1,720,975 research outputs found
Exome-wide association studies on familial and sporadic eosinophilic granulomatosis with polyangiitis
No full textEosinophilic granulomatosis with polyangiitis (EGPA), formerly known as Churg-Strauss syndrome, is a rare complex systemic disease. Together with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), EGPA belongs to the anti neutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitis (AAV). AAVs are characterised by inflammation of blood vessels, tissue damage and development of ANCA autoantibodies, targeting proteinase 3 (PR3) and myeloperoxidase (MPO) proteins. Despite being considered part of the ANCA-associated vasculitis syndromes, EGPA has a small overlap with GPA and MPA and shows unique features, such as severe asthma and high eosinophil levels. Moreover, the majority of affected individuals shows negativity toward ANCA, with just a discrete number of patients presenting an association with MPO-ANCA.
Currently, the causes of AAV are far from clear, with particular regards for EGPA. A growing number of studies has proposed multiple factors which may trigger these diseases, being either genetic or environmental. To date, three genome-wide association studies (GWAS) have identified possible candidate genes associated with GPA and MPA. However, only a single GWAS was performed on EGPA; this study identified 11 candidate loci: the strongest associations resulted in the major histocompatibility complex (MHC) region, on the human leukocyte antigen (HLA) gene.
The main focus of this thesis is to investigate the genetics of 79 EGPA-affected individuals, comprising 5 families presenting 2 affected individuals each as well as unrelated EGPA-affected individuals, belonging to an Italian cohort of AAV-affected patients who have been sequenced by whole exome sequencing (WES) technology.
The five families presenting EGPA-affected individuals were analysed to identify heritable pathogenic variants associated with EGPA, being single nucleotide polymorphisms, small insertions and deletions, and copy number variations. Genomic investigation resulted in a total of 8 candidate genes carrying likely causative variants.
The sporadic individuals underwent the first genotype imputation-empowered exome-wide association study (ExWAS) on EGPA. The ExWAS resulted in a total of 11 EGPA-associated loci, showing specificity for MPO-ANCA-positive and ANCA-negative EGPA as well as a common set of gene independent from the ANCA status.
Nowadays, genotype imputation is widely used in genomic analyses. However, it is rarely employed on sequencing data, particularly in whole exome sequencing. Hence, the research work presented in this dissertation is preceded by a performance analysis of genotype imputation on in silico WES data from the 1000 Genomes Project, which showed successful results.
EGPA largely remains an enigmatic disease, which shows to have features of both a vasculitis and an eosinophilic disease. This dissertation suggested novel candidate genes likely to be associated with EGPA, confirming pathophysiological pathways related to inflammation, immunity and eosinophilia, as well as proposing novel processes likely to be involved in EGPA onset and development. Genomic and multi-omic research will boost the current understanding of EGPA and in general AAV: the discovery of possible therapeutic targets and the development of novel clinical interventions will largely benefit from the identification of the genetic factors associated with EGPA
Start 2024 by asking: 'Why do science?'
No full textStep back from the usual lab-meeting format, and ask yourself and your colleagues why you all do what you do, say Mirko Treccani and Laura Veschetti
The BioVRPi project: a valuable and sustainable alternative for genomic analysis
Full text linkSince 2012, the Raspberry Pi Foundation has started developing pocket-sized and low-cost devices, originally meant to teach computer science in developing Countries. Its growing interest and constant improvement led Raspberry Pi devices to find different applications and to suit the needs of various research areas. In the previous years, different researchers already reported applications of Raspberry Pi devices in bioinformatics, such as basic train- ing and proteomics. In the beginning of 2021, we gave birth to BioVRPi, a project which aims to develop and offer a low-cost and stable bioinformatic environment for students and re- searchers involved in the genomics and transcriptomics fields. We evaluated performances and software compatibilities of different scenarios, focusing on Genome-Wide Association Studies for complex traits in Homo sapiens, transcriptomic analyses on RNA-seq data from Strongyloides stercoralis samples and alignment of small organisms, such as SARS-CoV-2 (virus), Escherichia Coli (bacterium) and Caenorhabditis elegans (nematode). Results from both the bioinformatic and benchmarking analyses showed that Raspberry Pi devices are capable of accomplishing different bioinformatic tasks in terms of results and performances. Moreover, they proved to be a valuable low-cost and sustainable alternative, in accordance with the United Nation 2030 Agenda, to answer the needs and the challenges of the current socio-economic situation
The Interplay between Microbiota and Human Complex Traits
Full text linkMicroorganisms have been one of the most influential drivers propelling some of the greatest environmental and evolutionary changes in the landscape and biology of the entire planet [...]
