Department Of Human Genetics And Molecular Medicine
Permanent URI for this communityhttps://kr.cup.edu.in/handle/32116/103
Browse
19 results
Search Results
Item Genetic Variants of Steroidogenesis and Gonadotropin Pathways and Polycystic Ovary Syndrome Susceptibility: A Systematic Review and Meta-analysis(Mary Ann Liebert Inc., 2023-10-25T00:00:00) Sharma, Priya; Singh, Abhilash Kumar; Senapati, Sabyasachi; Kapoor, Harmanpreet Singh; Goyal, Lajya Devi; Kaur, Balpreet; Kamra, Pooja; Khetarpal, PreetiGenetic variants are predisposing factors to polycystic ovary syndrome (PCOS), a multifactorial condition that often gets triggered due to various environmental factors. The study investigates the association of the variants of genes that are involved in the steroidogenesis pathway or gonadotropin pathway with the risk of PCOS. Appropriate keywords for predetermined genes were used to search in PubMed, Google Scholar, Science Direct, and Central Cochrane Library up to January 11, 2023. PROSPERO (CRD42022275425). Inclusion criteria: (a) case�control study; (b) genotype or allelic data. Exclusion criteria were: (a) duplicate studies; (b) clinical trials, systematic reviews, meta-analysis or conference abstract, case reports; (c) other than the English language; (d) having insufficient data; e) genetic variants for which meta-analysis has been reported recently and does not have a scope of the update. Various genetic models were applied as per data availability. Overall 12 variants of 7 genes were selected for the analysis. Relevant data were extracted from 47 studies which include 10,584 PCOS subjects and 16,150 healthy controls. Meta-analysis indicates a significant association between TOX3 rs4784165 [ORs = 1.08, 95% CI (1.00�1.16)], HMGA2 rs2272046 [ORs = 2.73, 95% CI (1.97�3.78)], YAP1 rs1894116 [OR = 1.22, 95% CI (1.13�1.33)] and increased risk of PCOS. Whereas FSHR rs2268361 [ORs = 0.84, 95% CI (0.78�0.89)] is associated with decreased PCOS risk. When sensitivity analysis was carried out, the association became significant for CYP19 rs700519 and FSHR rs6165 under an additive model. In addition, C9Orf3 rs3802457 became significantly associated with decreased PCOS risk with the removal of one study. Insignificant association was observed for CYP19A (rs2470152), FSHR (rs2349415, rs6166), C9Orf3 (rs4385527), GnRH1 (rs6185) and risk of PCOS. Our findings suggest association of CYP19A (rs700519), TOX3 (rs4784165), HMGA2 (rs2272046), FSHR (rs6165, rs2268361), C9orf3 (rs3802457), and YAP1 (rs1894116) with risk for PCOS. � Mary Ann Liebert, Inc.Item A duodenal mucosa transcriptome study identified reduced expression of a novel gene CDH18 in celiac disease(Elsevier B.V., 2023-10-09T00:00:00) Banerjee, Pratibha; Sood, Ajit; Midha, Vandhana; Narang, Vikram; Grover, Jasmine; Senapati, SabyasachiBackground: Celiac disease (CD) a complex immune disease that affects duodenal mucosa. Identification of tissue specific biomarkers is expected to improve the existing biopsy based CD diagnosis. Aims: To investigate the differentially expressed genes (DEGs) in duodenal mucosa tissue to identify clinically relevant gene expression pattern in CD. Methods: Whole RNA extracted from the duodenal biopsies of three CD patients and four non-CD controls were sequenced. Significant DEGs were identified. Prioritized DEGs were validated using qRT-PCR in an independent group (CD=23; Control=26). Enriched pathways were analyzed, protein-protein interaction networks were evaluated. Results: 923 DEGs comprising of 135 up-regulated, and 788 down-regulated genes, with p-value?0.05; log2FC>2 or <-2 were identified. A novel down-regulated gene CDH18 (p = 0.03; log2FC=?0.74) was identified. Previously known CXCL9 was replicated. CDH18, a trans-membrane protein was found to interact with other CDH proteins, ?