Richard James Allen

Background: Idiopathic pulmonary fibrosis (IPF) is a rare disease with a poor prognosis. Disease risk involves rare and common genetic variants. However, an inverse association have been described between them. Accordingly, IPF patients with a higher polygenic risk score (PRS) for IPF are less likely to carry rare deleterious variants and vice versa. Here, we evaluate weather PRS of IPF could serve as an additional criterion to patient prioritisation for rare variant discovery. Methods: We identified carriers based on the presence of rare qualifying variants (QVs) in genes linked to monogenic forms of pulmonary fibrosis in 888 IPF patients from the Pulmonary Fibrosis Foundation Patient Registry (PFFPR). Genome-wide association study (GWAS) summary statistics from independent cohorts were used to construct a whole-genome PRS (WG-PRS) using a clumping and thresholding method (C+T) and a Bayesian method (SBayesRC). PRS were also derived from 19 known common sentinel IPF variants (Sentinel-PRS). Logistic regression models were used to evaluate associations between PRS and carrier status. Discriminatory performancewas evaluated using area under the curve (AUC) analysis, and comparisons were made with DeLong’s test. Validation was performed in 472 IPF individuals from the UK PROFILE cohort. Findings: IPF-PRS were strongly associated with the QVs carrier status: Odds Ratio [OR] 0.65 (95% Confidence Interval [CI] 0.53-0.79) for WG-PRSC+T, OR 0.71 (95% CI 0.59-0.86) for WG-PRSSBayesRC, and OR 0.77 (95% CI 0.63-0.94) for Sentinel-PRS. Adding WG-PRS to the patient’s personal clinical history improved the prediction of QVs carriers: AUC=0.62 for the clinical model, AUC=0.68 for WG-PRSC+T (DeLong’s test, p=9.54x10-4) and AUC=0.66 for WG-PRSSBayesRC (DeLong’s test, p=0.02). Adding of IPF-PRS to clinical variables correctly reclassified 22.8% of carriers when using WG-PRSC+T, 20.8% when using Sentinel-PRS, and 16.7% for WG-PRSSBayesRC. WG-PRSSBayesRC and the Sentinel-PRS also demonstrated improved prediction of QVs carriers in telomere-related genes in PROFILE. Interpretation: Incorporating IPF-PRS into a model based on the patient’s clinical history improves the identification of QVs carriers. Although the overall discriminatory power was moderate, these findings raise de the possibility of using WG-PRS as useful criterion for rare variant discovery in patients with IPF and enhance decision-making.

Rationale: Idiopathic Pulmonary Fibrosis (IPF) is characterized by chronic progressive pulmonary fibrosis and high mortality. Genetic markers, summarized into a polygenic risk score (PRS), associate with IPF in well-phenotyped research cohorts. Objectives: To evaluate the performance of the PRS using real-world data from routinely captured electronic healthcare records. Methods: We conducted an observational study evaluating the association of a PRS for IPF with electronic healthcare record diagnosis of IPF as well as lung transplant-free survival in four independent cohorts; the Mass General Brigham Biobank (MGBB), Mayo Clinic Biobank (MCBB), Mayo Clinic Tapestry Cohort (Tapestry), and U.K. Biobank (UKBB). We used multivariable logistic regression and multivariable Cox proportional hazards models adjusting for age, gender, and principal components of ancestry. The cohorts then underwent fixed and random effects meta-analysis. Measurements and Main Results: Of 37,709; 44,195; 43,202; and 447,422 participants from MGBB, MCBB, Tapestry and UKBB respectively, 1,015 (2.7%) 2,879 (6.5%), 1,310 (3.0%), and 2,742 (0.6%) participants had an IPF diagnosis. Meta-analysis demonstrated a high-risk PRS associated with IPF diagnosis, OR 2.88 (95%CI 2.41-3.44) compared to all other individuals. A high-risk PRS also associated with the composite endpoint of mortality or lung transplant among those with an IPF diagnosis, HR 1.23(95%CI 1.11-1.35) compared to all other individuals. Conclusions: A PRS can identify those at risk for an IPF diagnosis and mortality in biobank-scale data, which may have implications for clinical decisions. Further work is necessary to evaluate the utility of adding genetics in clinical settings.

