Search

The Rotterdam Study is an ongoing prospective, population-based cohort study that started in 1989 in the city of Rotterdam, the Netherlands. The study aims to unravel etiology, preclinical course, natural history and potential targets for intervention for chronic diseases in mid-life and late-life. It focuses on cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, otolaryngological, locomotor, and respiratory diseases. In response to the COVID-19 pandemic, a substudy was designed and embedded within the Rotterdam Study. On the 20th of April, 2020, all living non-institutionalized participants of the Rotterdam Study (n = 8732) were invited to participate in this sub-study by filling out a series of questionnaires administered over a period of 8 months. These questionnaires included questions on COVID-19 related symptoms and risk factors, characterization of lifestyle and mental health changes, and determination of health care seeking and health care avoiding behavior during the pandemic. As of May 2021, the questionnaire had been sent out repeatedly for a total of six times with an overall response rate of 76%. This article provides an overview of the rationale, design, and implementation of this sub-study nested within the Rotterdam Study. Finally, initial results on participant characteristics and prevalence of COVID-19 in this community-dwelling population are shown. Supplementary Information The online version contains supplementary material available at 10.1007/s10654-021-00789-7.

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

Initial results from various phase-III trials on vaccines against SARS-CoV-2 are promising. For proper translation of these results to clinical guidelines, it is essential to determine how well the general population is reflected in the study populations of these trials. This study was conducted among 7162 participants (age-range: 51–106 years; 58% women) from the Rotterdam Study. We quantified the proportion of participants that would be eligible for the nine ongoing phase-III trials. We further quantified the eligibility among participants at high risk to develop severe COVID-19. Since many trials were not explicit in their exclusion criterion with respect to ‘acute’ or ‘unstable preexisting’ diseases, we performed two analyses. First, we included all participants irrespective of this criterion. Second, we excluded persons with acute or ‘unstable preexisting’ diseases. 97% of 7162 participants was eligible for any trial with eligibility for separate trials ranging between 11–97%. For high-risk individuals the corresponding numbers were 96% for any trial with separate trials ranging from 5–96%. Importantly, considering persons ineligible due to ‘acute’ or ‘unstable pre-existing’ disease drastically dropped the eligibilities for all trials below 43% for the total population and below 36% for high-risk individuals. The eligibility for ongoing vaccine trials against SARS-CoV-2 can reduce by half depending on interpretation and application of a single unspecified exclusion criterion. This exclusion criterion in our study would especially affect the elderly and those with pre-existing morbidities. These findings thus indicate the difficulty as well as importance of developing clinical recommendations for vaccination and applying these to the appropriate target populations. This becomes especially paramount considering the fact that many countries worldwide have initiated their vaccination programs by first targeting the elderly and most vulnerable persons. Supplementary Information The online version contains supplementary material available at 10.1007/s10654-021-00729-5.

Contains fulltext : 251528.pdf (Publisher’s version ) (Open Access) The interocular distance, or orbital telorism, is a distinctive craniofacial trait that also serves as a clinically informative measure. While its extremes, hypo- and hypertelorism, have been linked to monogenic disorders and are often syndromic, little is known about the genetic determinants of interocular distance within the general population. We derived orbital telorism measures from cranial magnetic resonance imaging by calculating the distance between the eyeballs' centre of gravity, which showed a good reproducibility with an intraclass correlation coefficient of 0.991 (95% confidence interval 0.985-0.994). Heritability estimates were 76% (standard error = 12%) with a family-based method (N = 364) and 39% (standard error = 2.4%) with a single nucleotide polymorphism-based method (N = 34 130) and were unaffected by adjustment for height (model II) and intracranial volume (model III) or head width (model IV). Genome-wide association studies in 34 130 European individuals identified 56 significantly associated genomic loci (P

