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  1. Article ; Online: A meta-analysis of genome-wide association studies of childhood wheezing phenotypes identifies ANXA1 as a susceptibility locus for persistent wheezing

    Raquel Granell / John A Curtin / Sadia Haider / Negusse Tadesse Kitaba / Sara A Mathie / Lisa G Gregory / Laura L Yates / Mauro Tutino / Jenny Hankinson / Mauro Perretti / Judith M Vonk / Hasan S Arshad / Paul Cullinan / Sara Fontanella / Graham C Roberts / Gerard H Koppelman / Angela Simpson / Steve W Turner / Clare S Murray /
    Clare M Lloyd / John W Holloway / Adnan Custovic

    eLife, Vol

    2023  Volume 12

    Abstract: Background: Many genes associated with asthma explain only a fraction of its heritability. Most genome-wide association studies (GWASs) used a broad definition of ‘doctor-diagnosed asthma’, thereby diluting genetic signals by not considering asthma ... ...

    Abstract Background: Many genes associated with asthma explain only a fraction of its heritability. Most genome-wide association studies (GWASs) used a broad definition of ‘doctor-diagnosed asthma’, thereby diluting genetic signals by not considering asthma heterogeneity. The objective of our study was to identify genetic associates of childhood wheezing phenotypes. Methods: We conducted a novel multivariate GWAS meta-analysis of wheezing phenotypes jointly derived using unbiased analysis of data collected from birth to 18 years in 9568 individuals from five UK birth cohorts. Results: Forty-four independent SNPs were associated with early-onset persistent, 25 with pre-school remitting, 33 with mid-childhood remitting, and 32 with late-onset wheeze. We identified a novel locus on chr9q21.13 (close to annexin 1 [ANXA1], p<6.7 × 10-9), associated exclusively with early-onset persistent wheeze. We identified rs75260654 as the most likely causative single nucleotide polymorphism (SNP) using Promoter Capture Hi-C loops, and then showed that the risk allele (T) confers a reduction in ANXA1 expression. Finally, in a murine model of house dust mite (HDM)-induced allergic airway disease, we demonstrated that anxa1 protein expression increased and anxa1 mRNA was significantly induced in lung tissue following HDM exposure. Using anxa1-/- deficient mice, we showed that loss of anxa1 results in heightened airway hyperreactivity and Th2 inflammation upon allergen challenge. Conclusions: Targeting this pathway in persistent disease may represent an exciting therapeutic prospect. Funding: UK Medical Research Council Programme Grant MR/S025340/1 and the Wellcome Trust Strategic Award (108818/15/Z) provided most of the funding for this study.
    Keywords GWAS ; ALSPAC ; wheezing phenotypes ; meta-analysis ; MAAS ; ANXA1 ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 616
    Language English
    Publishing date 2023-05-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: A polymorphism in gasdermin B (GSDMB) gene is associated with severe asthma exacerbations in childhood

    Aida Semic-Jusufagic / Angela Simpson / Jenny Hankinson / Adnan Custovic

    Acta Medica Academica, Vol 40, Iss 2, Pp 110-

    A population-based birth cohort study

    2011  Volume 121

    Abstract: Rationale. Markers on chromosome 17q12 have been associated withchildhood asthma in genome-wide association studies. Objective.We investigated the association of a single nucleotide polymorphism(SNP) in GSDMB (rs7216389) on 17q12 with asthma presence ... ...

    Abstract Rationale. Markers on chromosome 17q12 have been associated withchildhood asthma in genome-wide association studies. Objective.We investigated the association of a single nucleotide polymorphism(SNP) in GSDMB (rs7216389) on 17q12 with asthma presence andseverity in a population-based birth cohort study. Methods. Childrenwere followed from birth to age 8 years. Data on parentally-reportedsymptoms were collected using an interviewer-administered questionnaire at age 1, 3, 5 and 8 years. Atopy was assessed by skin testing at age 3, 5 and 8 years. Information on asthma/wheeze hospital admissions and severe asthma exacerbations was collected from child’s primary care medical record. Data were analyzed as a recessive genetic model, with T-allele homozygotes as the risk group. Results. Compared to C allele carriers, T-allele homozygotes of rs7216389 were significantly more likely to: wheeze at age 3, 5 and 8 years; have persistent wheeze (OR 1.69, 95% CI 1.05-2.71, p=0.03); have frequent episodes of wheezing and be on asthma medication. In a multiple logistic regression model adjusted for gender, atopic sensitisation and maternal smoking, T allele homozygotes were significantly more likely to be hospitalized (aOR 2.20 [1.22-3.99], p=0.0009) with Cox regression hazard ratio for T-allele homozygotes of 1.94 [1.13-3.33], p=0.016. Results of Cox regression analysis investigating the eff ect of genotype on the age of first severe exacerbation of asthma indicated an overall hazard ratio of severe asthma exacerbation among T-allele homozygotes of 1.53 [1.04-2.27], p=0.03. Conclusions. Th is is the fi rst population-based birth cohort study to confirm that the risk of childhood wheeze and severe asthma/wheeze exacerbations is increased among rs7216389 TT homozygotes.
    Keywords Childhood asthma ; Genetics ; rs7216389 ; GSDMB ; ORMDL3 ; Medicine (General) ; R5-920
    Language English
    Publishing date 2011-11-01T00:00:00Z
    Publisher Academy of Sciences and Arts of Bosnia and Herzegovina
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Mapping DNA interaction landscapes in psoriasis susceptibility loci highlights KLF4 as a target gene in 9q31

