Modelling multiplex testing for outbreak control.

During the SARS-CoV-2 pandemic, polymerase chain reaction (PCR) and lateral flow device (LFD) tests were frequently deployed to detect the presence of SARS-CoV-2. Many of these tests were singleplex, and only tested for the presence of a single pathogen. Multiplex tests can test for the presence of several pathogens using only a single swab, which can allow for: surveillance of more pathogens, targeting of antiviral interventions, a reduced burden of testing, and lower costs. Test sensitivity however, particularly in LFD tests, is highly conditional on the viral concentration dynamics of individuals. To inform the use of multiplex testing in outbreak detection it is therefore necessary to investigate the interactions between outbreak detection strategies and the differing viral concentration trajectories of key pathogens. Viral concentration trajectories are estimated for SARS-CoV-2, and Influenza A/B. Testing strategies for the first five symptomatic cases in an outbreak are then simulated and used to evaluate key performance indicators. Strategies that use a combination of multiplex LFD and PCR tests achieve; high levels of detection, detect outbreaks rapidly, and have the lowest burden of testing across multiple pathogens. Influenza B was estimated to have lower rates of detection due to its modelled viral concentration dynamics. DATA AVAILABILITY STATEMENT: The SARS-CoV-2 viral load trajectory data may be accessed by contacting Killingley et. al. The influenza A/B viral load trajectory may be accessed at https://github.com/bcowling/pediatric-vaccine-trial/tree/master/data.

Epithelial Interleukin-1 Receptor-Like-1 Activation Is Contingent on Interleukin-33 Isoforms and Asthma-Related Receptor Variation.

INTRODUCTION: The interleukin-33/interleukin-1 receptor-like-1 (IL-33/IL1RL1) signalling pathway is implicated in asthma pathogenesis, with IL1RL1 nonsynonymous genetic polymorphisms associated with disease risk. We aimed to determine these variants' effect on IL1RL1 signalling induced by different IL33 isoforms thought to be elevated in the asthmatic airway. METHOD: In a project funded by GSK plc, which has developed an IL-33 receptor inhibitor for asthma treatment, human embryonic kidney 293 (HEK293) cells expressing secreted embryonic alkaline phosphatase (SEAP) driven by a nuclear factor kappa-beta (NF-κB) promoter, were transiently transfected with IL1RL1, containing one of four extracellular and Toll/interleukin 1 receptor (TIR) domain haplotypes. Cells were stimulated with seven different splice and proteolytic-generated IL-33 isoforms (0.001-50 ng/mL) for 24 h. Supernatant SEAP activity and interleukin-8 (IL-8) levels were determined. Primary human bronchial epithelial cells (HBECs) representing different genotype carriers were stimulated with IL-33112-270 (50 ng/mL) and induced IL-8 mRNA expression measured. RESULTS: HEK293 cells carrying both asthma extracellular and TIR domain IL1RL1 risk haplotypes presented maximal IL33-driven signalling, with minimal signalling after IL-33 activation in other protective haplotypes. All IL-33 isoforms activated IL1RL1 but with differing magnitudes. Proteolytically cleaved IL3395-270 and IL33106-270 had the greatest effect and the IL33113-270, and Exon 3,4 deletion isoform exhibited the lowest. The effect of extracellular and TIR domain genetic variants on receptor signalling was replicated in primary HBECs. Maximal IL1RL1 signalling was observed in cells carrying both extracellular and TIR signalling domain risk haplotypes. CONCLUSIONS: Overall, our study suggests asthma patients carrying the extracellular and TIR domain risk haplotype and have a lung microenvironment that promotes elevated levels of cleaved IL33, particularly where IL3395-270 and IL33106-270 may be more amenable to IL33/IL1RL1 targeting.

Functional Validation of SAM Riboswitch Element A from Listeria monocytogenes.

