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Biomedical subjects

John W Holloway

Publications and source records attributed to John W Holloway.

At least 19 recordsLinked to original sources
PubMed2026

Genome-wide association study of asthma with high treatment burden and/or worse outcomes defined using electronic healthcare data in UK Biobank.

BACKGROUND: In ∼10% of asthma patients, symptoms remain uncontrolled despite maximal treatment, representing an unmet clinical need. The causal variants, genes and pathways underlying genetic risk factors have not been fully elucidated, and it is unclear whether there are unique genetic risk factors for this asthma subtype. METHODS: We used electronic healthcare records linked to UK Biobank to identify asthma patients with high treatment burden and/or worse outcomes. We performed a genome-wide association study (GWAS) with this case population and healthy controls. We sought replication for associated (p≤5×10-6) signals in four independent studies (12 152 cases and 32 316 controls). Replicated signals were fine-mapped and linked to genes and pathways. RESULTS: In total, 7681 participants met our case definition and showed enrichment for adult-onset asthma, female gender and higher body mass index compared to asthma individuals not meeting case criteria. GWAS with 7681 cases and 38 405 controls revealed 21 reproducible association signals that had previously been associated with asthma, but had a larger effect size in our study. Variant-to-gene mapping highlighted 85 candidate genes, five of which were considered high confidence (BACH2, D2HGDH, IL1RL1, RPS26, SMAD3). CONCLUSION: We present the first use of electronic healthcare records in UK Biobank to identify a subtype of asthma enriched for patients with high treatment burden and/or worse outcomes. Our findings support the role of known asthma genes, highlighting genetic risk variants with stronger effect in these groups of patients. The prioritised genes provide potential therapeutic opportunities for this difficult-to-treat patient population.

Journal Article↗
PubMed2025

Gene-environment interaction analysis in atopic eczema: evidence from large population datasets and modelling in vitro.

BACKGROUND: Environmental factors play a role in the pathogenesis of complex traits including atopic eczema (AE) and a greater understanding of gene-environment interactions (G*E) is needed to define pathomechanisms for disease prevention. We analysed data from 16 European studies to test for interaction between the 24 most significant AE-associated loci identified from genome-wide association studies and 18 early-life environmental factors. We tested for replication using a further 10 studies and in vitro modelling to independently assess findings. RESULTS: The discovery analysis showed suggestive evidence for interaction (p<0.05) between 7 environmental factors (antibiotic use, cat ownership, dog ownership, breastfeeding, elder sibling, smoking and washing practices) and at least one established variant for AE, 14 interactions in total (maxN=25,339). In replication analysis (maxN=252,040) dog exposure*rs10214237 (on chromosome 5p13.2 near IL7R) was nominally significant (ORinteraction=0.91 [0.83-0.99] P=0.025), with a risk effect of the T allele observed only in those not exposed to dogs. A similar interaction with rs10214237 was observed for siblings in the discovery analysis (ORinteraction=0.84[0.75-0.94] P=0.003), but replication analysis was under-powered ORinteraction=1.09[0.82-1.46]). Rs10214237 homozygous risk genotype is associated with lower IL-7R expression in human keratinocytes, and dog exposure modelled in vitro showed a differential response according to rs10214237 genotype. CONCLUSIONS: Interaction analysis and functional assessment provide evidence that early-life dog exposure may modify the genetic effect of rs10214237 on AE via IL7R, supporting observational epidemiology showing a protective effect for dog ownership. The lack of evidence for other G*E studied here implies that only weak effects are likely to occur.

Atopic eczema↗
PubMed2007

Gene-environmental interaction in asthma.

