Airway wall splice quantitative trait locus analysis reveals novel downstream mechanisms for known asthma single-nucleotide polymorphisms.
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ABSTRACT:
SUBMITTER: Kole TM
PROVIDER: S-EPMC10068516 | biostudies-literature | 2023 Mar
REPOSITORIES: biostudies-literature
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Airway wall splice quantitative trait locus analysis reveals novel downstream mechanisms for known asthma single-nucleotide polymorphisms.
Kole Tessa M TM Pouwels Simon D SD Bults Rene R Ketelaar Marlies E ME Guryev Victor V Koll Lisanne L Kerstjens Huib A M HAM Nawijn Martijn C MC Faiz Alen A van den Berge Maarten M
ERJ open research 20230301 2
<b>Studying the effects of asthma SNPs on alternative splicing can lead to new insights into asthma pathophysiology. More specifically, a 17q12 SNP is associated to alternative splicing of <i>GSDMB</i>.</b> https://bit.ly/3W49oTs. ...[more]
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Project description:BACKGROUND:Asthma is a chronic inflammatory disease of the airways with a complex genetic background. In this study, we carried out a meta-analysis of single nucleotide polymorphisms (SNPs) thought to be associated with asthma. METHODS:The literature (PubMed) was searched for SNPs within genes relevant in asthma. The SNP-modified genes were converted to corresponding proteins, and their protein-protein interactions were searched from six different databases. This interaction network was analyzed using annotated vocabularies (ontologies), such as the Gene Ontology and Nature pathway interaction databases. RESULTS:In total, 127 genes with SNPs related to asthma were found in the literature. The corresponding proteins were then entered into a large protein-protein interaction network with the help of various databases. Ninety-six SNP-related proteins had more than one interacting protein each, and a network containing 309 proteins and 644 connections was generated. This network was significantly enriched with a gene ontology entitled "protein binding" and several of its daughter categories, including receptor binding and cytokine binding, when compared with the background human proteome. In the detailed analysis, the chemokine network, including eight proteins and 13 toll-like receptors, were shown to interact with each other. Of great interest are the nonsynonymous SNPs which code for an alternative amino acid sequence of proteins and, of the toll-like receptor network, TLR1, TLR4, TLR5, TLR6, TLR10, IL4R, and IL13 are among these. CONCLUSIONS:Protein binding, toll-like receptors, and chemokines dominated in the asthma-related protein interaction network. Systems level analysis of allergy-related mutations can provide new insights into the pathogenetic mechanisms of disease.
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Project description:BackgroundAlternative splicing (AS) of mRNA plays an important roles in transcriptome diversity, involving regulation of plant growth and stress response. Understanding the variation of AS events underlying GWAS loci in a crop population can provide insight into the molecular mechanisms of complex agronomic traits. To date, genome-wide association studies relating AS events to agronomic traits have rarely been conducted at the population level in crops.ResultsHere, a pipeline was constructed to identify candidate AS events related to complex traits. Firstly, ovule transcriptome data were used to characterize intron retention (IR), the predominant type of AS in plants, on a genome-wide scale. This was done in a natural population consisting of 279 upland cotton lines. Secondly, splice quantitative trait locus (sQTL) analysis was carried out, which yielded a total of 2295 sQTLs involving 1607 genes. Of these, 14.25% (n = 427) were cis-regulatory loci. Integration with expression quantitative trait loci (eQTL) revealed that 53 (21.4%) cis-sGenes were regulated by both cis-sQTLs and cis-eQTLs. Finally, co-localization analysis integrated with GWAS loci in this population showed 32 cis-QTLs to be co-located with genetic regulatory loci related to fiber yield and quality traits, indicating that sQTLs are likely to participate in regulating cotton fiber yield and quality. An in-depth evaluation confirmed that differences in the IR rates of sQTL-regulated candidate genes such as GhLRRK1 and GhGC1 are associated with lint percentage (LP), which has potential in breeding applications.ConclusionThis study provides a clue that AS of mRNA has an impact on crop yield, along with functional sQTLs are new genetic resources for cotton precision breeding.
