Genome-wide association study of preserved ratio impaired spirometry (PRISm).

BACKGROUND: Preserved ratio impaired spirometry (PRISm) is defined as a forced expiratory volume in 1 s (FEV1) <80% predicted and FEV1/forced vital capacity ≥0.70. PRISm is associated with respiratory symptoms and comorbidities. Our objective was to discover novel genetic signals for PRISm and see if they provide insight into the pathogenesis of PRISm and associated comorbidities. METHODS: We undertook a genome-wide association study (GWAS) of PRISm in UK Biobank participants (Stage 1), and selected single nucleotide polymorphisms (SNPs) reaching genome-wide significance for replication in 13 cohorts (Stage 2). A combined meta-analysis of Stage 1 and Stage 2 was done to determine top SNPs. We used cross-trait linkage disequilibrium score regression to estimate genome-wide genetic correlation between PRISm and pulmonary and extrapulmonary traits. Phenome-wide association studies of top SNPs were performed. RESULTS: 22 signals reached significance in the joint meta-analysis, including four signals novel for lung function. A strong genome-wide genetic correlation (rg) between PRISm and spirometric COPD (rg=0.62, p<0.001) was observed, and genetic correlation with type 2 diabetes (rg=0.12, p=0.007). Phenome-wide association studies showed that 18 of 22 signals were associated with diabetic traits and seven with blood pressure traits. CONCLUSION: This is the first GWAS to successfully identify SNPs associated with PRISm. Four of the signals, rs7652391 (nearest gene MECOM), rs9431040 (HLX), rs62018863 (TMEM114) and rs185937162 (HLA-B), have not been described in association with lung function before, demonstrating the utility of using different lung function phenotypes in GWAS. Genetic factors associated with PRISm are strongly correlated with risk of both other lung diseases and extrapulmonary comorbidity.

Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk.

Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.

Frailty Transitions in Older Persons With Lung Function Impairment: A Population-Based Study.

BACKGROUND: The aging population and its burden on health care systems warrant early detection of patients at risk of functional decline and mortality. We aimed to assess frailty transitions and its accuracy for mortality prediction in participants with impaired spirometry (Preserved Ratio Impaired Spirometry [PRISm] or chronic obstructive pulmonary disease [COPD]). METHODS: In participants from the population-based Rotterdam Study (mean age 69.1 ± 8.9 years), we examined whether PRISm (forced expiratory volume in 1 second [FEV1]/forced vital capacity [FVC] ≥ 70% and FEV1 < 80%) or COPD (FEV1/FVC < 70%) affected frailty transitions (progression/recovery between frailty states [robust, prefrailty, and frailty], lost to follow-up, or death) using age-, sex- and smoking state-adjusted multinomial regression models yielding odds ratios (OR). Second, we assessed the diagnostic accuracy of frailty score for predicting mortality in participants with COPD using c-statistics. RESULTS: Compared to participants with normal spirometry, participants with PRISm were more likely to transit from robust (OR 2.2 [1.2-4.2], p < .05) or prefrailty (OR 2.6 [1.3-5.5], p < .01) toward frailty. Participants with PRISm (OR 0.4 [0.2-0.8], p < .05) and COPD (OR 0.6 [0.4-1.0], NS) were less likely to recover from their frail state, and were more likely to progress from any frailty state toward death (OR between 1.1 and 2.8, p < .01). Accuracy for predicting mortality in participants with COPD significantly improved when adding frailty score to age, sex, and smoking status (90.5 [82.3-89.8] vs 77.9 [67.2-88.6], p < .05). CONCLUSION: Participants with PRISm or COPD more often developed frailty with poor reversibility. Assessing physical frailty improved risk stratification for participants with impaired spirometry for predicting increased life years.

Sarcopenia, systemic immune-inflammation index and all-cause mortality in middle-aged and older people with COPD and asthma: a population-based study.

