Comprehensive functional annotation of susceptibility variants associated with asthma

Gautam, Yadu; Afanador, Yashira; Ghandikota, Sudhir; Mersha, Tesfaye B.

doi:10.1007/s00439-020-02151-5

Cited by 15 publications

(11 citation statements)

References 61 publications

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“…Studies of GWAS data combined with functional annotations and quantitative trait loci (QTL) have sought to strengthen their context-specific relevance. In addition to replicating previously known loci, new candidate genes including DGKQ, SLC26A1 , and IDUA genes, as well as variants of genes encoding transcription factors like NF-KB , cJUN , STAT family, ERG1 , ELF1 , EBF1 , and the GATA family have been identified ( 32 – 35 ). Atopy-associated GWAS have identified multiple relevant biological pathways, including autoimmune and inflammatory response pathways, thereby providing insights into the underlying heritable risk ( 31 , 36 ).…”

Section: Gwas Discovery Of Asthma Associated Genetic Linkagesmentioning

confidence: 90%

“…Atopy-associated GWAS have identified multiple relevant biological pathways, including autoimmune and inflammatory response pathways, thereby providing insights into the underlying heritable risk ( 31 , 36 ). Interestingly, asthma-risk variants identified in several studies have been mapped to 17q12-21 locus, including ORMDL3, GSDML , and CDHR3 genes ( 35 , 37 – 41 ) and have yielded several functional validations ( 42 – 44 ). In addition, variants of the TSLP gene, a cytokine secreted by epithelial cells that initiates allergic inflammation ( 45 ) have been replicated in several studies suggesting that this could be a potentially critical target for drug development ( 5 , 35 , 46 , 47 ).…”

Section: Gwas Discovery Of Asthma Associated Genetic Linkagesmentioning

confidence: 99%

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Asthma and the Missing Heritability Problem: Necessity for Multiomics Approaches in Determining Accurate Risk Profiles

et al. 2022

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Asthma is ranked among the most common chronic conditions and has become a significant public health issue due to the recent and rapid increase in its prevalence. Investigations into the underlying genetic factors predict a heritable component for its incidence, estimated between 35% and 90% of causation. Despite the application of large-scale genome-wide association studies (GWAS) and admixture mapping approaches, the proportion of variants identified accounts for less than 15% of the observed heritability of the disease. The discrepancy between the predicted heritable component of disease and the proportion of heritability mapped to the currently identified susceptibility loci has been termed the ‘missing heritability problem.’ Here, we examine recent studies involving both the analysis of genetically encoded features that contribute to asthma and also the role of non-encoded heritable characteristics, including epigenetic, environmental, and developmental aspects of disease. The importance of vertical maternal microbiome transfer and the influence of maternal immune factors on fetal conditioning in the inheritance of disease are also discussed. In order to highlight the broad array of biological inputs that contribute to the sum of heritable risk factors associated with allergic disease incidence that, together, contribute to the induction of a pro-atopic state. Currently, there is a need to develop in-depth models of asthma risk factors to overcome the limitations encountered in the interpretation of GWAS results in isolation, which have resulted in the missing heritability problem. Hence, multiomics analyses need to be established considering genetic, epigenetic, and functional data to create a true systems biology-based approach for analyzing the regulatory pathways that underlie the inheritance of asthma and to develop accurate risk profiles for disease.

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Section: Gwas Discovery Of Asthma Associated Genetic Linkagesmentioning

confidence: 90%

Section: Gwas Discovery Of Asthma Associated Genetic Linkagesmentioning

confidence: 99%

Asthma and the Missing Heritability Problem: Necessity for Multiomics Approaches in Determining Accurate Risk Profiles

et al. 2022

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“…In the last decade, several genome-wide association studies (GWAS) have identified numerous genetic variants responsible for asthma susceptibility [ 2 ]. These mainly non-coding variants play a regulatory role in gene expression and asthma heritability [ 3 ]. Despite these results, genetics could not fully explain asthma development and are of limited value.…”