    Helen Ray-Jones / Kate Duffus / Amanda McGovern / Paul Martin / Chenfu Shi / Jenny Hankinson / Oliver Gough / Annie Yarwood / Andrew P. Morris / Antony Adamson / Christopher Taylor / James Ding / Vasanthi Priyadarshini Gaddi / Yao Fu / Patrick Gaffney / Gisela Orozco / Richard B. Warren / Steve Eyre

    BMC Biology, Vol 18, Iss 1, Pp 1-

    2020  Volume 20

    Abstract: Abstract Background Genome-wide association studies (GWAS) have uncovered many genetic risk loci for psoriasis, yet many remain uncharacterised in terms of the causal gene and their biological mechanism in disease. This is largely a result of the ... ...

    Abstract Abstract Background Genome-wide association studies (GWAS) have uncovered many genetic risk loci for psoriasis, yet many remain uncharacterised in terms of the causal gene and their biological mechanism in disease. This is largely a result of the findings that over 90% of GWAS variants map outside of protein-coding DNA and instead are enriched in cell type- and stimulation-specific gene regulatory regions. Results Here, we use a disease-focused Capture Hi-C (CHi-C) experiment to link psoriasis-associated variants with their target genes in psoriasis-relevant cell lines (HaCaT keratinocytes and My-La CD8+ T cells). We confirm previously assigned genes, suggest novel candidates and provide evidence for complexity at psoriasis GWAS loci. For one locus, uniquely, we combine further epigenomic evidence to demonstrate how a psoriasis-associated region forms a functional interaction with the distant (> 500 kb) KLF4 gene. This interaction occurs between the gene and active enhancers in HaCaT cells, but not in My-La cells. We go on to investigate this long-distance interaction further with Cas9 fusion protein-mediated chromatin modification (CRISPR activation) coupled with RNA-seq, demonstrating how activation of the psoriasis-associated enhancer upregulates KLF4 and its downstream targets, relevant to skin cells and apoptosis. Conclusions This approach utilises multiple functional genomic techniques to follow up GWAS-associated variants implicating relevant cell types and causal genes in each locus; these are vital next steps for the translation of genetic findings into clinical benefit.
    Keywords Psoriasis ; Chromatin ; GWAS ; CHi-C ; HiChIP ; CRISPR ; Biology (General) ; QH301-705.5
    Subject code 612
    Language English
    Publishing date 2020-05-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Gene-environment interaction in the onset of eczema in infancy

    Hans Bisgaard / Angela Simpson / Colin N A Palmer / Klaus Bønnelykke / Irwin McLean / Somnath Mukhopadhyay / Christian B Pipper / Liselotte B Halkjaer / Brian Lipworth / Jenny Hankinson / Ashley Woodcock / Adnan Custovic

    PLoS Medicine, Vol 5, Iss 6, p e

    filaggrin loss-of-function mutations enhanced by neonatal cat exposure.

    2008  Volume 131

    Abstract: Background Loss-of-function variants in the gene encoding filaggrin (FLG) are major determinants of eczema. We hypothesized that weakening of the physical barrier in FLG-deficient individuals may potentiate the effect of environmental exposures. ... ...

    Abstract Background Loss-of-function variants in the gene encoding filaggrin (FLG) are major determinants of eczema. We hypothesized that weakening of the physical barrier in FLG-deficient individuals may potentiate the effect of environmental exposures. Therefore, we investigated whether there is an interaction between FLG loss-of-function mutations with environmental exposures (pets and dust mites) in relation to the development of eczema. Methods and findings We used data obtained in early life in a high-risk birth cohort in Denmark and replicated the findings in an unselected birth cohort in the United Kingdom. Primary outcome was age of onset of eczema; environmental exposures included pet ownership and mite and pet allergen levels. In Copenhagen (n = 379), FLG mutation increased the risk of eczema during the first year of life (hazard ratio [HR] 2.26, 95% confidence interval [CI] 1.27-4.00, p = 0.005), with a further increase in risk related to cat exposure at birth amongst children with FLG mutation (HR 11.11, 95% CI 3.79-32.60, p < 0.0001); dog exposure was moderately protective (HR 0.49, 95% CI 0.24-1.01, p = 0.05), but not related to FLG genotype. In Manchester (n = 503) an independent and significant association of the development of eczema by age 12 mo with FLG genotype was confirmed (HR 1.95, 95% CI 1.13-3.36, p = 0.02). In addition, the risk increased because of the interaction of cat ownership at birth and FLG genotype (HR 3.82, 95% CI 1.35-10.81, p = 0.01), with no significant effect of the interaction with dog ownership (HR 0.59, 95% CI 0.16-2.20, p = 0.43). Mite-allergen had no effects in either cohort. The observed effects were independent of sensitisation. Conclusions We have demonstrated a significant interaction between FLG loss-of-function main mutations (501x and 2282del4) and cat ownership at birth on the development of early-life eczema in two independent birth cohorts. Our data suggest that cat but not dog ownership substantially increases the risk of eczema within the first year of life in ...
    Keywords Medicine ; R
    Language English
    Publishing date 2008-06-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

    Your chosen title can be delivered directly to ZB MED Cologne location if you are registered as a user at ZB MED Cologne.

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