Association between perinatal and early life exposures and lung function in Australian Indigenous young adults: The Aboriginal Birth Cohort study.

BACKGROUND AND OBJECTIVE: Despite the high burden of respiratory disease amongst Indigenous populations, prevalence data on spirometric deficits and its determinants are limited. We estimated the prevalence of abnormal spirometry in young Indigenous adults and determined its relationship with perinatal and early life factors. METHODS: We used prospectively collected data from the Australian Aboriginal Birth Cohort, a birth cohort of 686 Indigenous Australian singletons. We calculated the proportion with abnormal spirometry (z-score <-1.64) and FEV1 below the population mean (FEV1 % predicted 0 to -2SD) measured in young adulthood. We evaluated the association between perinatal and early life exposures with spirometry indices using linear regression. RESULTS: Fifty-nine people (39.9%, 95%CI 31.9, 48.2) had abnormal spirometry; 72 (49.3%, 95%CI 40.9, 57.7) had a FEV1 below the population mean. Pre-school hospitalisations for respiratory infections, younger maternal age, being overweight in early childhood and being born remotely were associated with reduced FEV1 and FVC (absolute, %predicted and z-score). The association between maternal age and FEV1 and FVC were stronger in women, as was hospitalization for respiratory infections before age 5. Being born remotely had a stronger association with reduced FEV1 and FVC in men. Participants born in a remote community were over 6 times more likely to have a FEV1 below the population mean (odds ratio [OR] 6.30, 95%CI 1.93, 20.59). CONCLUSION: Young Indigenous adults have a high prevalence of impaired lung function associated with several perinatal and early life factors, some of which are modifiable with feasible interventions.

The relative contribution of co-morbidities to health-related quality of life of people with idiopathic pulmonary fibrosis using the Assessment of Quality of Life-8-Dimension multi-attribute utility instrument.

PURPOSE: Little is known about the impact of co-morbidities on health-related quality of life (HRQoL) for people with idiopathic pulmonary fibrosis (IPF). We aimed to investigate the relative contribution of co-morbidities to HRQoL of people with IPF. METHODS: N = 157 participants were recruited from the Australian IPF Registry (AIPFR). Health state utilities (HSUs), and the super-dimensions of physical and psychosocial scores were measured using the Assessment of Quality of Life-8-Dimensions (AQoL-8D). The impact of co-morbidities on HRQoL was investigated using linear regression and general dominance analyses. RESULTS: A higher number of co-morbidities was associated with lower HSUs (p trend = 0.002). Co-morbidities explained 9.1% of the variance of HSUs, 16.0% of physical super-dimensional scores, and 4.2% of psychosocial super-dimensional scores. Arthritis was associated with a significant reduction on HSUs (ß = - 0.09, 95% confidence interval [CI] - 0.16 to - 0.02), largely driven by reduced scores on the physical super-dimension (ß = - 0.13, 95% CI - 0.20 to - 0.06). Heart diseases were associated with a significant reduction on HSUs (ß = - 0.09, 95% CI - 0.16 to - 0.02), driven by reduced scores on physical (ß = - 0.09, 95% CI - 0.16 to - 0.02) and psychosocial (ß = -0.10, 95% CI - 0.17 to - 0.02) super-dimensions. CONCLUSIONS: Co-morbidities significantly impact HRQoL of people with IPF, with markedly negative impacts on their HSUs and physical health. A more holistic approach to the care of people with IPF is important as better management of these co-morbidities could lead to improved HRQoL in people with IPF.

Long-term exposure to low concentrations of air pollution and decline in lung function in people with idiopathic pulmonary fibrosis: Evidence from Australia.