Genome-wide association studies have identified numerous common genetic variants associated with spirometric measures of pulmonary function, including forced expiratory volume in one second (FEV1), forced vital capacity, and their ratio. However, variants with lower minor allele frequencies are less explored. We conducted a large-scale gene-smoking interaction meta-analysis on exonic rare and low-frequency variants involving 44,429 individuals of European ancestry in the discovery stage and sought replication in the UK BiLEVE study with 45,133 European ancestry samples and UK Biobank study with 59,478 samples. We leveraged data on cigarette smoking, the major environmental risk factor for reduced lung function, by testing gene-by-smoking interaction effects only and simultaneously testing the genetic main effects and interaction effects. The most statistically significant signal that replicated was a previously reported low-frequency signal in GPR126, distinct from common variant associations in this gene. Although only nominal replication was obtained for a top rare variant signal rs142935352 in one of the two studies, interaction and joint tests for current smoking and PDE3B were significantly associated with FEV1. This study investigates the utility of assessing gene-by-smoking interactions and underscores their effects on potential pulmonary function.

Sarcopenia is a heterogeneous skeletal muscle disorder involving the loss of muscle mass and function. However, the prevalence of sarcopenia based on the most recent definition remains to be determined in older people with chronic airway diseases. The aim was to evaluate sarcopenia prevalence and association with chronic airway diseases and its lung function in an older population, using the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) criteria. We performed a cross-sectional analysis in 5082 participants (mean age 69.0±8.8 years, 56% females) from the Rotterdam Study. Participants with interpretable spirometry and an available assessment of sarcopenia were included. The appendicular skeletal muscle mass index (ASMI) and handgrip strength (HGS) were assessed using dual-energy X-ray absorptiometry (DXA) and a hydraulic hand dynamometer, respectively. We analysed the association between sarcopenia and chronic airway diseases by using regression models adjusted for age, sex, smoking status, total fat percentage and other relevant confounders. Participants with chronic airway diseases had higher prevalence of probable sarcopenia (12.0%, 95% CI 10.2–13.8) and confirmed sarcopenia (3.0%, 95% CI 2.1–3.9) than without. Chronic airway diseases were associated with “probable sarcopenia” (OR 1.28, 95% CI 1.02–1.60), “confirmed sarcopenia” (OR 2.13, 95% CI 1.33–3.43), reduced HGS (β −0.51 (−0.90–−0.11)) and reduced ASMI (β −0.19 (−0.25–−0.14)). Forced expiratory volume in 1 s, Probable and confirmed sarcopenia prevalence among the older population with chronic airway diseases is higher than in those without. Given this prevalence, it could be essential to screen for sarcopenia in primary care units for older patients. https://bit.ly/34Fhc56

Background Epigenetics may play an important role in the pathogenesis of lung diseases. However, little is known about the epigenetic factors that influence impaired gas exchange at the lung. Aim To identify the epigenetic signatures of the diffusing capacity of the lung measured by carbon monoxide uptake (the diffusing capacity of the lung for carbon monoxide (DLCO)). Methods An epigenome-wide association study (EWAS) was performed on diffusing capacity, measured by carbon monoxide uptake (DLCO) and per alveolar volume (VA) (as DLCO/VA), using the single-breath technique in 2674 individuals from two population-based cohort studies. These were the Rotterdam Study (RS, the “discovery panel”) and the Framingham Heart Study (FHS, the “replication panel”). We assessed the clinical relevance of our findings by investigating the identified sites in whole blood and by lung tissue specific gene expression. Results We identified and replicated two CpG sites (cg05575921 and cg05951221) that were significantly associated with DLCO/VA and one (cg05575921) suggestively associated with DLCO. Furthermore, we found a positive association between aryl hydrocarbon receptor repressor (AHRR) gene (cg05575921) hypomethylation and gene expression of exocyst complex component 3 (EXOC3) in whole blood. We confirmed that the expression of EXOC3 in lung tissue is positively associated with DLCO/VA and DLCO. Conclusions We report on epigenome-wide associations with diffusing capacity in the general population. Our results suggest EXOC3 to be an excellent candidate, through which smoking-induced hypomethylation of AHRR might affect pulmonary gas exchange., Epigenetic changes, including smoking-induced hypomethylation, may affect pulmonary gas exchange https://bit.ly/3k4ZdvH