SreA is one of seven candidate S-adenosyl methionine (SAM) class I riboswitches identified in Listeria monocytogenes, a saprophyte and opportunistic foodborne pathogen. SreA precedes genes encoding a methionine ATP-binding cassette (ABC) transporter, which imports methionine and is presumed to regulate transcription of its downstream genes in a SAM-dependent manner. The proposed role of SreA in controlling the transcription of genes encoding an ABC transporter complex may have important implications for how the bacteria senses and responds to the availability of the metabolite SAM in the diverse environments in which L. monocytogenes persists. Here we validate SreA as a functional SAM-I riboswitch through ligand binding studies, structure characterization, and transcription termination assays. We determined that SreA has both a structure and SAM binding properties similar to those of other well-characterized SAM-I riboswitches. Despite the apparent structural similarities to previously described SAM-I riboswitches, SreA induces transcription termination in response to comparatively lower (nanomolar) ligand concentrations. Furthermore, SreA is a leaky riboswitch that permits some transcription of the downstream gene even in the presence of millimolar SAM, suggesting that L. monocytogenes may "dampen" the expression of genes for methionine import but likely does not turn them "OFF".

Selective deuteration of an RNA:RNA complex for structural analysis using small-angle scattering.

The structures of RNA:RNA complexes regulate many biological processes. Despite their importance, protein-free RNA:RNA complexes represent a tiny fraction of experimentally-determined structures. Here, we describe a joint small-angle X-ray and neutron scattering (SAXS/SANS) approach to structurally interrogate conformational changes in a model RNA:RNA complex. Using SAXS, we measured the solution structures of the individual RNAs in their free state and of the overall RNA:RNA complex. With SANS, we demonstrate, as a proof-of-principle, that isotope labeling and contrast matching (CM) can be combined to probe the bound state structure of an RNA within a selectively deuterated RNA:RNA complex. Furthermore, we show that experimental scattering data can validate and improve predicted AlphaFold 3 RNA:RNA complex structures to reflect its solution structure. Our work demonstrates that in silico modeling, SAXS, and CM-SANS can be used in concert to directly analyze conformational changes within RNAs when in complex, enhancing our understanding of RNA structure in functional assemblies.

Water-Enhancing Gels Exhibiting Heat-Activated Formation of Silica Aerogels for Protection of Critical Infrastructure During Catastrophic Wildfire.

A promising strategy to address the pressing challenges with wildfire, particularly in the wildland-urban interface (WUI), involves developing new approaches for preventing and controlling wildfire within wildlands. Among sprayable fire-retardant materials, water-enhancing gels have emerged as exceptionally effective for protecting civil infrastructure. They possess favorable wetting and viscoelastic properties that reduce the likelihood of ignition, maintaining strong adherence to a wide array of surfaces after application. Although current water-enhancing hydrogels effectively maintain surface wetness by creating a barricade, they rapidly desiccate and lose efficacy under high heat and wind typical of wildfire conditions. To address this limitation, unique biomimetic hydrogel materials from sustainable cellulosic polymers crosslinked by colloidal silica particles are developed that exhibit ideal viscoelastic properties and facile manufacturing. Under heat activation, the hydrogel transitions into a highly porous and thermally insulative silica aerogel coating in situ, providing a robust protective layer against ignition of substrates, even when the hydrogel fire suppressant becomes completely desiccated. By confirming the mechanical properties, substrate adherence, and enhanced substrate protection against fire, these heat-activatable biomimetic hydrogels emerge as promising candidates for next-generation water-enhancing fire suppressants. These advancements have the potential to dramatically improve the ability to protect homes and critical infrastructure during wildfire.

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a critical regulator of inflammatory signalling through toll-like receptors 4 and 7/8 in murine and human lungs.