BACKGROUND AND OBJECTIVE: Little is known about the association between ambient air pollution and idiopathic pulmonary fibrosis (IPF) in areas with lower levels of exposure. We aimed to investigate the impact of air pollution on lung function and rapid progression of IPF in Australia. METHODS: Participants were recruited from the Australian IPF Registry (n = 570). The impact of air pollution on changes in lung function was assessed using linear mixed models and Cox regression was used to investigate the association with rapid progression. RESULTS: Median (25th-75th percentiles) annual fine particulate matter (<2.5 µm, PM2.5 ) and nitrogen dioxide (NO2 ) were 6.8 (5.7, 7.9) µg/m3 and 6.7 (4.9, 8.2) ppb, respectively. Compared to living more than 100 m from a major road, living within 100 m was associated with a 1.3% predicted/year (95% confidence interval [CI] -2.4 to -0.3) faster annual decline in diffusing capacity of the lungs for carbon monoxide (DLco). Each interquartile range (IQR) of 2.2 µg/m3 increase in PM2.5 was associated with a 0.9% predicted/year (95% CI -1.6 to -0.3) faster annual decline in DLco, while there was no association observed with NO2 . There was also no association between air pollution and rapid progression of IPF. CONCLUSION: Living near a major road and increased PM2.5 were both associated with an increased rate of annual decline in DLco. This study adds to the evidence supporting the negative effects of air pollution on lung function decline in people with IPF living at low-level concentrations of exposure.

Biomarker signatures for progressive idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease in which circulatory biomarkers have the potential for guiding management in clinical practice. We assessed the prognostic role of serum biomarkers in three independent IPF cohorts: Australian Idiopathic Pulmonary Fibrosis Registry (AIPFR), Trent Lung Fibrosis (TLF) and Prospective Observation of Fibrosis in the Lung Clinical Endpoints (PROFILE). METHODS: In the AIPFR cohort, candidate proteins were assessed by ELISA as well as in an unbiased proteomic approach. LASSO (least absolute shrinkage and selection operator) regression was used to restrict the selection of markers that best accounted for the progressor phenotype at 1 year in the AIPFR cohort, and subsequently prospectively selected for replication in the validation TLF cohort and assessed retrospectively in the PROFILE cohort. Four significantly replicating biomarkers were aggregated into a progression index model based on tertiles of circulating concentrations. RESULTS: 189 participants were included in the AIPFR cohort, 205 participants from the TLF cohort and 122 participants from the PROFILE cohort. Differential biomarker expression was observed by ELISA and replicated for osteopontin, matrix metallopeptidase-7, intercellular adhesion molecule-1 and periostin for those with a progressor phenotype at 1 year. Proteomic data did not replicate. The progression index in the AIPFR, TLF and PROFILE cohorts predicted risk of progression, mortality and progression-free survival. A statistical model incorporating the progression index demonstrated the capacity to distinguish disease progression at 12 months, which was increased beyond the clinical GAP (gender, age and physiology) score model alone in all cohorts, and significantly so within the incidence-based TLF and PROFILE cohorts. CONCLUSION: A panel of circulatory biomarkers can provide potentially valuable clinical assistance in the prognosis of IPF patients.

Incidence and predictors of idiopathic pulmonary fibrosis complicating Type 2 diabetes: the Fremantle Diabetes Study Phase I.

During 106 865 person-years of follow up, 17 (1.3%) Fremantle Diabetes Study Phase I participants with Type 2 diabetes and 57 (1.1%) matched individuals without diabetes developed idiopathic pulmonary fibrosis (IPF), an incidence rate ratio (95% confidence interval) of 1.40 (0.76-2.44) (P = 0.22). In the diabetes cohort, age at diabetes diagnosis and total serum cholesterol (inversely) predicted incident IPF in competing risk multivariable models. The incidence of IPF was low in community-based cohorts, regardless of Type 2 diabetes status.

Changing causes of death for patients with chronic respiratory disease in England, 2005-2015.