Section: Introductionmentioning

confidence: 99%

Genetics and Epigenetics in Asthma

Ntontsi

Photiades

Ζervas

et al. 2021

IJMS

104

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Asthma is one of the most common respiratory disease that affects both children and adults worldwide, with diverse phenotypes and underlying pathogenetic mechanisms poorly understood. As technology in genome sequencing progressed, scientific efforts were made to explain and predict asthma’s complexity and heterogeneity, and genome-wide association studies (GWAS) quickly became the preferred study method. Several gene markers and loci associated with asthma susceptibility, atopic and childhood-onset asthma were identified during the last few decades. Markers near the ORMDL3/GSDMB genes were associated with childhood-onset asthma, interleukin (IL)33 and IL1RL1 SNPs were associated with atopic asthma, and the Thymic Stromal Lymphopoietin (TSLP) gene was identified as protective against the risk to TH2-asthma. The latest efforts and advances in identifying and decoding asthma susceptibility are focused on epigenetics, heritable characteristics that affect gene expression without altering DNA sequence, with DNA methylation being the most described mechanism. Other less studied epigenetic mechanisms include histone modifications and alterations of miR expression. Recent findings suggest that the DNA methylation pattern is tissue and cell-specific. Several studies attempt to describe DNA methylation of different types of cells and tissues of asthmatic patients that regulate airway remodeling, phagocytosis, and other lung functions in asthma. In this review, we attempt to briefly present the latest advancements in the field of genetics and mainly epigenetics concerning asthma susceptibility.

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“…Gene expression plays a pivotal role in controlling various cellular functions, including cellular growth, differentiation, inflammation, cell death, and immune function. Gene expression studies of asthmatic people have provided evidence that transcriptomic changes are crucial to initiating or promoting the cascade of immune reactions [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Identification of miRNA–mRNA–TFs regulatory network and crucial pathways involved in asthma through advanced systems biology approaches

Shaik

Nasser²,

Mohammed³

et al. 2022

PLoS ONE

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Asthma is a life-threatening and chronic inflammatory lung disease that is posing a true global health challenge. The genetic basis of the disease is fairly well examined. However, the molecular crosstalk between microRNAs (miRNAs), target genes, and transcription factors (TFs) networks and their contribution to disease pathogenesis and progression is not well explored. Therefore, this study was aimed at dissecting the molecular network between mRNAs, miRNAs, and TFs using robust computational biology approaches. The transcriptomic data of bronchial epithelial cells of severe asthma patients and healthy controls was studied by different systems biology approaches like differentially expressed gene detection, functional enrichment, miRNA-target gene pairing, and mRNA-miRNA-TF molecular networking. We detected the differential expression of 1703 (673 up-and 1030 down-regulated) genes and 71 (41 up-and 30 down-regulated) miRNAs in the bronchial epithelial cells of asthma patients. The DEGs were found to be enriched in key pathways like IL-17 signaling (KEGG: 04657), Th1 and Th2 cell differentiation (KEGG: 04658), and the Th17 cell differentiation (KEGG: 04659) (p-values = 0.001). The results from miRNAs-target gene pairs-transcription factors (TFs) have detected the key roles of 3 miRs (miR-181a-2-3p; miR-203a-3p; miR-335-5p), 6 TFs (TFAM, FOXO1, GFI1, IRF2, SOX9, and HLF) and 32 miRNA target genes in eliciting autoimmune reactions in bronchial epithelial cells of the respiratory tract. Through systemic implementation of comprehensive system biology tools, this study has identified key miRNAs, TFs, and miRNA target gene pairs as potential tissue-based asthma biomarkers.

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Comprehensive functional annotation of susceptibility variants associated with asthma

Cited by 15 publications

References 61 publications

Asthma and the Missing Heritability Problem: Necessity for Multiomics Approaches in Determining Accurate Risk Profiles

Asthma and the Missing Heritability Problem: Necessity for Multiomics Approaches in Determining Accurate Risk Profiles

Genetics and Epigenetics in Asthma

Identification of miRNA–mRNA–TFs regulatory network and crucial pathways involved in asthma through advanced systems biology approaches

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