/? catenins, and other membrane transporters such as SLC and ABCB. Pathways and protein networks contributing in channel activity (p = 2.15E-12), membrane transporters (p = 2.15E-12), and cellular adhesion (p = 8.05E-6) were identified. Conclusions: CDH18, a novel DEG identified in the present study is a pivotal gene involved in maintaining epithelial membrane organization and integrity. The functional significance of lower expression of CDH18 in pathogenesis of CD warranted to be investigated. CDH18 expression could be tested for its effectiveness in diagnostic, prognostic and therapeutic purposes. � 2023 Editrice Gastroenterologica Italiana S.r.l.Item Translational implications of humoral and cellular immune dysfunction in granulomatosis with polyangiitis(Academic Press, 2023-02-20T00:00:00) Singh, Harinder; Kumar, Uma; Senapati, SabyasachiGranulomatosis with polyangiitis (GPA) is a rare systemic ANCA (Anti-neutrophil cytoplasmic antibodies) associated vasculitis (AAV). In the last couple of decades, GPA has emerged as a disease of concern due to rapid increase in the prevalence and incidence especially in developing countries. Unknown aetiology and rapid progression have made GPA a critical disease. Thus, establishing specific tools to facilitate early and faster disease diagnosis and efficient disease management has immense importance. GPA may develop in genetically predisposed individuals on receiving the external stimulus (i.e. microbial pathogen, pollutant etc.) that triggers the immune response. B-cell activating factor (BAFF) produced by the neutrophils, promotes the B-cell maturation and survival which leads to increased ANCA production. Abnormal B-cell and T-cell proliferation and their cytokine response plays a major role in disease pathogenesis and granuloma formation. ANCA interacts with neutrophils and induces the neutrophil extracellular traps (NETs) formation and reactive oxygen species (ROS) production which leads to the endothelial cell injury. This review article summarizes the critical pathological events and how cytokines and immune cells shape the GPA pathogenesis. Decoding this complex network would facilitate in developing tools for diagnosis, prognosis and disease management. Recently developed specific monoclonal antibodies (MAbs) targeting cytokines and immune cells are being used for safer treatment and achieving longer remission. � 2023 Elsevier LtdItem A meta-analysis suggests the association of reduced serum level of vitamin D and T-allele of Fok1 (rs2228570) polymorphism in the vitamin D receptor gene with celiac disease(Frontiers Media S.A., 2023-01-19T00:00:00) Shree, Tanya; Banerjee, Pratibha; Senapati, SabyasachiPurpose: As an immune-modulator, vitamin D is known to regulate immune response and is implicated in disease pathogenesis. Celiac disease (CD) is a systemic autoimmune disease and susceptibility conferred by vitamin D metabolism is under investigation. Studies on the association of vitamin D metabolism and genetic polymorphisms are expected to explain CD pathogenesis. We performed a systematic review�based meta-analysis to investigate the 25(OH)D serum levels and susceptibility conferred by the genetic variants of VDR in CD. Methods: Systematic review was conducted through a web-based literature search following stringent study inclusion�exclusion criteria. The Newcastle�Ottawa Scale and GRADE tools were used to assess the quality of evidence in studies and the study outcome. Cohen's ? value was estimated to access the reviewer's agreement. RevMan 5.4.1 was used to perform the meta-analyses. Weighted mean difference and Meta p-value was assessed for 25(OH)D serum levels. Meta-odds ratio and Z-test p-value were evaluated to estimate the allelic susceptibility of VDR variants. Results: A total of 8 out of 12 studies were evaluated for �25(OH)D� serum level, while four studies were found eligible for SNPs (Bsm1, Apa1, Fok1, and Taq1) of VDR. Significantly higher levels [WMD = 5.49, p < 0.00001] of 25(OH)D were observed in healthy controls than in patients with CD. rs2228570-T (Fok1) [Meta-OR = 1.52, p = 0.02] was confirmed to be predisposing allele for CD. Conclusion: Reduced serum level of 25(OH)D and association of Fok1 T-allele of VDR confirmed in this study plays a critical role in immunomodulation and maintaining barrier integrity, which is majorly implicated in CD. Copyright � 2023 Shree, Banerjee and Senapati.Item Celiac