BACKGROUND: Chronic respiratory diseases (CRD) are common, are increasing in prevalence, and cause significant morbidity and mortality worldwide. However, we have limited knowledge on causes of death of patients with CRD in the general population. OBJECTIVE: We evaluated mortality rates and causes of death over time in patients with CRD. METHODS: We used linked primary care and mortality data to determine mortality rates and the most common causes of death in people with CRD (including asthma, bronchiectasis, COPD and interstitial lung diseases (ILD)) during 2005-2015 in England. RESULTS: We identified 558 888 patients with CRD (451 830 asthma, 137 709 COPD, 19 374 bronchiectasis, 10 745 ILD). The age-standardised mortality rate of patients with CRD was 1607 per 100 000 persons (asthma=856, COPD=1503, ILD=2609, bronchiectasis=1463). CRD mortality was overall 54% higher than the general population. A third of patients with CRD died from respiratory-related causes. Respiratory-related mortality was constant, while cardiovascular-related mortality decreased significantly over time. COPD accounted for the majority of respiratory-related deaths (66% overall) in all patient groups except ILD. CONCLUSIONS: Patients with CRD continue to experience substantial morbidity and mortality due to respiratory diseases. Disease-modifying intervention strategies are needed to improve outcomes for patients with CRD.

Paediatric and adult bronchiectasis: Monitoring, cross-infection, role of multidisciplinary teams and self-management plans.

Bronchiectasis is a chronic lung disease associated with structurally abnormal bronchi, clinically manifested by a persistent wet/productive cough, airway infections and recurrent exacerbations. Early identification and treatment of acute exacerbations is an integral part of monitoring and annual review, in both adults and children, to minimize further damage due to infection and inflammation. Common modalities used to monitor disease progression include clinical signs and symptoms, frequency of exacerbations and/or number of hospital admissions, lung function (forced expiratory volume in 1 s (FEV1 )% predicted), imaging (radiological severity of disease) and sputum microbiology (chronic infection with Pseudomonas aeruginosa). There is good evidence that these monitoring tools can be used to accurately assess severity of disease and predict prognosis in terms of mortality and future hospitalization. Other tools that are currently used in research settings such as health-related quality of life (QoL) questionnaires, magnetic resonance imaging and lung clearance index can be burdensome and require additional expertise or resource, which limits their use in clinical practice. Studies have demonstrated that cross-infection, especially with P. aeruginosa between patients with bronchiectasis is possible but infrequent. This should not limit participation of patients in group activities such as pulmonary rehabilitation, and simple infection control measures should be carried out to limit the risk of cross-transmission. A multidisciplinary approach to care which includes respiratory physicians, chest physiotherapists, nurse specialists and other allied health professionals are vital in providing holistic care. Patient education and personalized self-management plans are also important despite limited evidence it improves QoL or frequency of exacerbations.

Extracellular Matrix Cross-Linking Enhances Fibroblast Growth and Protects against Matrix Proteolysis in Lung Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is characterized by accumulation of extracellular matrix (ECM) proteins and fibroblast proliferation. ECM cross-linking enzymes have been implicated in fibrotic diseases, and we hypothesized that the ECM in IPF is abnormally cross-linked, which enhances fibroblast growth and resistance to normal ECM turnover. We used a combination of in vitro ECM preparations and in vivo assays to examine the expression of cross-linking enzymes and the effect of their inhibitors on fibroblast growth and ECM turnover. Lysyl oxidase-like 1 (LOXL1), LOXL2, LOXL3, and LOXL4 were expressed equally in control and IPF-derived fibroblasts. Transglutaminase 2 was more strongly expressed in IPF fibroblasts. LOXL2-, transglutaminase 2-, and transglutaminase-generated cross-links were strongly expressed in IPF lung tissue. Fibroblasts grown on IPF ECM had higher LOXL3 protein expression and transglutaminase activity than those grown on control ECM. IPF-derived ECM also enhanced fibroblast adhesion and proliferation compared with control ECM. Inhibition of lysyl oxidase and transglutaminase activity during ECM formation affected ECM structure as visualized by electron microscopy, and it reduced the enhanced fibroblast adhesion and proliferation of IPF ECM to control levels. Inhibition of transglutaminase, but not of lysyl oxidase, activity enhanced the turnover of ECM in vitro. In bleomycin-treated mice, during the postinflammatory fibrotic phase, inhibition of transglutaminases was associated with a reduction in whole-lung collagen. Our findings suggest that the ECM in IPF may enhance pathological cross-linking, which contributes to increased fibroblast growth and resistance to normal ECM turnover to drive lung fibrosis.