BACKGROUND AND PURPOSE: Toll-like receptors 4 (TLR4) and TLR7/TLR8 play an important role in mediating the inflammatory effects of bacterial and viral pathogens. Interleukin-1 receptor-associated kinase 4 (IRAK4) is an important regulator of signalling by toll-like receptor (TLR) and hence is a potential therapeutic target in diseases characterized by increased lung inflammatory signalling. EXPERIMENTAL APPROACH: We used an established murine model of acute lung inflammation, and studied human lung tissue ex vivo, to investigate the effects of inhibiting IRAK4 on lung inflammatory pathways. KEY RESULTS: We show that TLR4 stimulation produces an inflammatory response characterized by neutrophil influx and tumour necrosis factor-α (TNF-α) production in murine lungs and that these responses are markedly reduced in IRAK4 kinase-dead mice. In addition, we characterize a novel selective IRAK4 inhibitor, BI1543673, and show that this compound can reduce lipopolysaccharide (LPS)-induced airway inflammation in wild-type mice. Additionally, BI1543673 reduced inflammatory responses to both TLR4 and TLR7/8 stimulation in human lung tissue studied ex vivo. CONCLUSION AND IMPLICATIONS: These data demonstrate a key role for IRAK4 signalling in lung inflammation and suggest that IRAK4 inhibition has potential utility to treat lung diseases characterized by inflammatory responses driven through TLR4 and TLR7/8.

Transcriptomics using lung resection material to advance our understanding of COPD and idiopathic pulmonary fibrosis pathogenesis.

Genes involved in cell death, inflammation and viral infection are common to both COPD and IPF. A link to rheumatic disease is unique to COPD, and IPF-specific analyses showed increases in gene expression of keratins, collagens, mucins and MMPs. https://bit.ly/3JoW73H.

Structural Basis for the Interaction Between Yeast Chromatin Assembly Factor 1 and Proliferating Cell Nuclear Antigen.

Proliferating cell nuclear antigen (PCNA), the homotrimeric eukaryotic sliding clamp protein, recruits and coordinates the activities of a multitude of proteins that function on DNA at the replication fork. Chromatin assembly factor 1 (CAF-1), one such protein, is a histone chaperone that deposits histone proteins onto DNA immediately following replication. The interaction between CAF-1 and PCNA is essential for proper nucleosome assembly at silenced genomic regions. Most proteins that bind PCNA contain a PCNA-interacting peptide (PIP) motif, a conserved motif containing only eight amino acids. Precisely how PCNA is able to discriminate between binding partners at the replication fork using only these small motifs remains unclear. Yeast CAF-1 contains a PIP motif on its largest subunit, Cac1. We solved the crystal structure of the PIP motif of CAF-1 bound to PCNA using a new strategy to produce stoichiometric quantities of one PIP motif bound to each monomer of PCNA. The PIP motif of CAF-1 binds to the hydrophobic pocket on the front face of PCNA in a similar manner to most known PIP-PCNA interactions. However, several amino acids immediately flanking either side of the PIP motif bind the IDCL or C-terminus of PCNA, as observed for only a couple other known PIP-PCNA interactions. Furthermore, mutational analysis suggests positively charged amino acids in these flanking regions are responsible for the low micromolar affinity of CAF-1 for PCNA, whereas the presence of a negative charge upstream of the PIP prevents a more robust interaction with PCNA. These results provide additional evidence that positive charges within PIP-flanking regions of PCNA-interacting proteins are crucial for specificity and affinity of their recruitment to PCNA at the replication fork.

DYNamic Assessment of Multi-Organ level dysfunction in patients recovering from COVID-19: DYNAMO COVID-19.