disease-associated loci show considerable genetic overlap with neuropsychiatric diseases but with limited transethnic applicability(Springer, 2023-01-10T00:00:00) Sharma, Nidhi; Banerjee, Pratibha; Sood, Ajit; Midha, Vandana; Thelma, B.K.; Senapati, SabyasachiClinical and public health research has revealed the co-occurrence of several neuropsychiatric diseases among patients with celiac disease (CD). The significant presence of CD-specific autoantibodies in patients with neuropsychiatric diseases and vice versa are often reported. To explain the genetic basis of such frequent disease co-occurrence and investigate the underlying common pathways/processes, we performed an extensive cross-disease association study followed by supporting in silico functional validation of the leads. Genomewide association study (GWAS) data for CD and eight commonly co-occurring neuropsychiatric diseases from Caucasian populations were analysed, and the shared loci were determined. We performed Immunochip-based fine mapping of these overlapping association signals in an independent European CD data and tested their cross-ethnic transferability using CD association data from the genetically distinct north Indian population. This study identified 12 shared loci between the two diseases with genomewide significance (P ? 5e-8). Of these five loci, namely NFIA, KIA1109, NOTCH4-TSBP1-PBX2, HLA-DQA1 and CSK replicated in an independent Dutch cohort representing European ancestry. Three of these loci, namely NFIA, NOTCH4-TSBP1-PBX2 and HLA-DQA1 that are common between CD, anxiety, migraine and schizophrenia respectively withstood locus transferability test in north Indians. Tissue-specific eQTL analysis of SNPs from transferable loci revealed expression QTL effects in brain tissue besides the small intestine and whole blood. Pathway analysis and evidence of epigenetic regulation highlighted the potential contribution of these SNPs to disease pathology. The replicable and transferable association of genetic variants from MHC locus and their functional implications suggest the process of antigen presentation and adaptive/innate immune response regulated by non-HLA genes in the locus may dominate the shared pathogenesis of CD and neuropsychiatric diseases. Functional validation of the shared candidate genes is warranted to unravel the molecular mechanism for the co-occurrence of CD and specific neuropsychiatric diseases. � 2023, Indian Academy of Sciences.Item Targeting mitochondria in the regulation of neurodegenerative diseases: A comprehensive review(John Wiley and Sons Inc, 2022-07-20T00:00:00) Maurya, Shashank Kumar; Gupta, Suchi; Bakshi, Amrita; Kaur, Harpreet; Jain, Arushi; Senapati, Sabyasachi; Baghel, Meghraj SinghMitochondria are one of the essential cellular organelles. Apart from being considered as the powerhouse of the cell, mitochondria have been widely known to regulate redox reaction, inflammation, cell survival, cell death, metabolism, etc., and are implicated in the progression of numerous disease conditions including neurodegenerative diseases. Since brain is an energy-demanding organ, mitochondria and their functions are important for maintaining normal brain homeostasis. Alterations in mitochondrial gene expression, mutations, and epigenetic modification contribute to inflammation and neurodegeneration. Dysregulation of reactive oxygen species production by mitochondria and aggregation of proteins in neurons leads to alteration in mitochondria functions which further causes neuronal death and progression of neurodegeneration. Pharmacological studies have prioritized mitochondria as a possible drug target in the regulation of neurodegenerative diseases. Therefore, the present review article has been intended to provide a comprehensive understanding of mitochondrial role in the development and progression of neurodegenerative diseases mainly Alzheimer's, Parkinson's, multiple sclerosis, and amyotrophic lateral sclerosis followed by possible intervention and future treatment strategies to combat mitochondrial-mediated neurodegeneration. � 2022 Wiley Periodicals LLC.Item Functional