Timing of onset of symptoms in people with idiopathic pulmonary fibrosis.

Little is known about when symptoms of idiopathic pulmonary fibrosis first develop. We identified incident cases of idiopathic pulmonary fibrosis-clinical syndrome (IPF-CS) from a UK primary care database and assessed the frequency of consultations for common symptoms in the 5 years prior to diagnosis. 1671 cases were identified with 5 years of data prior to diagnosis. Breathlessness was the most common symptom, followed by cough. Cases were significantly more likely than controls to experience these symptoms (p<0.001), even 4-5 years before diagnosis (OR for breathlessness for this period 2.79, 95% CI 2.13 to 3.65). This suggests that some patients with IPF may be symptomatic for more than 5 years before diagnosis.

Bronchiectasis and the risk of cardiovascular disease: a population-based study.

BACKGROUND: There are limited data on the burden of cardiovascular comorbidities in people with bronchiectasis. Our cross-sectional study estimates the burden of pre-existing diagnoses of coronary heart disease (CHD) and stroke in people with bronchiectasis compared with the general population. The historical cohort study investigates if individuals with bronchiectasis are at increased risk of incident CHD and stroke events. METHODS: We used primary care electronic records from the Clinical Practice Research Datalink. The cross-sectional study used logistic regression to quantify the association between bronchiectasis and recorded diagnoses of CHD or stroke. Cox regression was used to investigate if people with bronchiectasis experienced increased incident CHD and strokes compared with the general population, adjusting for age, sex, smoking habit and other risk factors for cardiovascular disease. RESULTS: Pre-existing diagnoses of CHD (OR 1.33, 95% CI 1.25 to 1.41) and stroke (OR 1.92, 95% CI 1.85 to 2.01) were higher in people with bronchiectasis compared with those without bronchiectasis, after adjusting for age, sex, smoking and risk factors for cardiovascular disease. The rate of first CHD and stroke were also higher in people with bronchiectasis (HR for CHD 1.44 (95% CI 1.27 to 1.63) and HR for stroke 1.71 (95% CI 1.54 to 1.90)). CONCLUSION: The risk of CHD and stroke are higher among people with bronchiectasis compared with the general population. An increased awareness of these cardiovascular comorbidities in this population is needed to provide a more integrated approach to the care of these patients.

Surgical lung biopsy for the diagnosis of interstitial lung disease in England: 1997-2008.

International guidelines and new targeted therapies for idiopathic pulmonary fibrosis have increased the need for accurate diagnosis of interstitial lung disease (ILD), which may lead to more surgical lung biopsies. This study aimed to assess the risk of this procedure in patients from the UK.We used Hospital Episodes Statistics data from 1997 to 2008 to assess the frequency of surgical lung biopsy for ILD in England, UK. We identified cardiothoracic surgical patients using International Classification of Diseases revision 10 codes for ILD and Office of Population Censuses and Surveys Classification of Interventions and Procedures version 4 codes for surgical lung biopsy. We excluded those with lung resections or lung cancer. We estimated in-hospital, 30-day and 90-day mortality following the procedure, and linked to cause of death using data from the UK Office of National Statistics.We identified 2820 patients with ILD undergoing surgical lung biopsy during the 12-year period. The number of biopsies increased over the time period studied. In-hospital, 30-day and 90-day mortality were 1.7%, 2.4% and 3.9%, respectively. Male sex, increasing age, increasing comorbidity and open surgery were risk factors for mortality.Surgical lung biopsy for ILD has a similar mortality to lobectomy for lung cancer, and clinicians and patients should understand the likely risks involved.