BACKGROUND: Increasing evidence suggests that sarcopenia and a higher systemic immune-inflammation index (SII) are linked with morbidity in patients with COPD. However, whether these two conditions contribute to all-cause mortality in middle-aged and older patients with COPD or asthma is unclear. Therefore, we investigated the association between sarcopenia, SII, COPD or asthma and all-cause mortality in a large-scale population-based setting. METHODS: Between 2009 and 2014, 4482 participants (aged >55 years; 57.3% female) from the population-based Rotterdam Study were included. COPD and asthma patients were diagnosed clinically and based on spirometry. Six study groups were defined according to the presence or absence of COPD or asthma and sarcopenia. Cox regression models were used to assess all-cause mortality in the study groups, adjusted for sex, age, body mass index, SII, smoking, oral corticosteroid use and comorbidities. In addition, all participants were categorised into sex-specific quartiles of SII, and mortality in these groups was compared. RESULTS: Over a median follow-up of 6.1 years (interquartile range 5.0-7.2 years), 466 (10.4%) persons died. Independent of the presence of sarcopenia, participants with COPD had a higher risk of all-cause mortality (hazard ratio (HR) 2.13, 95% CI 1.46-3.12 and HR 1.70, 95% CI 1.32-2.18 for those with and without sarcopenia, respectively). Compared to lower SII levels, higher SII levels increased mortality risk even in people without sarcopenia, COPD or asthma. CONCLUSION: Middle-aged and older people with COPD, higher SII levels or sarcopenia had an independently increased mortality risk. Our study suggests prognostic usefulness of routinely evaluating sarcopenia and SII in older people with COPD or asthma.

Changes in lung function in European adults born between 1884 and 1996 and implications for the diagnosis of lung disease: a cross-sectional analysis of ten population-based studies.

BACKGROUND: During the past century, socioeconomic and scientific advances have resulted in changes in the health and physique of European populations. Accompanying improvements in lung function, if unrecognised, could result in the misclassification of lung function measurements and misdiagnosis of lung diseases. We therefore investigated changes in population lung function with birth year across the past century, accounting for increasing population height, and examined how such changes might influence the interpretation of lung function measurements. METHODS: In our analyses of cross-sectional data from ten European population-based studies, we included individuals aged 20-94 years who were born between 1884 and 1996, regardless of previous respiratory diagnoses or symptoms. FEV1, forced vital capacity (FVC), height, weight, and smoking behaviour were measured between 1965 and 2016. We used meta-regression to investigate how FEV1 and FVC (adjusting for age, study, height, sex, smoking status, smoking pack-years, and weight) and the FEV1/FVC ratio (adjusting for age, study, sex, and smoking status) changed with birth year. Using estimates from these models, we graphically explored how mean lung function values would be expected to progressively deviate from predicted values. To substantiate our findings, we used linear regression to investigate how the FEV1 and FVC values predicted by 32 reference equations published between 1961 and 2015 changed with estimated birth year. FINDINGS: Across the ten included studies, we included 243 465 European participants (mean age 51·4 years, 95% CI 51·4-51·5) in our analysis, of whom 136 275 (56·0%) were female and 107 190 (44·0%) were male. After full adjustment, FEV1 increased by 4·8 mL/birth year (95% CI 2·6-7·0; p<0·0001) and FVC increased by 8·8 mL/birth year (5·7-12·0; p<0·0001). Birth year-related increases in the FEV1 and FVC values predicted by published reference equations corroborated these findings. This height-independent increase in FEV1 and FVC across the last century will have caused mean population values to progressively exceed previously predicted values. However, the population mean adjusted FEV1/FVC ratio decreased by 0·11 per 100 birth years (95% CI 0·09-0·14; p<0·0001). INTERPRETATION: If current diagnostic criteria remain unchanged, the identified shifts in European values will allow the easier fulfilment of diagnostic criteria for lung diseases such as chronic obstructive pulmonary disease, but the systematic underestimation of lung disease severity. FUNDING: The European Respiratory Society, AstraZeneca, Chiesi Farmaceutici, GlaxoSmithKline, Menarini, and Sanofi-Genzyme.

Comparison of cerebral blood flow in subjects with and without chronic obstructive pulmonary disease from the population-based Rotterdam Study.