We evaluated the impacts of COVID-19 on multi-organ and metabolic function in patients following severe hospitalised infection compared to controls. Patients (n = 21) without previous diabetes, cardiovascular or cerebrovascular disease were recruited 5-7 months post-discharge alongside controls (n = 10) with similar age, sex and body mass. Perceived fatigue was estimated (Fatigue Severity Scale) and the following were conducted: oral glucose tolerance (OGTT) alongside whole-body fuel oxidation, validated magnetic resonance imaging and spectroscopy during resting and supine controlled exercise, dual-energy X-ray absorptiometry, short physical performance battery (SPPB), intra-muscular electromyography, quadriceps strength and fatigability, and daily step-count. There was a greater insulin response (incremental area under the curve, median (inter-quartile range)) during the OGTT in patients [18,289 (12,497-27,448) mIU/min/L] versus controls [8655 (7948-11,040) mIU/min/L], P < 0.001. Blood glucose response and fasting and post-prandial fuel oxidation rates were not different. This greater insulin resistance was not explained by differences in systemic inflammation or whole-body/regional adiposity, but step-count (P = 0.07) and SPPB scores (P = 0.004) were lower in patients. Liver volume was 28% greater in patients than controls, and fat fraction adjusted liver T1, a measure of inflammation, was raised in patients. Patients displayed greater perceived fatigue scores, though leg muscle volume, strength, force-loss, motor unit properties and post-exercise muscle phosphocreatine resynthesis were comparable. Further, cardiac and cerebral architecture and function (at rest and on exercise) were not different. In this cross-sectional study, individuals without known previous morbidity who survived severe COVID-19 exhibited greater insulin resistance, pointing to a need for physical function intervention in recovery.

Free-Breathing Functional Pulmonary Proton MRI: A Novel Approach Using Voxel-Wise Lung Ventilation (VOLVE) Assessment in Healthy Volunteers and Patients With Chronic Obstructive Pulmonary Disease.

BACKGROUND: In respiratory medicine, there is a need for sensitive measures of regional lung function that can be performed using standard imaging technology, without the need for inhaled or intravenous contrast agents. PURPOSE: To describe VOxel-wise Lung VEntilation (VOLVE), a new method for quantifying regional lung ventilation (V) and perfusion (Q) using free-breathing proton MRI, and to evaluate VOLVE in healthy never-smokers, healthy people with smoking history, and people with chronic obstructive pulmonary disease (COPD). STUDY TYPE: Prospective pilot. POPULATION: Twelve healthy never-smoker participants (age 30.3 ± 12.5 years, five male), four healthy participants with smoking history (>10 pack-years) (age 42.5 ± 18.3 years, one male), and 12 participants with COPD (age 62.8 ± 11.1 years, seven male). FIELD STRENGTH/SEQUENCE: Single-slice free-breathing two-dimensional fast field echo sequence at 3 T. ASSESSMENT: A novel postprocessing was developed to evaluate the MR signal changes in the lung parenchyma using a linear regression-based approach, which makes use of all the data in the time series for maximum sensitivity. V/Q-weighted maps were produced by computing the cross-correlation, lag and gradient between the respiratory/cardiac phase time course and lung parenchyma signal time courses. A comparison of histogram median and skewness values and spirometry was performed. STATISTICAL TESTS: Kruskal-Wallis tests with Dunn's multiple comparison tests to compare VOLVE metrics between groups; Spearman correlation to assess the correlation between MRI and spirometry-derived parameters; and Bland-Altman analysis and coefficient of variation to evaluate repeatability were used. A P-value <0.05 was considered significant. RESULTS: Significant differences between the groups were found for ventilation between healthy never-smoker and COPD groups (median XCCV, LagV, and GradV) and perfusion (median XCCQ, LagQ, and GradQ). Minimal bias and no significant differences between intravisit scans were found (P range = 0.12-0.97). DATA CONCLUSION: This preliminary study showed that VOLVE has potential to provide metrics of function quantification. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 1.

Modelled impact of virtual fractional flow reserve in patients undergoing coronary angiography (VIRTU-4).

