• B. K. THELMA

      Articles written in Journal of Genetics

    • Candidate gene polymorphisms among North Indians and their association with schizophrenia in a case-control study

      Prachi Semwal Suman Prasad Panchami G. Varma A. M. Bhagwat S. N. Deshpande B. K. Thelma

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      Knowledge of candidate gene polymorphisms in a population is useful for a variety of gene-disease association studies, particularly for some complex traits. A number of candidate genes, a majority of them from the monoaminergic pathway in the brain, have been very popular in association studies with schizophrenia, a neuropsychiatric disorder. In this study diallelic/multiallelic polymorphisms in some dopaminergic, serotonergic and membrane-phospholipid-related genes have been evaluated in a control population recruited from North India. Association, if any, of these allelic variants with schizopherenia has been tested using a case-control approach. The case data have been taken from our published family-based association studies in schizophrenia. Of the eight genes tested in this study, association with schizophrenia was observed for only two gene polymorphisms, one in the promoter region of the serotonin 2A receptor gene and the other in the tryptophan hydroxylase gene. One new allele for the dopamine transporter gene (with eight repeats, 570-bp size), not reported in any population so far, has been identified in one individual in our sample. The data generated in this study, besides providing a normative background for various disease association studies, are a significant contribution to the population-specific genome database, a currently growing requirement.

    • Advances in the discovery of genetic risk factors for complex forms of neurodegenerative disorders: contemporary approaches, success, challenges and prospects

      SUMEET KUMAR NAVNEESH YADAV SANJAY PANDEY B. K. THELMA

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      Neurodegenerative diseases constitute a large proportion of disorders in elderly, majority being sporadic in occurrence with ∼5–10% familial. A strong genetic component underlies the Mendelian forms but nongenetic factors together with genetic vulnerability contributes to the complex sporadic forms. Several gene discoveries in the familial forms have provided novel insights into the pathogenesis of neurodegeneration with implications for treatment. Conversely, findings from genetic dissection of the sporadic forms, despite large genomewide association studies and more recently whole exome and whole genome sequencing, have been limited. This review provides a concise account of the genetics that we know, the pathways that they implicate, the challengesthat are faced and the prospects that are envisaged for the sporadic, complex forms of neurodegenerative diseases, taking four most common conditions, namely Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and Huntington disease as examples. Poor replication across studies, inability to establish genotype–phenotype correlations and the overall failure to predictrisk and/or prevent disease in this group poses a continuing challenge. Among others, clinical heterogeneity emerges as the most important impediment warranting newer approaches. Advanced computational and system biology tools to analyse the big data are being generated and the alternate strategy such as subgrouping of case–control cohorts based on deep phenotyping using theprinciples of Ayurveda to overcome current limitation of phenotype heterogeneity seem to hold promise. However, at this point, with advances in discovery genomics and functional analysis of putative determinants with translation potential for the complex forms being minimal, stem cell therapies are being attempted as potential interventions. In this context, the possibility to generatepatient derived induced pluripotent stem cells, mutant/gene/genome correction through CRISPR/Cas9 technology and repopulating the specific brain regions with corrected neurons, which may fulfil the dream of personalized medicine have been mentioned briefly. Understanding disease pathways/biology using this technology, with implications for development of novel therapeutics are optimisticexpectations in the near future.

    • Genetics of ulcerative colitis: putting into perspective the incremental gains from Indian studies