Some individuals have characteristics of both asthma and COPD (asthma-COPD overlap, ACO), and evidence suggests they experience worse outcomes than those with either condition alone. Improved knowledge of the genetic architecture would contribute to understanding whether determinants of risk in this group differ from those in COPD or asthma.We conducted a genome-wide association study in 8,068 cases and 40,360 controls of European ancestry from UK Biobank (stage 1). After excluding variants only associated with asthma or COPD we selected 31 variants for further investigation in 12 additional cohorts (stage 2), and discovered eight novel signals for ACO in a meta-analysis of stage 1 and 2 studies.Our signals include an intergenic signal on chromosome 5 not previously associated with asthma, COPD or lung function, and suggest a spectrum of shared and distinct genetic influences in asthma, COPD and ACO. A number of signals may represent loci that predispose to serious long-term consequences in people with asthma.

Individuals with characteristics of both asthma and COPD (asthma-COPD overlap syndrome, ACOS) experience significantly worse outcomes than those with asthma or COPD alone. Despite hundreds of genetic associations with asthma, COPD and lung function, no genetic variants have specifically been associated with ACOS. We hypothesized that there are genetic determinants of ACOS and sought to identify these in a genome-wide association study. We defined ACOS based on self-reported doctor-diagnosed asthma and spirometric GOLD2+ airflow limitation. We tested 7693381 genetic variants for association with ACOS in 8068 cases and 40360 healthy controls from UK Biobank (stage 1). We identified signals where P Thirty-one genetic variants met criteria for inclusion in stage 2. Of these, eight were associated at genome-wide significance (P Whilst our results suggest that many genetic variants associated with ACOS are shared with asthma and/or COPD, we identify a new, distinct signal that may implicate cellular pathways characteristic of ACOS.

We have carried out meta-analyses of genome-wide association studies (GWAS) (n = 23 784) of the first two principal components (PCs) that group together cortical regions with shared variance in their surface area. PC1 (global) captured variations of most regions, whereas PC2 (visual) was specific to the primary and secondary visual cortices. We identified a total of 18 (PC1) and 17 (PC2) independent loci, which were replicated in another 25 746 individuals. The loci of the global PC1 included those associated previously with intracranial volume and/or general cognitive function, such as MAPT and IGF2BP1. The loci of the visual PC2 included DAAM1, a key player in the planar-cell-polarity pathway. We then tested associations with occupational aptitudes and, as predicted, found that the global PC1 was associated with General Learning Ability, and the visual PC2 was associated with the Form Perception aptitude. These results suggest that interindividual variations in global and regional development of the human cerebral cortex (and its molecular architecture) cascade—albeit in a very limited manner—to behaviors as complex as the choice of one’s occupation.

