Department Of Human Genetics And Molecular Medicine
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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 Genetic variants of metabolism and inflammatory pathways, and PCOS risk �Systematic review, meta-analysis, and in-silico analysis(Elsevier B.V., 2023-09-14T00:00:00) Sharma, Priya; Bhatia, Kabir; Singh Kapoor, Harmanpreet; Kaur, Balpreet; Khetarpal, PreetiImportance: Identification of genetic risk factors for PCOS susceptibility. Objective: To identify genetic risk variants of the genes involved in metabolic or inflammatory pathways. Data sources: Relevant literature was identified and extracted from PubMed, Central Cochrane Library, Google Scholar, and Science Direct by using a set of keywords related to pre-determined genes up to 06 May 2023. Study selection and synthesis: PRISMA guidelines were followed to design the protocol which is registered in PROSPERO (CRD42023422501). Pooled odds ratio (OR) and 95% confidence interval (95% CI) for different gene variants were calculated under different genetic models (dominant model, recessive model, additive model, and allele model) by using Review Manager software 4.2. Main outcomes: Metabolic genetic variants FTO rs9939609, IL-6 rs1800795 and CAPN10 rs3842570, rs2975760, and RAB5B rs705702 are associated with PCOS risk. Results: Forty-four relevant articles have been identified for genes involved in metabolic (n = 23) or inflammatory pathways (n = 21). There is a significant association (p < 0.05) of IL-6 rs1800795 and FTO rs9939609 with increased risk.CAPN10 rs2975760 Ins allele is suggested as a protective factor among only the non-Asian population. Also, a significant association of CAPN10 rs2975760 and RAB5B rs705702 with increased risk among the Asian population is suggested. However, no significant association could be found between CAPN10 rs3792267, rs5030952, and SUMO1P1 rs2272046, and the risk of PCOS in any of the subpopulations analysed. In silico analysis suggests the deleterious effect of IL-6 rs1800795. Conclusion: and relevance: The study suggests the role of various genetic variants for genetic predisposition to PCOS among different subpopulations. � 2023 Elsevier B.V.Item Diagnostic and therapeutic approaches for endometriosis: a patent landscape(Springer Science and Business Media Deutschland GmbH, 2023-08-25T00:00:00) Singh, Maninder; Jassal, Reena; Khetarpal, PreetiObjective: The aim of this review is to analyze the patent filings and to systematize the main technological trends in patent protection for the diagnosis and therapeutics for endometriosis. Patent literature has also been explored to identify active inventors and applicants in this field. Methodology: Patent search was carried out in the freely accessible patent search databases namely, patentscope using various combinations of the keywords �Endometriosis OR Adenomyosis� AND �Diagnostic OR Therapeutics� were used along with wildcard search queries in the �Title�, �Abstract� and �Descriptions� fields. Results: A patent search revealed 144 patents describing inventions for diagnostic and therapeutic purposes of endometriosis. These patents include 26 patent applications in the diagnostic utility and 116 patent applications under the therapeutic approaches. Out of these 116 patent applications, 43 describe traditional medicines for endometriosis. Two patent applications describe inventions that can fall into both categories. Conclusion: Efforts are being made to improve current diagnostic instruments.�Hormonal alteration methods is the most common field of invention, followed by surgical interventions for therapeutics. A general trend of increase in patent application filings has been observed with a slight decrease in recent years. � 2023, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.Item Maternal candidate gene variants, epigenetic factors, and susceptibility to idiopathic recurrent pregnancy loss: A systematic review(John Wiley and Sons Ltd, 2023-01-30T00:00:00) Kaur, Mandeep; Kaur, Rajinder; Chhabra, Kiran; Khetarpal, PreetiBackground: Recurrent pregnancy loss is defined as the loss of two or more pregnancies and is a distressing condition for couples. Objective: To investigate the relationship between variants in the candidate susceptibility genes and epigenetic factors to identify risk factors for idiopathic recurrent pregnancy loss (iRPL). Search Strategy: A systematic literature search was performed using PubMed, Google Scholar, ScienceDirect, and Scopus databases. Insilico analysis was carried out using ShinyGO and STRING software. Selection Criteria: Research papers examining the association between variations in genetic and epigenetic factors and iRPL. Data Collection and Analysis: Data were independently extracted by two authors. Main Results: In total, 83 research papers were finally selected for the present study. Among all the genes involved in the pathogenesis of recurrent pregnancy loss, polymorphisms in IL superfamily genes, VEGF, ESR, and MTHFR were the most investigated. Conclusion: Polymorphisms in angiogenesis, immune tolerance, and thrombophilia pathway genes, which occur independently or synergistically, may lead to various complications during fetal development. Identification of multi-allele risk variants and epigenetic factors in women will be helpful in the identification of high-risk pregnancies. Prospero Registration Number: Prospero CRD42021287315. � 2023 International Federation of Gynecology and Obstetrics.Item A systematic review of the monogenic causes of Non-Syndromic Hearing Loss (NSHL) and discussion of Current Diagnosis and Treatment options(John Wiley and Sons Inc, 2022-09-12T00:00:00) Sharma, Nandita; Kumari, Divya; Panigrahi, Inusha; Khetarpal, PreetiHearing impairment is one of the most widespread inheritable sensory disorder affecting at least 1 in every 1000 born. About two-third of hereditary hearing loss (HHL) disorders