BACKGROUND: The practical application of 'virtual' (computed) fractional flow reserve (vFFR) based on invasive coronary angiogram (ICA) images is unknown. The objective of this cohort study was to investigate the potential of vFFR to guide the management of unselected patients undergoing ICA. The hypothesis was that it changes management in >10% of cases. METHODS: vFFR was computed using the Sheffield VIRTUheart system, at five hospitals in the North of England, on 'all-comers' undergoing ICA for non-ST-elevation myocardial infarction acute coronary syndrome (ACS) and chronic coronary syndrome (CCS). The cardiologists' management plan (optimal medical therapy, percutaneous coronary intervention (PCI), coronary artery bypass surgery or 'more information required') and confidence level were recorded after ICA, and again after vFFR disclosure. RESULTS: 517 patients were screened; 320 were recruited: 208 with ACS and 112 with CCS. The median vFFR was 0.82 (0.70-0.91). vFFR disclosure did not change the mean number of significantly stenosed vessels per patient (1.16 (±0.96) visually and 1.18 (±0.92) with vFFR (p=0.79)). A change in intended management following vFFR disclosure occurred in 22% of all patients; in the ACS cohort, there was a 62% increase in the number planned for medical management, and in the CCS cohort, there was a 31% increase in the number planned for PCI. In all patients, vFFR disclosure increased physician confidence from 8 of 10 (7.33-9) to 9 of 10 (8-10) (p<0.001). CONCLUSION: The addition of vFFR to ICA changed intended management strategy in 22% of patients, provided a detailed and specific 'all-in-one' anatomical and physiological assessment of coronary artery disease, and was accompanied by augmentation of the operator's confidence in the treatment strategy.

Unsupervised identification of significant lineages of SARS-CoV-2 through scalable machine learning methods.

Since its emergence in late 2019, SARS-CoV-2 has diversified into a large number of lineages and caused multiple waves of infection globally. Novel lineages have the potential to spread rapidly and internationally if they have higher intrinsic transmissibility and/or can evade host immune responses, as has been seen with the Alpha, Delta, and Omicron variants of concern. They can also cause increased mortality and morbidity if they have increased virulence, as was seen for Alpha and Delta. Phylogenetic methods provide the "gold standard" for representing the global diversity of SARS-CoV-2 and to identify newly emerging lineages. However, these methods are computationally expensive, struggle when datasets get too large, and require manual curation to designate new lineages. These challenges provide a motivation to develop complementary methods that can incorporate all of the genetic data available without down-sampling to extract meaningful information rapidly and with minimal curation. In this paper, we demonstrate the utility of using algorithmic approaches based on word-statistics to represent whole sequences, bringing speed, scalability, and interpretability to the construction of genetic topologies. While not serving as a substitute for current phylogenetic analyses, the proposed methods can be used as a complementary, and fully automatable, approach to identify and confirm new emerging variants.

Risk factors for SARS-CoV-2 infection at a UK electricity-generating company: a test-negative design case-control study.

OBJECTIVES: Identify workplace risk factors for SARS-CoV-2 infection, using data collected by a UK electricity-generating company. METHODS: Using a test-negative design case-control study, we estimated the OR of infection by job category, site, test reason, sex, vaccination status, vulnerability, site outage and site COVID-19 weekly risk rating, adjusting for age, test date and test type. RESULTS: From an original 80 077 COVID-19 tests, there were 70 646 included in the final analysis. Most exclusions were due to being visitor tests (5030) or tests after an individual first tested positive (2968).Women were less likely to test positive than men (OR=0.71; 95% CI 0.58 to 0.86). Test reason was strongly associated with positivity and although not a cause of infection itself, due to differing test regimes by area, it was a strong confounder for other variables. Compared with routine tests, tests due to symptoms were highest risk (94.99; 78.29 to 115.24), followed by close contact (16.73; 13.80 to 20.29) and broader-defined work contact 2.66 (1.99 to 3.56). After adjustment, we found little difference in risk by job category, but some differences by site with three sites showing substantially lower risks, and one site showing higher risks in the final model. CONCLUSIONS: In general, infection risk was not associated with job category. Vulnerable individuals were at slightly lower risk, tests during outages were higher risk, vaccination showed no evidence of an effect on testing positive, and site COVID-19 risk rating did not show an ordered trend in positivity rates.

Genetics of chronic respiratory disease.

Chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD), asthma and interstitial lung diseases are frequently occurring disorders with a polygenic basis that account for a large global burden of morbidity and mortality. Recent large-scale genetic epidemiology studies have identified associations between genetic variation and individual respiratory diseases and linked specific genetic variants to quantitative traits related to lung function. These associations have improved our understanding of the genetic basis and mechanisms underlying common lung diseases. Moreover, examining the overlap between genetic associations of different respiratory conditions, along with evidence for gene-environment interactions, has yielded additional biological insights into affected molecular pathways. This genetic information could inform the assessment of respiratory disease risk and contribute to stratified treatment approaches.

Faster detection of asymptomatic COVID-19 cases among care home staff in England through the combination of SARS-CoV-2 testing technologies.

To detect SARS-CoV-2 amongst asymptomatic care home staff in England, a dual-technology weekly testing regime was introduced on 23 December 2020. A lateral flow device (LFD) and quantitative reverse transcription polymerase chain reaction (qRT-PCR) test were taken on the same day (day 0) and a midweek LFD test was taken three to four days later. We evaluated the effectiveness of using dual-technology to detect SARS-CoV-2 between December 2020 to April 2021. Viral concentrations derived from qRT-PCR were used to determine the probable stage of infection and likely level of infectiousness. Day 0 PCR detected 1,493 cases of COVID-19, of which 53% were in the early stages of infection with little to no risk of transmission. Day 0 LFD detected 83% of cases that were highly likely to be infectious. On average, LFD results were received 46.3 h earlier than PCR, enabling removal of likely infectious staff from the workplace quicker than by weekly PCR alone. Demonstrating the rapidity of LFDs to detect highly infectious cases could be combined with the ability of PCR to detect cases in the very early stages of infection. In practice, asymptomatic care home staff were removed from the workplace earlier, breaking potential chains of transmission.

A beta-Poisson model for infectious disease transmission.

Outbreaks of emerging and zoonotic infections represent a substantial threat to human health and well-being. These outbreaks tend to be characterised by highly stochastic transmission dynamics with intense variation in transmission potential between cases. The negative binomial distribution is commonly used as a model for transmission in the early stages of an epidemic as it has a natural interpretation as the convolution of a Poisson contact process and a gamma-distributed infectivity. In this study we expand upon the negative binomial model by introducing a beta-Poisson mixture model in which infectious individuals make contacts at the points of a Poisson process and then transmit infection along these contacts with a beta-distributed probability. We show that the negative binomial distribution is a limit case of this model, as is the zero-inflated Poisson distribution obtained by combining a Poisson-distributed contact process with an additional failure probability. We assess the beta-Poisson model's applicability by fitting it to secondary case distributions (the distribution of the number of subsequent cases generated by a single case) estimated from outbreaks covering a range of pathogens and geographical settings. We find that while the beta-Poisson mixture can achieve a closer to fit to data than the negative binomial distribution, it is consistently outperformed by the negative binomial in terms of Akaike Information Criterion, making it a suboptimal choice on parsimonious grounds. The beta-Poisson performs similarly to the negative binomial model in its ability to capture features of the secondary case distribution such as overdispersion, prevalence of superspreaders, and the probability of a case generating zero subsequent cases. Despite this possible shortcoming, the beta-Poisson distribution may still be of interest in the context of intervention modelling since its structure allows for the simulation of measures which change contact structures while leaving individual-level infectivity unchanged, and vice-versa.

Association study of human leukocyte antigen variants and idiopathic pulmonary fibrosis.