Background: Delays in the diagnosis of endometriosis are well documented from patient surveys. However, there is a paucity of population-level evidence regarding diagnostic pathways and healthcare utilisation.Objective: We aimed to characterise diagnostic pathways, healthcare utilisation and factors associated with delayed diagnosis among women with surgically confirmed endometriosis.Study design: We conducted a population-based cohort study using linked primary and secondary care electronic health records. We analysed Clinical Practice Research Datalink (CPRD) Aurum linked to Hospital Episode Statistics Admitted Patient Care, representative of the population of England. Women aged 16–55 years with surgically confirmed endometriosis were included.Results: Among 44,981 women with surgically confirmed endometriosis, the median interval between first recorded symptom and diagnosis was 4·4 years (IQR 1·2–9·2). Diagnostic intervals varied by symptom profile, age, ethnicity and BMI. Importantly, diagnostic delay frequently occurred despite repeated healthcare contact and prior specialist investigation. Overall, 27,405 (60.93%) women had undergone at least one previous laparoscopy that did not result in a recorded diagnosis of endometriosis, of which 41.37% required multiple prior laparoscopies. 7,994/44,981 women experienced an emergency hospital admission before diagnosis. Healthcare utilisation increased progressively in the years preceding diagnosis and declined following surgical confirmation.Conclusion: Women with endometriosis experience prolonged diagnostic delay despite repeated engagement with healthcare services. The high frequency of emergency presentations and repeated non-diagnostic laparoscopies suggests that current diagnostic pathways are inefficient. Earlier recognition of endometriosis represents an important opportunity to improve patient outcomes and reduce healthcare utilisation.

Introduction: Acute respiratory distress syndrome (ARDS) is a severe inflammatory process of the lung, often due to sepsis, and poses significant mortality burden in intensive care units. Here we conducted the largest genome-wide association study (GWAS) of sepsis-associated ARDS to identify novel genetic risk loci that can help guide the development of new therapeutic options. Methods: We performed a case-control GWAS in 716 patients with sepsis-associated ARDS and 4,399 at-risk sepsis controls from three independent studies. Results were meta-analysed across the three studies, with significance set at p -8 . Suggestive associations were declared for variants exhibiting consistent effects, likely to replicate and nominal significance ( p in-silico functional assessments, and gene-based rare variant collapsing analysis using whole exome sequencing (WES) data. Two independent studies with 430 ARDS cases and 1,398 controls served as replication samples. Results: We identified a variant showing genome-wide significant association with sepsis-associated ARDS risk intergenic to ANKRD31 and HMGCR , previously linked to cholesterol metabolism. Suggestive associations were found for eight other variants. The rare exonic variant analysis showed associations between HMGCR and POC5 and sepsis-associated ARDS at nominal level ( p ANKRD31 and HMGCR was associated with sepsis-associated ARDS risk, suggesting a link between cholesterol metabolism and ARDS risk. Validation in independent studies is needed.

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. Research in context: Evidence before this study: The prevalence of IPF is higher in males than females. IPF risk has a genetic component, but analyses have only been performed in studies where males and females have been combined. One previous study reported sex-specific differences in association for the MUC5B promoter variant, rs35705950, however the finding was not replicated in an independent study. No genome-wide association studies assessing for different genetic risk factors between males and females have been conducted for IPF. It is not known whether approaches to predict individuals at risk of IPF should take sex- specific genetic risk into consideration. Added value of this study: This was the largest study to test whether there are genetic variants whose effects on IPF susceptibility are different in males and females. The MUC5B promotor variant rs35705950 did not show a different magnitude of effect in males vs females. We identified three genetic variants with opposite directions of effect on IPF risk in males vs females. Our polygenic risk score analyses suggested that genetic prediction based on data from males and females separately did not perform better than when males and females were combined. Implications of all available evidence: Although we found some preliminary evidence of genetic variants with sex-specific effects on IPF risk, our analyses suggest that genome-wide genetic risk from common single nucleotide polymorphisms is similar in males and females. This is important when considering integration of polygenic risk scores into clinical prediction models for IPF. There may be other forms of genetic variation, such as complex structural variation or rare variants, not captured in this analysis, that may improve risk prediction for males and females separately.

