Landscape of Pharmacogenetic Variants Associated With Non-Insulin Antidiabetic Drugs in the Indian Population

INTRODUCTION: Genetic variants contribute to differential responses to non-insulin antidiabetic drugs (NIADs), and consequently to variable plasma glucose control. Optimal control of plasma glucose is paramount to minimizing type 2 diabetes-related long-term complications. India\u27s distinct genetic architecture and its exploding burden of type 2 diabetes warrants a population-specific survey of NIAD-associated pharmacogenetic (PGx) variants. The recent availability of large-scale whole genomes from the Indian population provides a unique opportunity to generate a population-specific map of NIAD-associated PGx variants. RESEARCH DESIGN AND METHODS: We mined 1029 Indian whole genomes for PGx variants, drug-drug interaction (DDI) and drug-drug-gene interactions (DDGI) associated with 44 NIADs. Population-wise allele frequencies were estimated and compared using Fisher\u27s exact test. RESULTS: Overall, we found 76 known and 52 predicted deleterious common PGx variants associated with response to type 2 diabetes therapy among Indians. We report remarkable interethnic differences in the relative cumulative counts of decreased and increased response-associated alleles across NIAD classes. Indians and South Asians showed a significant excess of decreased metformin response-associated alleles compared with other global populations. Network analysis of shared PGx genes predicts high DDI risk during coadministration of NIADs with other metabolic disease drugs. We also predict an increased CYP2C19-mediated DDGI risk for CYP3A4/3A5-metabolized NIADs, saxagliptin, linagliptin and glyburide when coadministered with proton-pump inhibitors (PPIs). CONCLUSIONS: Indians and South Asians have a distinct PGx profile for antidiabetes drugs, marked by an excess of poor treatment response-associated alleles for various NIAD classes. This suggests the possibility of a population-specific reduced drug response in atleast some NIADs. In addition, our findings provide an actionable resource for accelerating future diabetes PGx studies in Indians and South Asians and reconsidering NIAD dosing guidelines to ensure maximum efficacy and safety in the population

Genomic characterization and epidemiology of an emerging SARS-CoV-2 variant in Delhi, India

Delhi, the national capital of India, experienced multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreaks in 2020 and reached population seropositivity of >50% by 2021. During April 2021, the city became overwhelmed by COVID-19 cases and fatalities, as a new variant, B.1.617.2 (Delta), replaced B.1.1.7 (Alpha). A Bayesian model explains the growth advantage of Delta through a combination of increased transmissibility and reduced sensitivity to immune responses generated against earlier variants (median estimates: 1.5-fold greater transmissibility and 20% reduction in sensitivity). Seropositivity of an employee and family cohort increased from 42% to 87.5% between March and July 2021, with 27% reinfections, as judged by increased antibody concentration after a previous decline. The likely high transmissibility and partial evasion of immunity by the Delta variant contributed to an overwhelming surge in Delhi

Understanding the landscape of structural variants in Indian population and their implications in genetic diseases

<p><strong><span>Appendix datasets for Thesis</span></strong></p> <p><strong><span>Appendix 1 </span></strong></p> <p><span>List of 38560 variants in the final SV callset with the chromosomal coordinates and variant frequencies</span></p> <p><strong><span>Appendix 2 </span></strong></p> <p><span>List of 22589 rare deletions with their comprehensive annotations</span></p> <p><strong><span>Appendix 3</span></strong></p> <p><span>List of 192 P/LP deletion/duplication from the AnnotSV classification</span></p> <p><strong><span>Appendix 4 </span></strong></p> <p><span>List of final 134 P/LP deletions after manual review</span></p> <p><strong><span>Appendix 5 </span></strong></p> <p><span>List of 10 P/LP deletions having full gene deletions</span></p> <p><strong><span>Appendix 6 </span></strong></p> <p><span>List of 27 P/LP deletions with their previously reported P_loss_sources</span></p> <p><strong><span>Appendix 7</span></strong></p> <p><span>Table of disease-gene enrichment analysis for the genes affected by 134 P/LP deletions </span></p&gt

An amplicon-based approach for sequencing of SARS-CoV-2 using COVIDSeq assay on Illumina MiSeq sequencing platforms