PURPOSE OF REVIEW: Asthma is likely to result from the effects of environmental stimuli in genetically susceptible individuals. This review summarizes recent studies of gene-environmental interaction in the pathogenesis of asthma, focusing on study designs. RECENT FINDINGS: Studies using genetic epidemiology, in-vitro and ex-vivo models and in-vivo model organisms demonstrate that gene-environmental interaction in involved in the development of asthma. Genetic association studies show a reduced risk of asthma and atopy with early life exposure to farming environments and house dust endotoxin, and increased risk with environmental tobacco smoke. These associations are modified by CD14 genotype. In people with a specific genotype, high environmental exposure may have the opposite effect of low exposure, possibly explaining some of the inconsistencies in previous studies. In-vitro and ex-vivo cell culture experiments show gene-environmental interactions with Toll-like receptor agonists, viruses and tobacco smoke. Interactions between innate immunity genes and exposure to endotoxin and air pollution have been observed in in-vivo mouse models. SUMMARY: The expanding evidence for gene-environmental interaction in asthma indicates the importance of measuring environmental factors in genetic studies of asthma. Understanding gene-environmental interaction would facilitate risk prognostication, improve preventive strategies and develop targeted interventions in people with asthma.

Animals↗
PubMed2007

Identifying novel genes contributing to asthma pathogenesis.

PURPOSE OF REVIEW: To illustrate recent examples of novel asthma genes such as those encoding G-protein-coupled receptor for asthma susceptibility, filaggrin and tenascin-C, and to describe the process that is needed to translate these findings to the clinic. RECENT FINDINGS: Many hundreds of studies have been published investigating the association of genetic polymorphisms in candidate genes with asthma. These genes were selected on the basis of the gene's product known involvement in the disease process. Moreover, it is the identification of novel genes through hypothesis-independent approaches such as genome-wide linkage studies that is likely to radically alter our understanding of asthma pathophysiology. The identification of a gene is, however, only the first step in a long process that may eventually lead from gene to treatment. This process includes replication, functional studies and, finally, intervention studies. SUMMARY: While significant progress has been made in the identification of asthma susceptibility genes, it is clear that issues such as replication and functional characterization mean that considerably more research is required. This may enable us to realize benefits to patient treatment that studies of the genetic basis of asthma have the potential to deliver.

Animals↗
PubMed2006

IL-13 receptor alpha 2: a regulator of IL-13 and IL-4 signal transduction in primary human fibroblasts.

BACKGROUND: IL-13 and IL-4 share many functional properties as a result of their use of a common receptor complex comprising IL-13 receptor alpha 1 (IL-13Ralpha1) and IL-4 receptor alpha (IL-4Ralpha). The nonsignaling receptor IL-13 receptor alpha 2 (IL-13Ralpha2) binds IL-13 with high affinity and specificity and is believed to be a decoy receptor for IL-13. OBJECTIVE: We sought to examine the inhibitory effects of soluble and membrane-bound IL-13Ralpha2 on IL-13- and IL-4-mediated effects. METHODS: Primary human fibroblasts were grown from endobronchial biopsy specimens obtained from volunteers. Upregulation of IL-13Ralpha2 mRNA was measured by means of RT-PCR, and the level of surface expression was measured by means of FACS. RESULTS: We found that a recombinant soluble form of IL-13Ralpha2 blocked the effects of IL-13, but not IL-4, in fibroblasts in vitro. However, we found that the transmembrane form of IL-13Ralpha2 could attenuate both IL-13 and IL-4 responses, even though the response to TNF-alpha was unaffected. Furthermore, we found that IL-13Ralpha2 became associated with IL-4Ralpha in the presence of IL-4. Addition of a blocking antibody to the extracellular domain of IL-13Ralpha2 restored responses of both IL-13 and IL-4. CONCLUSION: The ability of IL-13Ralpha2 to regulate IL-4 was previously unrecognized in primary airway cells. These data reveal a novel role for IL-13Ralpha2 as a negative regulator of both IL-13 and IL-4 signaling in human bronchial fibroblasts. CLINICAL IMPLICATIONS: It appears that IL-13Ralpha2 might be a powerful suppressor of TH2-mediated responses and thus represents a potential therapeutic target for the treatment of asthma.

Bronchi↗
PubMed2006

Association between a TGFbeta1 promoter polymorphism and rhinosinusitis in aspirin-intolerant asthmatic patients.