Changes in the incidence, prevalence and mortality of bronchiectasis in the UK from 2004 to 2013: a population-based cohort study.

There is a paucity of data on incidence, prevalence and mortality associated with non-cystic fibrosis bronchiectasis.Using the Clinical Practice Research Datalink for participants registered between January 1, 2004 and December 31, 2013, we determined incidence, prevalence and mortality associated with bronchiectasis in the UK and investigated changes over time.The incidence and point prevalence of bronchiectasis increased yearly during the study period. Across all age groups, the incidence in women increased from 21.2 per 100 000 person-years in 2004 to 35.2 per 100 000 person-years in 2013 and in men from 18.2 per 100 000 person-years in 2004 to 26.9 per 100 000 person-years in 2013. The point prevalence in women increased from 350.5 per 100 000 in 2004 to 566.1 per 100 000 in 2013 and in men from 301.2 per 100 000 in 2004 to 485.5 per 100 000 in 2013. Comparing morality rates in women and men with bronchiectasis in England and Wales (n=11 862) with mortality rates in the general population from Office of National Statistics data showed that in women the age-adjusted mortality rate for the bronchiectasis population was 1437.7 per 100 000 and for the general population 635.9 per 100 000 (comparative mortality figure of 2.26). In men, the age-adjusted mortality rate for the bronchiectasis population was 1914.6 per 100 000 and for the general population 895.2 per 100 000 (comparative mortality figure of 2.14).Bronchiectasis is surprisingly common and is increasing in incidence and prevalence in the UK, particularly in older age groups. Bronchiectasis is associated with a markedly increased mortality.

Evaluation of the risk of cardiovascular events with clarithromycin using both propensity score and self-controlled study designs.

AIM: Some previous studies suggest a long term association between clarithromycin use and cardiovascular events. This study investigates this association for clarithromycin given as part of Helicobacter pylori treatment (HPT). METHODS: Our source population was the Clinical Practice Research Datalink (CPRD), a UK primary care database. We conducted a self-controlled case series (SCCS), a case-time-control study (CTC) and a propensity score adjusted cohort study comparing the rate of cardiovascular events in the 3 years after exposure to HPT containing clarithromycin with exposure to clarithromycin free HPT. Outcomes were first incident diagnosis of myocardial infarction (MI), arrhythmia and stroke. For the cohort analysis we included secondary outcomes all cause and cardiovascular mortality. RESULTS: Twenty-eight thousand five hundred and fifty-two patients were included in the cohort. The incidence rate ratio of first MI within 1 year of exposure to HPT containing clarithromycin was 1.07 (95% CI 0.85, 1.34, P = 0.58) and within 90 days was 1.43 (95% CI 0.99, 2.09 P = 0.057) in the SCCS analysis. CTC and cohort results were consistent with these findings. CONCLUSIONS: There was some evidence for a short term association for first MI but none for a long term association for any outcome.

Presence of a prothrombotic state in people with idiopathic pulmonary fibrosis: a population-based case-control study.

BACKGROUND: Laboratory studies suggest that the clotting cascade is activated in fibrotic lungs. Since humans vary in their tendency to clot due to a variety of inherited or acquired defects, we investigated whether a prothrombotic state increases the chance of developing idiopathic pulmonary fibrosis (IPF) and/or worsens the prognosis of IPF. METHODS: We recruited 211 incident cases of IPF and 256 age- and sex-matched general population controls and collected data on medical history, medication, smoking habit, blood samples as well as lung function and high-resolution CT scans done as part of routine clinical care. A prothrombotic state was defined as the presence of at least one inherited or acquired clotting defect or marker of fibrinolytic dysfunction. We used logistic regression to quantify the association between a prothrombotic state and IPF adjusted for age, sex, smoking habit and highly sensitive C reactive protein. Cox regression was used to determine the influence of a prothrombotic state on survival. RESULTS: Cases were more than four times more likely than controls to have a prothrombotic state (OR 4.78, 95% CI 2.93 to 7.80; p<0.0001). Cases with a prothrombotic state were also likely to have more severe disease (forced vital capacity <70% predicted) at presentation (OR 10.79, 95% CI 2.43 to 47.91) and had a threefold increased risk of death (HR 3.26, 95% CI 1.09 to 9.75). CONCLUSIONS: People with IPF are more likely to have a prothrombotic state than general population controls and the presence of a prothrombotic state has an adverse impact on survival.