Rationale: Idiopathic Pulmonary Fibrosis (IPF) is a disease of progressive lung scarring. There is a known association between IPF and diabetes mellitus (DM), but it is unclear whether this association is due to causal relationships between these traits. Objectives: To examine causal relationships between DM, diabetes-associated traits, and IPF using a Mendelian randomisation approach. Methods: Following a two-sample Mendelian randomisation (MR) approach, we used genetic variants identified from genome wide association studies (GWAS) for type 1 diabetes (T1D), type 2 diabetes (T2D), glycated haemoglobin level (HbA1c), fasting insulin level, and body mass index (BMI) to assess for evidence of causal effects of these traits on IPF risk. Further analyses using pleiotropy-robust and multivariable MR methods were performed to account for the inherent complexity of the traits being investigated. Results: Results did not suggest that either T1D (OR = 1.00, 95% CI: 0.93-1.07, p = 0.902) or T2D (OR = 1.02, 95% CI: 0.93-1.11, p = 0.692) are in the causal pathway of IPF. No significant effects were suggested of HbA1c (OR = 1.19, 95% CI: 0.63-2.22, p = 0.592) or fasting insulin level (OR = 0.60, 95% CI: 0.31-1.15, p = 0.124) on IPF risk, but effects of BMI on IPF risk were indicated (OR = 1.44, 95% CI: 1.12-1.85, p = 0.004). Conclusion: This study suggests that DM and IPF are unlikely to be causally linked. This comorbid relationship may instead be driven by shared risk factors or treatment effects. Key messages: What is already known on this topic: Idiopathic pulmonary fibrosis is associated with diabetes mellitus epidemiologically, but it is unclear if these traits are linked by causal effects. What this study adds: Idiopathic pulmonary fibrosis and diabetes mellitus are unlikely to be causally linked, suggesting that shared environmental risk factors or treatment effects may drive this comorbid relationship. How this study might affect research, practice, or policy: Further research investigating the relationship between diabetes mellitus and idiopathic pulmonary fibrosis should focus on potential shared risk factors such as smoking, and treatment effects including corticosteroid use.

A variant in the mucin 5B gene (MUC5B) is strongly associated with the risk of idiopathic pulmonary fibrosis. However, the same variant is associated with increased survival time. Previous work suggested that this may be explained by index event bias, with the true effect being to decrease survival. Here, we reassessed this claim using more recent methods and datasets. We found that the statistical assumptions of the previous analysis did not hold, and instead, we applied recent methods of corrected weighted least squares, MR‐RAPS and Slope‐hunter to both the previous data and an updated consortium meta‐analysis. However, these analyses did not yield robust evidence for increased or decreased survival. In simulations of a true effect of decreased survival, we did not observe any realistic scenario in which index event bias led to an observed effect of increased survival. We therefore regard as unsafe the claim that MUC5B has a true effect of decreased survival. Alternative explanations should be sought to explain the observed association with increased survival.

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. Due 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 a total of 5,159 cases and 27,459 controls, including the 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 p 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.

Introduction: Coronavirus disease 2019 (COVID-19) survivors can develop residual lung abnormalities consistent with lung fibrosis. A shared genetic component between COVID-19 and idiopathic pulmonary fibrosis (IPF) has been shown. However, genetic overlap studies of IPF and COVID-19 have primarily concentrated on the IPF genome-wide significant risk variants that have been previously identified, rather than combined into a genome-wide polygenic risk. Here we used IPF genome-wide association study (GWAS) results to calculate polygenic risk scores (PRSs) and study their association with COVID-19 severity. Methods: We used results from the largest meta-GWAS of clinically defined IPF risk (base dataset; n=24,589) and individual-level imputed data from the SCOURGE study of patients with COVID-19 (target dataset; n=15,024). We calculated IPF PRSs using PRSice-2 and assessed their association with COVID-19 hospitalisation, severe illness, and critical illness. We also evaluated the effect of age and sex stratification. Results were validated using an independent PRS method. Enrichment analyses and pathway-specific PRSs were performed to study biological pathways associated with COVID-19 severity. Results: IPF PRSs were significantly associated with COVID-19 hospitalisation and severe illness. The strongest association was found in patients aged −5 ). A pathway enrichment analysis of the variants included in the best model fit and subsequent pathway-specific PRSs analyses supported the link of Cadherin and Integrin signalling pathways to COVID-19 severity when stratified by age and sex. Conclusion: Our results suggest that there is genome-wide genetic overlap between IPF and severe COVID-19 that is dependent on age and sex and adds further support that the pathogenesis of both IPF and severe COVID-19 share underlying biological mechanisms. This could imply that individuals with a high IPF genetic risk are at an overall increased risk of developing lung sequelae resulting from severe COVID-19.