BACKGROUND: Rhinosinusitis is highly associated with aspirin-intolerant asthma (AIA). The risk of aspirin intolerance is higher in people with rhinosinusitis than in those without it. Recently, the role of transforming growth factor beta1 (TGFbeta1) in the pathogenesis of chronic rhinosinusitis has come under investigation. The goal of this study was to evaluate the association of TGFbeta1 gene polymorphism with an AIA phenotype in the Korean population. METHODS: A promoter polymorphism of the TGFbeta1 gene, TGFbeta1-509C>T, and a coding polymorphism (L10P), were genotyped in 203 patients with AIA, 324 patients with aspirin-tolerant asthma (ATA), and 456 normal controls (NC). Serum TGFbeta1 levels were determined by ELISA. RESULTS: The TGFbeta1-509C>T polymorphism was not significantly associated with the AIA phenotype; however, a significant association with the prevalence of rhinosinusitis in AIA (P=0.012), but not in ATA (P>0.05), was observed. When stratified by the presence of rhinosinusitis, the frequency of T allele carriers (CT or TT genotype) of TGFbeta1-509C>T was significantly higher in AIA (87.1%) compared to ATA (52.9%, P<0.001, OR=6.0, 95% CI=3.3-11.1). In addition, AIA patients carrying the TGFbeta1-509T allele showed a lower serum TGFbeta1 level compared to AIA patients carrying the TGFbeta1-509 CC genotype, especially when stratified by the presence of rhinosinusitis (P=0.002). CONCLUSION: Our results show that the TGFbeta1 polymorphisms are not associated with the AIA phenotype in the Korean population, but may contribute to the development of the AIA phenotype with rhinosinusitis.

Adult↗
PubMed2006

IL-4 receptor alpha is an important modulator of IL-4 and IL-13 receptor binding: implications for the development of therapeutic targets.

IL-4 is a key cytokine associated with allergy and asthma. Induction of cell signaling by IL-4 involves interaction with its cognate receptors, a complex of IL-4Ralpha with either the common gamma-chain or the IL-13R chain alpha1 (IL-13Ralpha1). We found that IL-4 bound to the extracellular domain of IL-4Ralpha (soluble human (sh)IL-4Ralpha) with high affinity and specificity. In contrast with the sequential mechanism of binding and stabilization afforded by IL-4Ralpha to the binding of IL-13 to IL-13Ralpha1, neither common gamma-chain nor IL-13Ralpha1 contributed significantly to the stabilization of the IL-4:IL-4Ralpha complex. Based on the different mechanisms of binding and stabilization of the IL-4R and IL-13R complexes, we compared the effects of shIL-4Ralpha and an IL-4 double mutein (R121D/Y124D, IL-4R antagonist) on IL-4- and IL-13-mediated responses. Whereas IL-4R antagonist blocked responses to both cytokines, shIL-4Ralpha only blocked IL-4. However, shIL-4Ralpha stabilized and augmented IL-13-mediated STAT6 activation and eotaxin production by primary human bronchial fibroblasts at suboptimal doses of IL-13. These data demonstrate that IL-4Ralpha plays a key role in the binding affinity of both IL-13R and IL-4R complexes. Under certain conditions, shIL-4Ralpha has the potential to stabilize binding IL-13 to its receptor to augment IL-13-mediated responses. Thus, complete understanding of the binding interactions between IL-4 and IL-13 and their cognate receptors may facilitate development of novel treatments for asthma that selectively target these cytokines without unpredicted or detrimental side effects.

Adjuvants, Immunologic↗
PubMed2006

Association of asthma with a functional promoter polymorphism in the IL16 gene.