OBJECTIVES: Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of cerebrovascular disease, which might be associated with decreases in cerebral blood flow. Since studies examining cerebral blood flow in COPD remain scarce and are limited by sample size, we aimed to study cerebral blood flow in participants with and without COPD. DESIGN: Observational cohort study. SETTING: Population-based Rotterdam Study. PARTICIPANTS: 4177 participants (age 68.0±8.5 years; 53% females) with and without COPD. PREDICTOR VARIABLE: Spirometry and pulmonary diffusing capacity. OUTCOME MEASURES: Cerebral blood flow by two-dimensional phase-contrast cerebral MRI. RESULTS: Compared with subjects with normal spirometry (forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ≥0.7 and FEV1 ≥80%), multivariable adjusted cerebral blood flow (mL/min) was preserved in subjects with COPD Global initiative for Chronic Obstructive Lung Disease (GOLD1) (FEV1/FVC <0.7 and FEV1 ≥80%), but significantly lower in subjects with COPD GOLD2-3 (FEV1/FVC <0.7 and FEV1 <80%), even after adjustment for cardiovascular comorbidities. In sex-stratified analyses, this difference in cerebral blood flow was statistically significant in women but not in men. Cerebral blood flow was lowest in subjects with FEV1, FVC and diffusion lung capacity for carbon monoxide % predicted values in the lowest quintile, even after adjustment for cardiovascular comorbidities and cardiac function. CONCLUSION: We observed a lowered cerebral blood flow in subjects with COPD GOLD2-3.

Lung Function Impairment and the Risk of Incident Dementia: The Rotterdam Study.

BACKGROUND: The etiology of dementia may partly be underpinned by impaired lung function via systemic inflammation and hypoxia. OBJECTIVE: To prospectively examine the association between chronic obstructive pulmonary disease (COPD) and subclinical impairments in lung function and the risk of dementia. METHODS: In the Rotterdam Study, we assessed the risk of incident dementia in participants with Preserved Ratio Impaired Spirometry (PRISm; FEV1/FVC≥0.7, FEV1 < 80% predicted) and in participants with COPD (FEV1/FVC < 0.7) compared to those with normal spirometry (controls; FEV1/FVC≥0.7, FEV1≥80% predicted). Hazard ratios (HRs) with 95% confidence intervals (CI) for dementia were adjusted for age, sex, education attainment, smoking status, systolic blood pressure, body mass index, triglycerides, comorbidities and Apolipoprotein E (APOE) genotype. RESULTS: Of 4,765 participants, 110 (2.3%) developed dementia after 3.3 years. Compared to controls, participants with PRISm, but not COPD, had an increased risk for all-type dementia (adjusted HRPRISm 2.70; 95% CI, 1.53-4.75; adjusted HRCOPD 1.03; 95% CI, 0.61-1.74). These findings were primarily driven by men and smokers. Similarly, participants with FVC% predicted values in the lowest quartile compared to those in the highest quartile were at increased risk of all-type dementia (adjusted HR 2.28; 95% CI, 1.31-3.98), as well as Alzheimer's disease (AD; adjusted HR 2.13; 95% CI, 1.13-4.02). CONCLUSION: Participants with PRISm or a low FVC% predicted lung function were at increased risk of dementia, compared to those with normal spirometry or a higher FVC% predicted, respectively. Further research is needed to elucidate whether this association is causal and how PRISm might contribute to dementia pathogenesis.

Effect of ACE1 polymorphism rs1799752 on protein levels of ACE2, the SARS-CoV-2 entry receptor, in alveolar lung epithelium.

Increased protein levels of ACE2 in alveolar epithelium of subjects who are homozygous for the ACE1 insertion of rs1799752 might facilitate host cell entry of #SARSCoV2 and explain the higher prevalence of #COVID19 in certain regions https://bit.ly/3k6aAE8.

Expression of ACE2, the SARS-CoV-2 Receptor, in Lung Tissue of Patients With Type 2 Diabetes.

Increased expression of pulmonary ACE2, the SARS-CoV-2 receptor, could contribute to increased infectivity of COVID-19 in patients with diabetes, but ACE2 expression has not been studied in lung tissue of subjects with diabetes. We therefore studied ACE2 mRNA and protein expression in lung tissue samples of subjects with and without diabetes that were collected between 2002 and 2020 from patients undergoing lobectomy for lung tumors. For RT-PCR analyses, samples from 15 subjects with diabetes were compared with 91 randomly chosen control samples. For immunohistochemical staining, samples from 26 subjects with diabetes were compared with 66 randomly chosen control samples. mRNA expression of ACE2 was measured by quantitative RT-PCR. Protein levels of ACE2 were visualized by immunohistochemistry on paraffin-embedded lung tissue samples and quantified in alveolar and bronchial epithelium. Pulmonary ACE2 mRNA expression was not different between subjects with or without diabetes. In contrast, protein levels of ACE2 were significantly increased in both alveolar tissue and bronchial epithelium of patients with diabetes compared with control subjects, independent of smoking, chronic obstructive pulmonary disease, BMI, renin-angiotensin-aldosterone system inhibitor use, and other potential confounders. To conclude, we show increased bronchial and alveolar ACE2 protein expression in patients with diabetes. Further research is needed to elucidate whether upregulation of ACE2 expression in airways and lungs has consequences on infectivity and clinical outcomes of COVID-19.

