association with pemphigus: Case–control study and meta-analysis

Abstract Pemphigus is an autoimmune blistering disorder of skin and/or mucosal surfaces characterized by intraepithelial lesions and immunoglobulin-G autoantibodies against desmogleins (proteins critical in cell-to-cell adhesion). Genetic, immunological, hormonal, and environmental factors are known to contribute to its etiology. Tumor necrosis factor-alpha (TNF-α) which plays a key role in pathogenesis of many infectious and inflammatory diseases has been found in high levels in lesional skin and sera of pemphigus patients. However, studies on association of single nucleotide polymorphism (SNP) in promoter region of TNF-α at position −308 affecting G to A transition with pemphigus has been scarce. This study was conducted to evaluate the TNF-α −308G/A SNP distribution in North Indian cohort, and to define the association between the TNF-α −308G/A SNP distribution and pemphigus, globally, by means of meta-analysis. TNF-α −308G/A SNP in pemphigus patients was investigated by cytokine genotyping using genomic DNA by PCR with sequence-specific primers. Meta-analysis of the data, including four previously published studies from other populations, was performed to generate a meaningful relationship. The results of our case–control study indicate non-significant differences between patients and controls in TNF-α −308G/A SNP. The meta-analysis also revealed that TNF-α −308G/A SNP is not associated with pemphigus risk in population at large; however, it may be contributing towards autoimmune phenomenon in pemphigus by being a part of its multi-factorial etiology. This study provides evidence that the TNF-α −308G/A polymorphism is not associated with overall pemphigus susceptibility. Nevertheless, further studies on specific ethnicity and pemphigus variants are necessary to validate the findings.

Evaluating the association between p53 codon 72 Arg>pro polymorphism and risk of ovary cancer: a meta-analysis.

Aim Allelic polymorphism in codon 72 of the p53 tumor suppressor gene causes imbalance of p53 protein expression. Earlier studies have shown association between allelic polymorphism in codon 72 of the p53 gene with risk of ovary cancer (OC); however the results are inconclusive and conflicting. Therefore, we performed this meta-analysis to investigate the relation between p53 codon 72 Arg>Pro polymorphism and overall OC susceptibility. Methods We searched all eligible published studies based on the association between codon 72 of the p53 Arg>Pro polymorphism and risk of OC. Data were pooled together from individual studies and meta-analysis was performed. Pooled odds ratios (ORs) and 95% CI were calculated for allele contrast, homozygous, heterozygous, dominant and recessive genetic models. Results A total of twelve studies comprising of 993 OC cases and 1264 healthy controls were included in this meta-analysis. Overall, no significant association was detected for Pro allele carrier (Pro vs. Arg: pu200a=u200a0.916; ORu200a=u200a0.980, 95% CIu200a=u200a0.677 to 1.419), homozygous (Pro/Pro vs. Arg/Arg: pu200a=u200a0.419; ORu200a=u200a0.731, 95% CIu200a=u200a0.341 to 1.564), heterozygous (Arg/Pro vs. Arg/Arg: pu200a=u200a0.248; ORu200a=u200a1.237, 95% CIu200a=u200a0.862 to 1.773), dominant (Pro/Pro+Arg/Pro vsArg/Arg: pu200a=u200a0.699; ORu200a=u200a1.089, 95% CIu200a=u200a0.706 to 1.681), and recessive (Pro/Pro vs Arg/Arg+Arg/Pro: pu200a=u200a0.329; ORu200a=u200a0.754, 95% CIu200a=u200a0.428 to 1.329) genetic models, respectively. Also, in the stratified analysis by ethnicity, no significant association of this polymorphism with risk of OC was found in the Caucasian population. Conclusions This meta-analysis suggested that codon 72 of the p53 Arg>Pro polymorphism may not significantly contribute in ovary cancer susceptibility. However, future large studies with gene-gene and gene-environment interactions are needed to validate these findings.