BACKGROUND: IL-16, a multifunctional cytokine with increased expression in the airways of asthmatic subjects, inhibits allergic airway inflammation in animal models. A T-->C single nucleotide polymorphism (SNP) at the -295 position in the promoter region of the IL16 gene has been described. OBJECTIVE: We sought to examine the functional significance of this promoter SNP and its relationship to asthma. METHODS: We examined the effect of the -295 SNP on promoter activity in cell-line (HBE4-E6/E7) transfection experiments. We investigated the association of the IL16 -295 genotype with asthma among 341 affected sib-pair white families and 184 unrelated nonasthmatic control subjects. We analyzed the association between the IL16 genotype and asthma using family-based association test and case-control analyses. RESULTS: In in vitro transfection experiments the T allele in the -295 position was associated with substantially reduced promoter activity compared with the C allele. In the family study the more common T allele at the -295 position was significantly associated with all asthma phenotypes (P = .002 to P = .015). In the case-control analysis asthmatic subjects were more likely than unrelated nonasthmatic control subjects to have the -295 TT genotype, but this did not reach statistical significance (odds ratio, 1.36; 95% CI, 0.92-2.02). CONCLUSIONS: The T allele at the -295 position in the IL16 promoter region is associated with reduced promoter activity relative to the C allele and with asthma in this white population. Further investigation is needed to delineate the mechanisms underlying these findings and the relationship of the IL16 -295 genotype to asthma in other populations.

Adolescent↗
PubMed2006

The role of Toll-like receptors and related receptors of the innate immune system in asthma.

PURPOSE OF REVIEW: The biology of the innate immunity receptors is of central importance in the host response to the environment. Identifying genetic variants that alter the innate immune response is highly relevant to understanding asthma pathogenesis. This review summarizes recent studies of the role of innate immunity receptors, including Toll-like receptors and CD14, in the pathogenesis of asthma. RECENT FINDINGS: The majority of studies published since 2004 have been genetic association studies in various clinical settings, which have found positive associations of single nucleotide polymorphisms in TLR2, TLR4, TLR6 and TLR10 with asthma or atopy, although the number of studies is small and the results not yet replicated. The designs for CD14 genetic studies have been more sophisticated and have included gene-environment interaction. The results of CD14 gene associations with asthma and atopy are suggestive but have not been fully replicated. Potential reasons for non-replication of TLR and CD14 association studies include insufficient power, type I error, population heterogeneity and different phenotypes studied. In addition, there may be differences in CD14 genetic effects between childhood and adulthood, and between levels of endotoxin exposure. SUMMARY: The evidence is still being accumulated for the role of Toll-like receptor polymorphisms in the pathogenesis of asthma. There is emerging evidence for the role of CD14 polymorphisms in the development of asthma and atopy. Further studies of innate immunity in asthma and allergy are required, using rigorous study design, measurement of environmental exposure and intermediate phenotypes to demonstrate single nucleotide polymorphism functionality.

Asthma↗
PubMed2006

The genetics of asthma: ADAM33 as an example of a susceptibility gene.

The ability to identify novel disease genes by positional cloning led to the identification of a disintegrin and metalloprotease (ADAM)33 gene on chromosome 20p13 as a susceptibility gene for asthma. Case-control and family-based association studies have mostly confirmed a link between ADAM33 and asthma. Its restricted expression to mesenchymal cells as well as its association with bronchial hyperresponsiveness and accelerated decline in lung function over time point strongly to its involvement in the structural airway components of asthma, such as remodeling. Extensive alternative splicing, expression during branching morphogensis in the developing fetus, impaired lung function in childhood, the production of a soluble form linked to chronic asthma, and tight epigenetic regulation indicate a level of complexity in the way ADAM33 influences disease phenotype. Its recent association with chronic obstructive pulmonary disease as well as with asthma and lung development points to functions relating to airway wall modeling and remodeling as a general morphogenetic repair gene rather than being restricted to asthma.

ADAM Proteins↗
PubMed2005

ADAM33: a newly identified protease involved in airway remodelling.

Asthma is a complex disorder in which major genetic and environmental factors interact to both initiate the disease and modify its progression. While asthma is recognised as a disorder of the conducting airways characterised by Th2-directed inflammation, it is being increasingly apparent that alteration of the structural cells of the airways (airway remodelling) is also fundamental to disease chronicity and severity. The gene ADAM33, encoding a novel member of a identified as an asthma susceptibility gene as the result of a positional cloning effort in a cohort of families recruited form the UK and USA. Subsequent genetic studies have now provided evidence that ADAM33 may be involved in determining lung function throughout life, associated with early life lung function as well as increased decline therapeutic intervention in asthma and future work will focus on the mechanisms by which it alters lung function and bronchial hyperresponsiveness.