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.

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.

Mapping EQ5D utilities from forced vital capacity and diffusing capacity in fibrotic interstitial lung disease.

OBJECTIVES: Fibrotic interstitial lung disease (ILD) includes a large group of conditions that lead to scarring of the lungs. The lack of available 5-level EuroQol 5D (EQ5D) data has limited the ability to conduct economic evaluations in ILD. The purpose of this study was to develop and validate a mapping algorithm that predicts EQ5D utilities from commonly collected pulmonary function measurements (forced vital capacity [FVC] and diffusing capacity of the lung for carbon monoxide [DLCO]) in fibrotic ILDs. METHODS: EQ5D utility and pulmonary function measurements from the Canadian Registry for Pulmonary Fibrosis were included. Ordinary least squares (OLS), beta regression, two-part, and tobit models were used to map EQ5D utilities from FVC or DLCO. Model performance was assessed by comparing the predicted and observed utilities. Subgroup analyses were also conducted to test how well models performed across different patient characteristics. The models were then externally validated in the Australian Idiopathic Pulmonary Fibrosis Registry. RESULTS: The OLS model performed as well as other more complex models (root mean squared error: 0.17 for FVC and 0.16 for DLCO). As with the other models, the OLS algorithm performed well across the different subgroups (except for EQ5D utilities < 0.5) and in the external validation cohort. CONCLUSION: We developed a mapping algorithm that predicts EQ5D utilities from FVC and DLCO, with the intent that this algorithm can be applied to clinical trial populations and real-world cohorts that have not prioritized collection of health-related utilities. The mapping algorithm can be used in future economic evaluations of potential ILD therapies.

Longitudinal lung function and gas transfer in individuals with idiopathic pulmonary fibrosis: a genome-wide association study.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an incurable lung disease characterised by progressive scarring leading to alveolar stiffness, reduced lung capacity, and impeded gas transfer. We aimed to identify genetic variants associated with declining lung capacity or declining gas transfer after diagnosis of IPF. METHODS: We did a genome-wide meta-analysis of longitudinal measures of forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO) in individuals diagnosed with IPF. Individuals were recruited to three studies between June, 1996, and August, 2017, from across centres in the US, UK, and Spain. Suggestively significant variants were investigated further in an additional independent study (CleanUP-IPF). All four studies diagnosed cases following American Thoracic Society/European Respiratory Society guidelines. Variants were defined as significantly associated if they had a meta-analysis p<5 × 10-8 when meta-analysing across all discovery and follow-up studies, had consistent direction of effects across all four studies, and were nominally significant (p<0·05) in each study. FINDINGS: 1329 individuals with a total of 5216 measures were included in the FVC analysis. 975 individuals with a total of 3361 measures were included in the DLCO analysis. For the discovery genome-wide analyses, 7 611 174 genetic variants were included in the FVC analysis and 7 536 843 in the DLCO analysis. One variant (rs115982800) located in an antisense RNA gene for protein kinase N2 (PKN2) showed a genome-wide significant association with FVC decline (-140 mL/year per risk allele [95% CI -180 to -100]; p=9·14 × 10-12). INTERPRETATION: Our analysis identifies a genetic variant associated with disease progression, which might highlight a new biological mechanism for IPF. We found that PKN2, a Rho and Rac effector protein, is the most likely gene of interest from this analysis. PKN2 inhibitors are currently in development and signify a potential novel therapeutic approach for IPF. FUNDING: Action for Pulmonary Fibrosis, Medical Research Council, Wellcome Trust, and National Institutes of Health National Heart, Lung, and Blood Institute.