Introduction: Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial pneumonia marked by progressive lung fibrosis and a poor prognosis. Recent studies have highlighted the potential role of infection in the pathogenesis of IPF, and a prior association of the HLA-DQB1 gene with idiopathic fibrotic interstitial pneumonia (including IPF) has been reported. Owing to the important role that the human leukocyte antigen (HLA) region plays in the immune response, here we evaluated if HLA genetic variation was associated specifically with IPF risk. Methods: We performed a meta-analysis of associations of the HLA region with IPF risk in individuals of European ancestry from seven independent case-control studies of IPF (comprising 5159 cases and 27 459 controls, including a prior study of fibrotic interstitial pneumonia). Single nucleotide polymorphisms, classical HLA alleles and amino acids were analysed and signals meeting a region-wide association threshold of p<4.5×10-4 and a posterior probability of replication >90% were considered significant. We sought to replicate the previously reported HLA-DQB1 association in the subset of studies independent of the original report. Results: The meta-analysis of all seven studies identified four significant independent single nucleotide polymorphisms associated with IPF risk. However, none met the posterior probability for replication criterion. The HLA-DQB1 association was not replicated in the independent IPF studies. Conclusion: Variation in the HLA region was not consistently associated with risk in studies of IPF. However, this does not preclude the possibility that other genomic regions linked to the immune response may be involved in the aetiology of IPF.

Asthma exacerbations and eosinophilia in the UK Biobank: a genome-wide association study.

Background: Asthma exacerbations reflect disease severity, affect morbidity and mortality, and may lead to declining lung function. Inflammatory endotypes (e.g. T2-high (eosinophilic)) may play a key role in asthma exacerbations. We aimed to assess whether genetic susceptibility underlies asthma exacerbation risk and additionally tested for an interaction between genetic variants and eosinophilia on exacerbation risk. Methods: UK Biobank data were used to perform a genome-wide association study of individuals with asthma and at least one exacerbation compared to individuals with asthma and no history of exacerbations. Individuals with asthma were identified using self-reported data, hospitalisation data and general practitioner records. Exacerbations were identified as either asthma-related hospitalisation, general practitioner record of asthma exacerbation or an oral corticosteroid burst prescription. A logistic regression model adjusted for age, sex, smoking status and genetic ancestry via principal components was used to assess the association between genetic variants and asthma exacerbations. We sought replication for suggestive associations (p<5×10-6) in the GERA cohort. Results: In the UK Biobank, we identified 11 604 cases and 37 890 controls. While no variants reached genome-wide significance (p<5×10-8) in the primary analysis, 116 signals were suggestively significant (p<5×10-6). In GERA, two single nucleotide polymorphisms (rs34643691 and rs149721630) replicated (p<0.05), representing signals near the NTRK3 and ABCA13 genes. Conclusions: Our study has identified reproducible associations with asthma exacerbations in the UK Biobank and GERA cohorts. Confirmation of these findings in different asthma subphenotypes in diverse ancestries and functional investigation will be required to understand their mechanisms of action and potentially inform therapeutic development.

Genome-wide SNP-sex interaction analysis of susceptibility to idiopathic pulmonary fibrosis.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic lung condition that is more prevalent in males than females. The reasons for this are not fully understood, with differing environmental exposures due to historically sex-biased occupations, or diagnostic bias, being possible explanations. To date, over 20 independent genetic variants have been identified to be associated with IPF susceptibility, but these have been discovered when combining males and females. Our aim was to test for the presence of sex-specific associations with IPF susceptibility and assess whether there is a need to consider sex-specific effects when evaluating genetic risk in clinical prediction models for IPF. Methods: We performed genome-wide single nucleotide polymorphism (SNP)-by-sex interaction studies of IPF risk in six independent IPF case-control studies and combined them using inverse-variance weighted fixed effect meta-analysis. In total, 4,561 cases (1,280 females and 2,281 males) and 23,500 controls (8,360 females and 14,528 males) of European genetic ancestry were analysed. We used polygenic risk scores (PRS) to assess differences in genetic risk prediction between males and females. Findings: Three independent genetic association signals were identified. All showed a consistent direction of effect across all individual IPF studies and an opposite direction of effect in IPF susceptibility between females and males. None had been previously identified in IPF susceptibility genome-wide association studies (GWAS). The predictive accuracy of the PRSs were similar between males and females, regardless of whether using combined or sex-specific GWAS results. Interpretation: We prioritised three genetic variants whose effect on IPF risk may be modified by sex, however these require further study. We found no evidence that the predictive accuracy of common SNP-based PRSs varies significantly between males and females.