ADAM Proteins↗
PubMed2005

Polymorphisms in a disintegrin and metalloprotease 33 (ADAM33) predict impaired early-life lung function.

RATIONALE: Asthma commonly originates in early life in association with impaired lung function, which tracks to adulthood. OBJECTIVES: Within the context of a prospective birth cohort study, we investigated the association between single nucleotide polymorphisms (SNPs) in a disintegrin and metalloprotease 33 (ADAM33) gene and early-life lung function. METHODS: Children were genotyped for 17 SNPs in ADAM33. Lung function at age 3 (n = 285) and 5 years (n = 470) was assessed using plethysmographic measurement of specific airway resistance (sRaw). At age 5, we also measured FEV(1). SNPs were analyzed individually using logistic regression, followed by linkage disequilibrium mapping to identify the causal locus. MAIN RESULTS: Carriers of the rare allele of F+1 SNP had reduced lung function at age 3 years (p = 0.003). When the recessive model was considered, four SNPs (F+1, S1, ST+5, V4) showed association with sRaw at age 5 years (p < 0.04). Using linkage disequilibrium mapping, we found evidence of a significant causal location between BC+1 and F1 SNPs, at the 5' end of the gene. Four SNPs were associated with lower FEV(1) (F+1, M+1, T1, and T2; p < or = 0.04). The risk of transient early wheezing more than doubled among children homozygous for the A allele of F+1 (odds ratio, 2.39; 95% confidence intervals, 1.18-4.86; p = 0.02), but there was no association between any SNP and allergic sensitization or physician-diagnosed asthma. CONCLUSIONS: Polymorphisms in ADAM33 predict impaired early-life lung function. The functionally relevant polymorphism is likely to be at the 5' end of the gene.

ADAM Proteins↗
PubMed2005

Beta-catenin/T-cell factor-mediated transcription is modulated by cell density in human bronchial epithelial cells.

The embryonic Wnt/beta-catenin ('canonical') pathway has been implicated in epithelial regeneration. To investigate the role of Wnt signal transduction in the airways, we characterised the expression of key pathway components in human bronchial epithelial cells (HBEC) and studied the influence of cell density on pathway activity, using sub-confluent cells in log-phase growth as a simple model of repairing epithelium. Primary HBEC and H292 bronchial epithelial cells were found to express TCF-4, TCF-3 and isoforms of LEF-1, transcription factors that are regulated by Wnt signalling. The cells also had the potential to respond to Wnt signalling through expression of several members of the Frizzled receptor family, including FZD-5 and -6. In confluent H292 cells, 20 mM lithium and 25% v/v Wnt-3a conditioned medium induced 4.5-fold (p = 0.008) and 1.4-fold (p = 0.006) increases in TOPflash activity, respectively. Under conditions of reduced cell density, TOPflash activity increased 1.8-fold (p = 0.002) in association with increased nuclear localisation of hypophosphorylated (active) beta-catenin and increased cell proliferation. This up-regulation in reporter activity occurred independently of EGF receptor activation and could not be recapitulated by use of low-calcium medium to disrupt cadherin-mediated cell-cell adhesion, but was associated with changes in FZD-6 expression. We conclude that reactivation of this embryonic pathway may play an important role in bronchial epithelial regeneration, and that modulation of Fzd-6 receptors may regulate Wnt signalling at confluence. Recognising that many chronic inflammatory disorders of the airways involve epithelial damage and repair, altered Wnt signalling might contribute to disease pathogenesis or progression.

Adolescent↗
PubMed2005

ADAM33: a newly identified gene in the pathogenesis of asthma.