Recent developments and obstacles in the treatment of melanoma with BRAF and MEK inhibitors

Metastatic melanoma is a least common form of cancer as it accounts only for 1% of all cancer cases. But, it is most deadly in nature and is haunting mankind for long emotionally as well as economically. The sites for the onset of the disease are pigment-producing cells of the skin, mucosa, eye etc. It has the potential to spread other sites like subcutaneous tissue, lymph nodes, lungs, liver, bone and brain. The United States Food & Drug Administration has approved various drug molecules from time to time. The molecules (Dabrafenib-BRAF inhibitor and Trametinib-MEK inhibitor) have proved their credentials alone and in combination as well. These molecules have demonstrated good results for various end points like median progression free survival, overall survival, objective response etc. The median progression free survival for patients using dabrafenib and trametinib were 5.1 and 4.8 months, respectively (administered singly). It has increased to 11.4 months in the combination treatment dabrafenibu202f+u202ftrametinib, which is approximately 104% and 138% greater than dabrafenib and trametinib treated groups alone. Similarly, the overall survival rate and objective response rate for the patients administered with dabrafenibu202f+u202ftrametinib have been increased by 72% 64%, respectively. All these increments in these parameters were for a short period of time as the molecules were unable to withstand the pressure of resistance developed in the patients. So, the current review suggests the use of BRAF and MEK inhibitors as intermittent therapy along with heat shock protein 90 (HSP90) molecules.

Cytomegalovirus aggravates the autoimmune phenomenon in systemic autoimmune diseases

BACKGROUNDnHuman Cytomegalovirus (CMV), because of its ability to extensively manipulate host immunity during active infection, has been suggested to be involved in autoimmunity. However, its influence on T-cells and cytokines in systemic autoimmune diseases like systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) is indistinct.nnnMETHODSnWe investigated the in-vitro response of T lymphocytes from SLE and SSc patients to CMV antigen. Functional activity of T lymphocytes was determined by estimating Th1 (IL-2 and IFN-γ) and Th2 (IL-4 and IL-10) cytokines.nnnRESULTSnWe observed that CMV antigen stimulation in-vitro resulted in significant increase in CD4:CD8 T-cell ratio in peripheral blood mononuclear cells (PBMCs) from SLE and SSc patients; response dominated by CD4+ than CD8+ memory T-cells. SSc T-cell response was differentiated by aberrant increase in CD4+CD25+ T-cells. CMV antigen caused elevation in IL-4 and IFN-γ production in both patient PBMCs, whereas IL-2 was also raised in SLE PBMCs. The development of large pool of memory T-cells and overproduction of IFN-γ may result in flare-up of autoimmunity in these patients.nnnCONCLUSIONnOur study provides an insight into the immunopathological potential of CMV-reactive immune cells to develop new potential strategies for targeted therapeutic intervention.

Inhibition of C298S mutant of human aldose reductase for antidiabetic applications: Evidence from in silico elementary mode analysis of biological network model

Human aldose reductase (hAR) is the key enzyme in sorbitol pathway of glucose utilization and is implicated in the etiology of secondary complications of diabetes, such as, cardiovascular complications, neuropathy, nephropathy, retinopathy, and cataract genesis. It reduces glucose to sorbitol in the presence of NADPH and the major cause of diabetes complications could be the change in the osmotic pressure due to the accumulation of sorbitol. An activated form of hAR (activated hAR or ahAR) poses a potential obstacle in the development of diabetes drugs as hAR‐inhibitors are ineffective against ahAR. The therapeutic efficacy of such drugs is compromised when a large fraction of the enzyme (hAR) undergoes conversion to the activated ahAR form as has been observed in the diabetic tissues. In the present study, attempts have been made to employ systems biology strategies to identify the elementary nodes of human polyol metabolic pathway, responsible for normal metabolic states, followed by the identification of natural potent inhibitors of the activated form of hAR represented by the mutant C298S for possible antidiabetic applications. Quantum Mechanical Molecular Mechanical docking strategy was used to determine the probable inhibitors of ahAR. Rosmarinic acid was found as the most potent natural ahAR inhibitor and warrants for experimental validation in the near future.