implications of the CpG island methylation in the pathogenesis of celiac disease(Springer Science and Business Media B.V., 2022-05-28T00:00:00) Ghosh, Souparni; Khetarpal, Preeti; Senapati, SabyasachiInvestigation of gene-environment cross talk through epigenetic modifications led to better understanding of the number of complex diseases. Clinical heterogeneity and differential treatment response often contributed by the epigenetic signatures which could be personal. DNA methylation at CpG islands presents a critical nuclear process as a result of�gene-environment interactions. These CpG islands are frequently present near the promoter sequence of genes and get differentially methylated under specific environmental conditions. Technical advancements facilitate in high throughput screening of differentially methylated CpG islands. Recent epigenetic studies unraveled several CD susceptibility genes expressed in peripheral blood lymphocytes�(PBLs), duodenal mucosa, lamina and epithelial cells that are influenced by differentially methylated CpG islands. Here we highlighted these susceptibility genes; classify these genes based on cellular functions and tissue of expression. We further discussed how these genes interacts with each other to influence critical pathways like NF-?B signaling pathway, IL-17 signaling cascade, RIG-I like receptor signaling pathway, NOD-like receptor pathways among several others. This review also shed light on how gut microbiota may lead to the differential methylation of CpG islands of CD susceptibility genes. Large scale epigenetic studies followed by estimation of heritability of these CpG methylation and polygenic risk score estimation of these genes would prioritize potentially druggable targets for better therapeutics. In vivo studies are warranted to unravel further cellular responses to CpG methylation. � 2022, The Author(s), under exclusive licence to Springer Nature B.V.Item Withania somnifera phytochemicals possess SARS-CoV-2 RdRp and human TMPRSS2 protein binding potential(Springer, 2022-06-15T00:00:00) Prajapati, Kumari Sunita; Singh, Atul Kumar; Kushwaha, Prem Prakash; Shuaib, Mohd; Maurya, Santosh Kumar; Gupta, Sanjay; Senapati, Sabyasachi; Singh, Surya Pratap; Waseem, Mohammad; Kumar, ShashankAbstract: Coronavirus disease-19 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has infected approximately 26�million people and caused more than 6�million deaths globally. Spike (S)-protein on the outer surface of the virus uses human trans-membrane serine protease-2 (TMPRSS2) to gain entry into the cell. Recent reports indicate that human dipeptidyl peptidase-4 inhibitors (DPP4 or CD26) could also be utilized to check the S-protein mediated viral entry into COVID-19 patients. RNA dependent RNA polymerase (RdRp) is another key virulence protein of SARS-CoV-2 life cycle. The study aimed to identify the potential anti-SARS-CoV-2 inhibitors present in Withania somnifera (Solanaceae) using computer aided drug discovery approach. Molecular docking results showed that flavone glycoside, sugar alcohol, and flavonoid present in W. somnifera showed ? 11.69, ? 11.61, ? 10.1, ? 7.71�kcal/mole binding potential against S-protein, CD26, RdRp, and TMPRSS2 proteins. The major standard inhibitors of the targeted proteins (Sitagliptin, VE607, Camostat mesylate, and Remdesivir) showed the ? 7.181, ? 6.6, ? 5.146, and ? 7.56�kcal/mole binding potential. Furthermore, the lead phytochemicals and standard inhibitors bound and non-bound RdRp and TMPRSS2 proteins were subjected to molecular dynamics (MD) simulation to study the complex stability and change in protein conformation. The result showed energetically favorable and stable complex formation in terms of RMSD, RMSF, SASA, Rg, and hydrogen bond formation. Drug likeness and physiochemical properties of the test compounds exhibited satisfactory results. Taken together, the present study suggests the presence of potential anti-SARS-CoV-2 phytochemicals in W. somnifera that requires further validation in in vitro and in vivo studies. Graphical Abstract: [Figure not available: see fulltext.] � 2022, The