are non-syndromic. To provide comprehensive update of monogenic causes of non-syndromic hearing loss (NSHL), literature search has been carried out with appropriate keywords in the following databases�PubMed, Google Scholar, Cochrane library, and Science Direct. Out of 2214 papers, 271 papers were shortlisted after applying inclusion and exclusion criterion. Data extracted from selected papers include information about gene name, identified pathogenic variants, ethnicity of the patient, age of onset, gender, title, authors' name, and year of publication. Overall, pathogenic variants in 98 different genes have been associated with NSHL. These genes have important role to play during early embryonic development in ear structure formation and hearing development. Here, we also review briefly the recent information about diagnosis and treatment approaches. Understanding pathogenic genetic variants are helpful in the management of affected and may offer targeted therapies in future. � 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.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 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.Item Clinical and Molecular Heterogeneity of Silver-Russell Syndrome and Therapeutic Challenges: A Systematic Review(Bentham Science Publishers, 2022-03-16T00:00:00) Singh, Amit; Pajni, Ketan; Panigrahi, Inusha; Khetarpal, PreetiBackground: Silver-Russell syndrome (SRS) is a developmental disorder involving ex-treme growth failure, characteristic facial features and underlying genetic heterogeneity. As the clinical heterogeneity of SRS makes diagnosis a challenging task, the worldwide incidence of SRS could vary from 1:30,000 to 1:100,000. Although various chromosomal, genetic, and epigenetic mutations have been linked with SRS, the cause had only been identified in half of the cases. Material and Methods: To have a better understanding of the SRS clinical presentation and mutation/epimutation responsible for SRS, a systematic review of the literature was carried out using ap-propriate keywords in various scientific databases (PROSPERO protocol registration CRD42021273211). Clinical features of SRS have been compiled and presented corresponding to the specific genetic subtype. An attempt has been made to understand the recurrence risk and the role of model organisms in understanding the molecular mechanisms of SRS pathology, treatment, and management strategies of the affected patients through the analysis of selected literature. Results: 156 articles were selected to understand the clinical and molecular heterogeneity of SRS. Information about detailed clinical features was available for 228 patients only, and it was observed that body asymmetry and relative macrocephaly were most prevalent in cases with methylation defects of the 11p15 region. In about 38% of cases, methylation defects in ICRs or genomic mutations at the 11p15 region have been implicated. Maternal uniparental disomy of chromosome 7 (mUPD7) accounts for about 7% of SRS cases, and rarely, uniparental disomy of other autosomes (11, 14, 16, and 20 chromosomes) has been documented. Mutation in half of the cases is yet to be identified. Studies involving mice as experimental animals have been helpful in understanding the underlying molecular mechanism. As the clinical presentation of the syndrome varies a lot, treatment needs to be individualized with multidisciplinary effort. Conclusion: SRS is a clinically and genetically heterogeneous disorder, with most of the cases being implicated with a mutation in the 11p15 region and maternal disomy of chromosome 7. Recurrence risk varies according to the molecular subtype. Studies with mice as a model organism have been useful in understanding the underlying molecular mechanism leading to the characteristic clinical presentation of the syndrome. Management strategies often need to be individualized due to varied clinical presentations. � 2023 Bentham Science Publishers.Item Assessment of Serum Elements Concentration and Polycystic Ovary Syndrome (PCOS): Systematic Review and Meta-analysis(Springer, 2022-01-14T00:00:00) Sharma, Priya; Gupta, Vartika; Kumar, Kush; Khetarpal, PreetiChange in the levels of trace elements has been linked with PCOS pathogenesis by various studies, whereas some had reported no such association. Therefore, in order to evaluate association of eleven trace element (Cu, Zn, Cr, Cd, Se, Mn, Fe, Mg, Co, Ni and Pb) serum concentration with PCOS pathogenesis, current systematic review and meta-analysis has been carried out. Literature search was conducted using PubMed, Central Cochrane Library, Google Scholar and Science Direct databases with appropriate keywords. Studies published upto 3rd of September were evaluated for eligibility with suitable inclusion and exclusion criteria. Only case�control studies examining the association of serum trace element concentrations between PCOS cases and controls were selected. Present meta-analysis identified 32 articles with 2317 PCOS and 1898 controls. The serum Cu (MD = 15.40; 95% CI = 4.32 to 26.48; p = 0.006), Co (MD = 0.01; 95% CI = 0.01 to 0.02; p = 0.000), Cr (MD = 0.04; 95% CI = 0.00 to 0.07; p = 0.03) and Fe (MD = 12.98; 95% CI = 5.87�20.09; p = 0.0003) concentration is significantly higher, while lower concentration has been observed for Se (MD = ? 0.99; 95% CI = ? 1.31 to ? 0.67; p = 0.000) and Mg (MD = ? 223.41; 95% CI = ? 391.60 to ? 55.23; p = 0.009) among women with PCOS in comparison with the healthy group. Concentration of other elements which were analysed is not significantly related to PCOS. In short, PCOS women has higher serum concentrations of Cu, Co, Cr and Fe and lower concentrations of Se and Mg. Studies with sub-population of obese, non-obese and with and without insulin resistance are important to understand the pathomechanism of these elements in the syndrome. � 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.