Blood eosinophil level and lung function trajectories: cross-sectional and longitudinal studies in European cohorts.

BACKGROUND: Elevated blood eosinophils have been associated with lower lung function and are believed to be associated with accelerated lung function decline. METHOD: Blood eosinophils were measured in four cohorts: <45 years cohort within the Vlagtwedde-Vlaardingen (V&V) study, the Uppsala cohort of the European Community Respiratory Health Survey (ECRHS-Uppsala; <45 years), ≥45 years cohort within the V&V study, and the Rotterdam study (≥45 years). Blood eosinophils at baseline were classified as normal (<300 cells·µL-1) or elevated (≥300 cells·µL-1). Lung function was measured at baseline and follow-up with spirometry: forced expiratory volume in 1 s (FEV1), vital capacity (VC) and their ratio FEV1/VC. The association between blood eosinophils and lung function was tested cross-sectionally using linear regression and longitudinally using a mixed model, both adjusted for age, sex, height, pack-years smoking and smoking status. Stratified analyses were done for asthma. RESULTS: Elevated blood eosinophils were associated with lower FEV1 (regression coefficient -147 mL (95% CI -188 to -105 mL)), VC (-120 mL (-165 to -75 mL)) and FEV1/VC (-1.3% (-1.9% to -0.6%)) at baseline in the two <45 years cohorts, and with lower FEV1 (-70 mL (-112 to -27 mL)) and FEV1/VC (-1.8% (-2.6% to -1.0%)) in the two ≥45 years cohorts. Elevated blood eosinophils were associated with an accelerated decline in FEV1 (-5.5 mL·year-1 (95% CI -10.5 to -0.5 mL·year-1)) and VC (-6.4 mL·year-1 (-11.26 to -1.5 mL·year-1)) compared to normal blood eosinophils in the younger asthmatic subjects in the longitudinal studies. CONCLUSION: Elevated blood eosinophils are associated with lower lung function in the general population and with an accelerated lung function decline among asthmatic individuals.

Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts.

BACKGROUND: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes. METHODS: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV1 and FEV1/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV1/FVC <0·7 and FEV1 <80% of predicted). Associations were tested using logistic regression models, adjusting for age, sex, height, smoking pack-years, and principal components of genetic ancestry. We assessed predictive performance of models by area under the curve. In a subset of studies, we also studied quantitative and qualitative CT imaging phenotypes that reflect parenchymal and airway pathology, and patterns of reduced lung growth. FINDINGS: The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·81 [95% CI 1·74-1·88] and non-European (1·42 [1·34-1·51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56-9·72) in European ancestry and 4·83 (3·45-6·77) in non-European ancestry cohorts. The polygenic risk score was superior to previously described genetic risk scores and, when combined with clinical risk factors (ie, age, sex, and smoking pack-years), showed improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79-0·81] vs 0·76 [0·75-0·76]). The polygenic risk score was associated with CT imaging phenotypes, including wall area percent, quantitative and qualitative measures of emphysema, local histogram emphysema patterns, and destructive emphysema subtypes. The polygenic risk score was associated with a reduced lung growth pattern. INTERPRETATION: A risk score comprised of genetic variants can identify a small subset of individuals at markedly increased risk for moderate-to-severe COPD, emphysema subtypes associated with cigarette smoking, and patterns of reduced lung growth. FUNDING: US National Institutes of Health, Wellcome Trust.

Validation of the BOADICEA model and a 313-variant polygenic risk score for breast cancer risk prediction in a Dutch prospective cohort.