Author(s) under exclusive licence to Society for Plant Research.Item Meta-analysis confirmed genetic susceptibility conferred by multiple risk variants from CTLA4 and SERPINA1 in granulomatosis with polyangiitis(John Wiley and Sons Inc, 2022-06-03T00:00:00) Banerjee, Pratibha; Kumar, Uma; Khetarpal, Preeti; Senapati, SabyasachiBackground: Granulomatosis with polyangiitis (GPA) is a rare systemic autoimmune disease. Smaller sample size and complex nature of the disease pathogenesis has made it challenging to perform well-powered genetic investigations. We performed a systematic review based meta-analysis in GPA to investigate the genetic susceptibility conferred by non-human leukocyte antigen (non-HLA) candidate genes. Methods: A systematic review was performed using web-based literature search and eligible studies were included following inclusion-exclusion criteria. Studies were evaluated for their quality of evidence and study outcome was assessed using the Newcastle-Ottawa Scale and Grades of Research, Assessment, Development and Evaluation tools. Reviewer's agreement was accessed through Cohen's ? value. Meta-analyses were performed using RevMan 5 tool. Meta-odds ratio (meta-OR) and Z test P value were evaluated to estimate the genetic susceptibility for each of the variants. Results: Eighteen studies were found eligible and 7 genetic variants from only 4 genes, namely CTLA4, PRTN3, SERPINA1 and PTPN22 could be studied for meta-analysis. rs231775-G (49-G) (Meta-OR�=�1.42 [1.14-1.76]; P�=.001) of CTLA4 and rs7151526-A (Meta-OR�=�2.70 [1.51-4.85]; P�=.0008) of SERPINA1 were confirmed to be predisposing alleles, and rs5742909-C (318-C) (Meta-OR�=�0.65 [0.44-0.97]; P�=.03) of CTLA4 was found to be protective for GPA. In concordance with the genetic association of rs7151526-A, serological marker for the same variant �Z� allele of SERPINA1 was found to be predisposing (Meta-OR�=�12.60 [5.01-31.68]; P <.00001) for GPA. Conclusion: Genetic variants confirmed in this study play critical roles in T-cell mediated immune function and could be significantly implicated in GPA. Molecular pathology studies are warranted to confirm their role. These markers could be used for efficient patient classification and disease management. � 2022 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.Item Components of IGF-axis in growth disorders: a systematic review and patent landscape report(Springer, 2022-05-06T00:00:00) Singh, Amit; Pajni, Ketan; Panigrahi, Inusha; Dhoat, Navdeep; Senapati, Sabyasachi; Khetarpal, PreetiPurpose: In this review, epi/genetic mutations of IGF-axis components associated with growth disorders have been summarized alongwith assessment of relevant diagnostic and therapeutic technology through patent literature. Methodology: PROSPERO protocol registration CRD42021279468. For scientific literature search Literature databases (PubMed, EMBASE, ScienceDirect, and Google Scholar) were queried using the appropriate syntax. Various filters were applied based on inclusion and exclusion criteria. Search results were further refined by two authors for finalizing studies to be included in this synthesis. For patent documents search Patent databases (Patentscope and Espacenet) were queried using keywords: IGF or IGFBP. Filters were applied according to International Patent Classification (IPC) and Cooperative Patent Classification (CPC). Search results were reviewed by two authors for inclusion in the patent landscape report. Results: For scientific literature analysis, out of 545 search results, 196 were selected for review based on the inclusion criteria. For Patent literature search, out of 485 results, 37 were selected for this synthesis. Conclusion: Dysregulation of IGF-axis components leads to various abnormalities and their key role in growth and development suggests epi/mutations or structural defects among IGF-axis genes can be associated with growth disorders and may explain some of the idiopathic short stature cases. Trend of patent filings indicate advent of recombinant technology for therapeutics. � 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.