There is much to find out about this fascinating and complex molecule in relation to the development and progression of asthma. Added to it are three further new asthma/allergy genes identified by positional cloning: PDH Finger Protein II (PHF11) on chromosome 13q14, which encodes NY-REN-34 a protein first described in patients with renal cell carcinoma [67]; Dipeptidyl diptidase 10 (DDP10) on chromosome 2q14 [68]; and G protein-coupled receptor for asthma susceptibility (GPRA) on chromosome 7p [69]. For each of these genes, as is the case for ADAM33, determining their normal function(s) and how these become disordered in asthma is the future challenge.

ADAM Proteins↗
PubMed2005

Variation in the toll-like receptor 4 gene and susceptibility to myocardial infarction.

Variation in the gene encoding toll-like receptor 4 (TLR4), a transmembrane receptor that mediates inflammatory responses to bacterial endotoxin, has been associated with susceptibility to atherosclerosis and its complications, such as myocardial infarction (MI), the pathogenesis of which involves inflammation. A recent study has also indicated that TLR4 gene variation influences the effect of statin treatment on reducing atherosclerosis complications. We studied the TLR4 gene Asp299Gly polymorphism in relation to susceptibility to myocardial infarction in a cohort of patients with angiographically documented coronary artery disease, and performed a meta-analysis using data sets from three independent studies. The meta-analysis showed that overall, odds ratio (OR) for MI was 0.73 [95% confidence interval (CI) 0.55-0.96, P=0.024] in 299Gly carriers compared to non-carriers, and there was no evidence of heterogeneity among the sample sets (P=0.679). In our patient cohort, a significant association of 299Gly bearing genotypes with lower susceptibility to myocardial infarction was observed only in patients receiving statin treatment, with 299Gly carriers having an OR of 0.49 (95% CI 0.27-0.78, P=0.015) for MI compared to non-carriers. These results are consistent with the notion that variation in the TLR4 gene contributes to inter-individual variability in susceptibility to coronary ischaemic events, and that TLR4 genotype and statin treatment may have a synergistic effect.

Aged↗
PubMed2004

Association of tumor necrosis factor-alpha polymorphisms and ozone-induced change in lung function.

Ozone is a major air pollutant with adverse health effects which exhibit marked inter-individual variability. In mice, regions of genetic linkage with ozone-induced lung injury include the tumor necrosis factor-alpha (TNF), lymphotoxin-alpha (LTA), Toll-like receptor 4 (TLR4), superoxide dismutase (SOD2), and glutathione peroxidase (GPX1) genes. We genotyped polymorphisms in these genes in 51 individuals who had undergone ozone challenge. Mean change in FEV1 with ozone challenge, as a percentage of baseline, was -3% in TNF -308G/A or A/A individuals, compared with -9% in G/G individuals (p = 0.024). When considering TNF haplotypes, the smallest change in FEV1 with ozone exposure was associated with the TNF haplotype comprising LTA +252G/TNF -1031T/TNF -308A/TNF -238G. This association remained statistically significant after correction for age, sex, disease, and ozone concentration (p = 0.047). SOD2 or GPX1 genotypes were not associated with lung function, and the TLR4 polymorphism was too infrequent to analyze. The results of this study support TNF as a genetic factor for susceptibility to ozone-induced changes in lung function in humans, and has potential implications for stratifying health risks of air pollution.

Adult↗
PubMed2004

The discovery and role of ADAM33, a new candidate gene for asthma.

Asthma is a complex disorder in which major genetic and environmental factors interact to initiate the disease and propagate it as a chronic relapsing disorder. Until recently, genetic factors implicated in the disease pathogenesis have been restricted to variants in known molecules involved in the inflammatory or remodelling pathways. This review discusses evidence for a new susceptibility gene for asthma, ADAM33, which was identified by positional cloning and shown to be selectively expressed in mesenchymal but not immune or inflammatory cells. ADAM33 belongs to a family of membrane-anchored metalloproteinases that also have fusagenic, adhesion and intracellular signalling properties. ADAM33 might play a key role in predisposing to the reduced lung function characteristic of asthma, possibly by influencing airway wall remodelling.

ADAM Proteins↗