      GARIMA JUYAL AJIT SOOD VANDANA MIDHA B. K. THELMA

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      Ulcerative colitis (UC), one of the two clinical subtypes of inflammatory bowel disease is perceived as a potential 'sleeping giant' in the Indian subcontinent. Clinical manifestation is overall believed to be the same across ethnic groups but overwhelming genetics from large European and fewer non-European studies have revealed shared as well as unique disease susceptibly signaturesbetween them, pointing to population specific differences at genomic and environmental levels. A systematic recount of the four major eras in UC genetics spanning earliest linkage analysis, cherry picked candidate gene association studies, unbiased genomewide association studies, their logical extension in trans-ethnic setting (Immunochip study), lastly whole exome sequencing efforts forrare variant burden; and lessons learnt thereof in context of genetically distinct Indian population was attempted in this review. Genetic heterogeneity manifesting at allelic/locus level across these approaches has been the consistent finding through the range of pan India studies. On the other hand, these salient findings also highlight the limitations of even the best of these genetic leadsfor prognostic/clinical application. The imminent need, therefore, for the UC research community to adopt newer approaches/tools with improved study design to (i) gain better insight into genetic/mechanistic basis of disease; (ii) identify biomarkers of immediate translational value; and (iii) develop new/alternate therapeutic options is emphasized at the end.

    • Age-related gene expression alterations by SARS-CoV-2 infection contribute to poor prognosis in elderly

      UPASANA BHATTACHARYYA B. K. THELMA

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      The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions ofpeople worldwide and with notable heterogeneity in its clinical presentation. Probability of contracting this highly contagious infection issimilar across age groups but disease severity and fatality among aged patients with or without comorbidities are reportedly higher.Previous studies suggest that age associated transcriptional changes in lung and immune system results in a proinflammatory state andincreased susceptibility to infectious lung diseases. Similarly, SARS-CoV-2 infection could augment ageing-related gene expressionalterations resulting in severe outcomes in elderly patients. To identify genes that can potentially increase covid-19 disease severity inageing people, we compared age associated gene expression changes with disease-associated expression changes in lung/BALF and wholeblood obtained from publicly available data. We observed (i) a significant overlap of gene expression profiles of patients’ BALF and bloodwith lung and blood of the healthy group, respectively; (ii) a more pronounced overlap in blood compared to lung; and (iii) a similar overlapbetween host genes interacting with SARS-CoV-2 and ageing blood transcriptome. Pathway enrichment analysis of overlapping gene setssuggest that infection alters expression of genes already dysregulated in the elderly, which together may lead to poor prognosis. eQTLs inthese genes may also confer poor outcome in young patients worsening with age and comorbidities. Further, the pronounced overlapobserved in blood may explain clinical symptoms including blood clots, strokes, heart attack, multi-organ failure etc. in severe cases. Thismodel based on a limited patient dataset seems robust and holds promise for testing larger tissue specific datasets from patients with variedseverity and across populations.

    • Correlation between an intronic SNP genotype and ARL15 level in rheumatoid arthritis

      ANUJ KUMAR PANDEY AISHWARYA SAXENA SANJAY KUMAR DEY MAUMITA KANJILAL UMA KUMAR B. K. THELMA

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      ADP ribosylation factor like protein 15 (ARL15) was identified as a novel susceptibility gene for rheumatoid arthritis (RA) based on a genomewide association study in a north Indian cohort. Mechanism of its action and functional relevance in RA biology remain largely unknown. In this study, we aimed to establish (i) ARL15 protein level in sera samples of RA patients; and (ii) its correlation, if any, with the RA associated ARL15 intronic single-nucleotide polymorphism (SNP) rs255758 (A [C). DNA, RNA and sera were isolated fromblood samples of 117 RA patients and 25 age-matched healthy controls recruited at All India Institute of Medical Sciences, New Delhi with institutional ethical committee clearance. SNP rs255758 (A [C) was genotyped by Sanger sequencing; ARL15 RNA and protein levels were estimated by quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA), respectively; and genotype–phenotype correlation established using Mann–Whitney nonparametric test. Very low level of ARL15 expression in human blood was confirmed at both RNA and protein levels. Genotype-wise distribution showed increased levels (P = 0.05) of ARL15 protein in RA patients with the homozygous variant (CC) as compared to AA ? AC genotypes of rs255758. This first-ever correlation between higher ARL15 protein levels and the intronic susceptibility genotype (CC; rs255758) in RA patients may be of diagnostic and therapeutic relevance encouraging additional investigations.

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