PURPOSE: We evaluated the performance of the recently extended Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA version 5) in a Dutch prospective cohort, using a polygenic risk score (PRS) based on 313 breast cancer (BC)-associated variants (PRS313) and other, nongenetic risk factors. METHODS: Since 1989, 6522 women without BC aged 45 or older of European descent have been included in the Rotterdam Study. The PRS313 was calculated per 1 SD in controls from the Breast Cancer Association Consortium (BCAC). Cox regression analysis was performed to estimate the association between the PRS313 and incident BC risk. Cumulative 10-year risks were calculated with BOADICEA including different sets of variables (age, risk factors and PRS313). C-statistics were used to evaluate discriminative ability. RESULTS: In total, 320 women developed BC. The PRS313 was significantly associated with BC (hazard ratio [HR] per SD of 1.56, 95% confidence interval [CI] [1.40-1.73]). Using 10-year risk estimates including age and the PRS313, other risk factors improved the discriminatory ability of the BOADICEA model marginally, from a C-statistic of 0.636 to 0.653. CONCLUSIONS: The effect size of the PRS313 is highly reproducible in the Dutch population. Our results validate the BOADICEA v5 model for BC risk assessment in the Dutch general population.

Atherosclerotic calcification in major vessel beds in chronic obstructive pulmonary disease: The Rotterdam Study.

BACKGROUND AND AIMS: COPD is associated with an increased risk of cardiovascular morbidity and mortality, potentially by mechanisms of atherosclerosis. Insight into location-specific vulnerability to atherosclerosis in COPD, including intracranial arteries, is lacking. We aimed to investigate the relation between COPD and atherosclerosis in multiple vessel beds within a large population-based cohort study. METHODS: From 2003 to 2006, a random sample of 2187 elderly participants (mean age, 69.6 ±â€¯6.8 years; 50.9% female; 11.7% COPD) from the population-based Rotterdam Study underwent computed tomography to quantify atherosclerotic coronary artery calcification (CAC), aortic arch calcification (AAC), extracranial carotid artery calcification (ECAC), and intracranial carotid artery calcification (ICAC). We investigated the association of COPD [ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC) < 70%] with the presence of calcification and with calcification volumes in each vessel bed using logistic and linear regression, with adjustments for cardiovascular risk factors including smoking. RESULTS: The prevalence of CAC, AAC and ECAC was significantly higher in subjects with COPD compared to those without. After adjusting for age and smoking, COPD remained associated with the presence of ECAC (odds ratio 1.46 [95% confidence interval, 1.02-2.07, p = 0.037]). COPD was significantly associated with larger calcification volumes in all four vessel beds in people in whom calcification was present. CONCLUSIONS: The results of this study suggest that COPD plays a role in extracranial carotid artery atherosclerosis initiation and systemic atherosclerosis aggravation.

Prevalence of Asthma and COPD and Blood Eosinophil Count in a Middle-Aged Belgian Population.

Various phenotypes exist in asthma and Chronic Obstructive Pulmonary Disease (COPD). These are important to identify in order to guide treatment decisions. We aim to investigate the prevalence and clinical characteristics of obstructive airway diseases in the middle-aged population. We estimated the prevalence of COPD and/or asthma in the Asklepios cohort study (Belgium), using information from the third European Community Respiratory Health Survey (ECRHS3), medical records, and spirometry. Respiratory symptoms, respiratory medication, and current disease status distinguished clinical from sub-clinical cases. In addition, we compared the blood eosinophil count/µL (median [IQR]) between cases and controls. Of the 2221 participants (mean age 56.1 ± 5.9 years; 48.7% males), 138 (6.2%) participants had clinical current asthma, 22 (1.0%) participants had sub-clinical ever asthma, 102 (4.6%) had sub-clinical spirometry-defined COPD, 104 (4.6%) participants had clinical spirometry-confirmed COPD, and 11 (0.5%) had asthma and COPD overlap (ACO). Clinical current asthma (160.0 [110.0-250.0]), sub-clinical ever asthma (170.0 [110.0-230.0]), and clinical COPD (160.0 [110.0-220.0])-but less sub-clinical COPD (140.0 [90.0-210.0])-had higher eosinophil counts, compared to controls (130.0 [80.0-200.0]). We conclude that obstructive airway diseases are prevalent in the middle-aged Asklepios cohort. Moreover, the systemic eosinophil count is increased in clinical COPD cases, and in asthma cases regardless of clinical remission.