A broad overview of genotype imputation: Standard guidelines, approaches, and future investigations in genomic association studies
Full text linkThe advent of genomic big data and the statistical need for reaching significant results have led genome-wide association studies to be ravenous of a huge number of genetic markers scattered along the whole genome. Since its very beginning, the so-called genotype imputation served this purpose; this statistical and inferential procedure based on a known reference panel opened the theoretical possibility to extend association analyses to a greater number of polymorphic sites which have not been previously assayed by the used technology. In this review, we present a broad overview of the genotype imputation process, showing the most known methods and presenting the main areas of interest, with a closer look to the most up-to-date approaches and a deeper understanding of its usage in the present-day genomic landscape, shedding a light on its future developments and investigation areas
Genomic Instability Evolutionary Footprints on Human Health: Driving Forces or Side Effects?
Full text linkIn this work, we propose a comprehensive perspective on genomic instability comprising not only the accumulation of mutations but also telomeric shortening, epigenetic alterations and other mechanisms that could contribute to genomic information conservation or corruption. First, we present mechanisms playing a role in genomic instability across the kingdoms of life. Then, we explore the impact of genomic instability on the human being across its evolutionary history and on present-day human health, with a particular focus on aging and complex disorders. Finally, we discuss the role of non-coding RNAs, highlighting future approaches for a better living and an expanded healthy lifespan
Correction: Concordance study on Y-STRs typing between SeqStudioTM genetic analyzer for HID and MiSeqTM FGx forensic genomics system
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A computational reference for human genomics analysis in (poly)phenol research
No full text: (Poly)phenols are bioactive compounds found in plant-based food. They have been associated with numerous health-promoting features. To date, several research studies are investigating their contribution to human health and disease by applying different omics techniques. However, a standard reference for human genomics investigation is missing, limiting the current understanding and knowledge on the impact of (poly)phenols on humans when using omics approaches. In this study, we present a computational functional investigation of 121 candidate human genes involved in (poly)phenol absorption, distribution, metabolism, and excretion to propose a standard reference for genomics analyses in personalised nutrition and health research. Starting from genomics information, this reference framework includes gene networks, exploring their functional consequences and favouring the understanding of protein-protein interactions, thus paving the way for future multi-omics approaches
Genetic and Non-Genetic Contributions to Eosinophilic Granulomatosis with Polyangiitis: Current Knowledge and Future Perspectives
Full text linkIn this work, we present a comprehensive overview of the genetic and non-genetic complexity of eosinophilic granulomatosis with polyangiitis (EGPA). EGPA is a rare complex systemic disease that occurs in people presenting with severe asthma and high eosinophilia. After briefly introducing EGPA and its relationship with the anti-neutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitis (AAVs), we delve into the complexity of this disease. At first, the two main biological actors, ANCA and eosinophils, are presented. Biological and clinical phenotypes related to ANCA positivity or negativity are explained, as well as the role of eosinophils and their pathological subtypes, pointing out their intricate relations with EGPA. Then, the genetics of EGPA are described, providing an overview of the research effort to unravel them. Candidate gene studies have investigated biologically relevant candidate genes; the more recent genome-wide association studies and meta-analyses, able to analyze the whole genome, have confirmed previous associations and discovered novel risk loci; in the end, family-based studies have dissected the contribution of rare variants and the heritability of EGPA. Then, we briefly present the environmental contribution to EGPA, reporting seasonal events and pollutants as triggering factors. In the end, the latest omic research is discussed and the most recent epigenomic, transcriptomic and microbiome studies are presented, highlighting the current challenges, open questions and suggesting approaches to unraveling this complex disease
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