Sequencing genomes of SARS-CoV-2 is crucial for understanding the genetic epidemiology of COVID-19pandemic. It is also critical for understanding the evolution of the virus and also for the rapid development of the diagnostic tools. The present protocol is the modification of the Illumina COVIDSeq amplicon-based sequencing approach adapted for benchtop sequencers like MiSeq, iSeq and MiniSeq

Asymptomatic reinfection in two healthcare workers from India with genetically distinct SARS-CoV-2

Reinfection of SARS-CoV-2 is an apparently rare entity and only a few cases have been reported from across the world with the genetic characterization of the virus, differentiating reinfection from persistent virus shedding. These cases, therefore, provide unique insights into the long term protective immunity to SARS-CoV-2. The earlier reports suggest that patients were symptomatic in either one or both the episodes of infection. Here we report a unique case of asymptomatic SARS-CoV-2 reinfection in two healthcare workers from India identified in routine surveillance. Genome sequencing of the virus suggests that genetically distinct SARS-CoV-2 caused the infections. Our analysis demonstrates that asymptomatic reinfection could potentially be an under-reported entity with implications in long term surveillance of SARS-CoV-2 infections. This report also highlights the need for genomic surveillance of healthcare workers who are potentially not only at higher risk for primary infections but also for reinfections

Symptomatic reinfection of SARS‐CoV‐2 with spike protein variant N440K associated with immune escape

Here we describe a case of re-infection in an individual from South India characterized by whole genome sequencing of the virus isolated from both episodes. The analysis shows the presence of an immune escape variant N440K in the Spike protein in both episodes of infection. Incidentally, this variant was also found in a case of reinfection previously reported by us in a healthcare worker from North Indi

Landscape of pharmacogenetic variants associated with non-insulin antidiabetic drugs in the Indian population

Introduction Genetic variants contribute to differential responses to non-insulin antidiabetic drugs (NIADs), and consequently to variable plasma glucose control. Optimal control of plasma glucose is paramount to minimizing type 2 diabetes-related long-term complications. India’s distinct genetic architecture and its exploding burden of type 2 diabetes warrants a population-specific survey of NIAD-associated pharmacogenetic (PGx) variants. The recent availability of large-scale whole genomes from the Indian population provides a unique opportunity to generate a population-specific map of NIAD-associated PGx variants.Research design and methods We mined 1029 Indian whole genomes for PGx variants, drug–drug interaction (DDI) and drug–drug–gene interactions (DDGI) associated with 44 NIADs. Population-wise allele frequencies were estimated and compared using Fisher’s exact test.Results Overall, we found 76 known and 52 predicted deleterious common PGx variants associated with response to type 2 diabetes therapy among Indians. We report remarkable interethnic differences in the relative cumulative counts of decreased and increased response-associated alleles across NIAD classes. Indians and South Asians showed a significant excess of decreased metformin response-associated alleles compared with other global populations. Network analysis of shared PGx genes predicts high DDI risk during coadministration of NIADs with other metabolic disease drugs. We also predict an increased CYP2C19-mediated DDGI risk for CYP3A4/3A5-metabolized NIADs, saxagliptin, linagliptin and glyburide when coadministered with proton-pump inhibitors (PPIs).Conclusions Indians and South Asians have a distinct PGx profile for antidiabetes drugs, marked by an excess of poor treatment response-associated alleles for various NIAD classes. This suggests the possibility of a population-specific reduced drug response in atleast some NIADs. In addition, our findings provide an actionable resource for accelerating future diabetes PGx studies in Indians and South Asians and reconsidering NIAD dosing guidelines to ensure maximum efficacy and safety in the population

The genomic landscape of CYP2D6 variation in the Indian population

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Genomic survey of SARS-CoV-2 vaccine breakthrough infections in healthcare workers from Kerala, India

We describe genomic analysis of SARS-CoV-2 isolates from breakthrough infections in six healthcare workers following vaccination with AZD1222/Covishield. Four patients were infected by the variant of concern B.1.1.7 while other isolates possessed E484K and S477N mutations in spike protein associated with immune escape