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Project description:RationaleT-bet (TBX21 or T-box 21) is a critical regulator of T-helper 1 lineage commitment and IFN-gamma production. Knockout mice lacking T-bet develop airway hyperresponsiveness (AHR) to methacholine, peribronchial eosinophilic and lymphocytic inflammation, and increased type III collagen deposition below the bronchial epithelium basement membrane, reminiscent of both acute and chronic asthma histopathology. Little is known regarding the role of genetic variation surrounding T-bet in the development of human AHR.ObjectivesTo assess the relationship between T-bet polymorphisms and asthma-related phenotypes using family-based association.MethodsSingle nucleotide polymorphism discovery was performed by resequencing the T-bet genomic locus in 30 individuals (including 22 patients with asthma). Sixteen variants were genotyped in 580 nuclear families ascertained through offspring with asthma from the Childhood Asthma Management Program clinical trial. Haplotype patterns were determined from this genotype data. Family-based tests of association were performed with asthma, AHR, lung function, total serum immunoglobulin E, and blood eosinophil levels.Main resultsWe identified 24 variants. Evidence of association was observed between c.-7947 and asthma in white families using both additive (p = 0.02) or dominant models (p = 0.006). c.-7947 and three other variants were also associated with AHR (log-methacholine PC(20), p = 0.02-0.04). Haplotype analysis suggested that an AHR locus is in linkage disequilibrium with variants in the 3'UTR. Evidence of association of AHR with c.-7947, but not with other 3'UTR SNPs, was replicated in an independent cohort of adult males with AHR.ConclusionsThese data suggest that T-bet variation contributes to airway responsiveness in asthma.
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Project description:BackgroundAsthma is a frequent chronic disease of the airways. In spite of the fact that symptoms of asthma are well known, the pathogenesis has not yet been fully understood. Quantitative computed tomography (qCT) of the lung allows for the measurment of a set of parameters. The aim of this study was to evaluate the usefulness of quantitative computed tomography in the assessment of airway wall thickness in asthma.MethodsThe prospective study was performed on a group of 83 patients with well-defined, long-term asthma between 2016 and 2018. The control group was composed of 30 healthy volunteers. All examined subjects were non-smokers. All computed tomography (CT) studies were performed using a 128 multi-slice CT scanner with no contrast, following a chest scanning protocol in the supine position, at full inspiration and breath-holds.ResultsQuantitative bronchial tree measurements were obtained from the third up to the ninth generation of the posterior basal bronchi (B10) of the right lung in a blinded fashion. The value of the wall thickness in patients with asthma was significantly higher in all measured generations of the bronchial tree (third to ninth generation). The lumen area and the inner diameter significantly correlated with the lung function tests and were substantially smaller in the examined group from the seventh to the ninth generation of the bronchi (p < 0.05).ConclusionsWe conclude that airway remodelling occurs in most patients with long-term asthma and is associated mainly with the medium and small airways. Imaging techniques, especially qCT can be useful in the diagnosis and management of asthma. The reviews of this paper are available via the supplemental material section.
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Project description:Recent literature has reported a higher occurrence of cognitive impairment among individuals with Age-related Macular Degeneration (AMD) compared to older adults with normal vision. This pilot study explored potential links between single nucleotide polymorphisms (SNPs) in AMD and cognitive status. Individuals with AMD (N = 21) and controls (N = 18) were genotyped for the SNPs CFHY402H, ARMS2A69S and FADS1 rs174547. Cognitive status was evaluated using the Montreal Cognitive Assessment. The two groups differed significantly on which subscales were most difficult. The control group had difficulty with delayed recall while those with AMD had difficulty on delayed recall in addition to abstraction and orientation. Homozygous carriers of the FADS1 rs174547 SNP had significantly lower scores than heterozygotes or non-carriers on the MoCA. The results suggest that the FADS1 SNP may play a role in visual impairment/cognitive impairment comorbidity as reflected in the poorer cognitive scores among homozygotes with AMD compared to those carrying only one, or no copies of the SNP.
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