Background Variations in thyroid function within reference ranges are associated with increased risk of diseases and death. However, the impact of thyroid function on life expectancy (LE) with and without noncommunicable diseases (NCDs) remains unknown. We therefore aimed to investigate the association of thyroid function with total LE and LE with and without NCD among euthyroid individuals. Methods and findings The study was embedded in the Rotterdam Study, a prospective population-based study carried out in the Netherlands. In total, 7,644 participants without known thyroid disease and with thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels within reference ranges were eligible. NCDs were defined as presence of cardiovascular disease, diabetes mellitus type 2, or cancer. We used the demographic tool of multistate life tables to calculate LE estimates at the age of 50 years, using prevalence, incidence rates, and hazard ratios for three transitions (healthy to NCD, healthy to death, and NCD to death). The total LE and LE with and without NCD among TSH and FT4 tertiles were calculated separately in men and women. Analyses were adjusted for sociodemographic and cardiovascular risk factors. The mean (standard deviation) age of the participants was 64.5 (9.7) years, and 52.3% were women. Over a median follow-up of 8 years (interquartile range 2.7–9.9 years), 1,396 incident NCD events and 1,422 deaths occurred. Compared with those in the lowest TSH tertile, men and women in the highest TSH tertile were expected to live 1.5 years (95% confidence interval [CI] 0.8–2.3, p < 0.001) and 1.5 years (CI 0.8–2.2, p < 0.001) longer, respectively, of which 1.4 years (CI 0.5–2.3, p = 0.002) and 1.3 years (CI 0.3–2.1, p = 0.004) with NCD. Compared with those in the lowest FT4 tertile, the difference in LE for men and women in the highest FT4 tertile was −3.7 years (CI −5.1 to −2.2, p < 0.001) and −3.3 years (CI −4.7 to −1.9, p < 0.001), respectively, of which −1.8 years (CI −3.1 to −0.7, p = 0.003) and −2.0 years (CI −3.4 to −0.7, p = 0.003) without NCD. A limitation of the study is the observational design. Thus, the possibility of residual confounding cannot be entirely ruled out. Conclusions In this study, we found that people with low–normal thyroid function (i.e., highest tertile of TSH and lowest tertile of FT4 reference ranges) are expected to live more years with and without NCD than those with high–normal thyroid function (i.e., lowest tertile of TSH and highest tertile of FT4 reference ranges). These findings provide support for a re-evaluation of the current reference ranges of thyroid function., Arjola Bano and colleagues reveal that people with a lower-normal level of thyroid function are more likely to live longer and without NCDs., Author summary Why was this study done? Thyroid dysfunction is an important public health problem that is associated with an increased risk of noncommunicable diseases (NCDs), such as cardiovascular diseases, diabetes, and cancer. The diagnosis and treatment of thyroid dysfunction is based on thyrotropin and free thyroxine measurements. Accumulating evidence has suggested that the clinical consequences of thyroid dysfunction are extended even within the reference ranges of thyrotropin and free thyroxine levels. However, the impact of thyroid function on life expectancy with and without NCD remains unknown. What did the researchers do and find? We performed a large prospective population-based cohort study within the framework of the Rotterdam Study. We investigated the association of thyroid function with life expectancy with and without NCD among euthyroid individuals. We found that individuals with low–normal thyroid function live up to 3.7 years longer overall, of which up to 1.9 years longer with NCD, than individuals with high–normal thyroid function. What do these findings mean? Our study provides novel insights about the qualitative and quantitative impact of thyroid function on life expectancy. Our findings provide support for a re-evaluation of the reference ranges of thyroid function in middle-aged and older adults. This can have further implications on the diagnosis and treatment of thyroid disease.

Introduction: Longitudinal studies on PRISm are scarce but studies in smoking populations have suggested worse outcomes. Objective: To compare mortality in PRISm subjects with COPD and normal spirometry in the general population. Methods: In a population-based study enrolling subjects aged ≥45 (asthma excluded), we examined all-cause and cardiovascular (CV) mortality in subjects with PRISm (FEV1/FVC≥0.7 and FEV1 Results: Of 4824 participants (69.1±8.9 years, 45.4% males), 3703 (76.8%) had normal spirometry, 324 (6.7%) had PRISm and 797 (16.5%) had COPD. During 4.2 years of follow-up, 619 (12.8%) participants died; 379 (10.2%) controls, 62 (19.1%) PRISm subjects and 178 (22.3%) COPD subjects. Relative to controls, PRISm and COPD GOLD2-3 had increased risks of all-cause and CV mortality (PRISm: HR 1.7 [1.3 -2.2] and 2.3 [1.2-4.5]; COPD: HR 1.8 [1.4-2.2] and 1.9 [1.1-3.5]). Risks of all-cause and CV mortality were increased in PRISm relative to COPD GOLD1 (HR 1.8 [1.2-2.5] and HR 4.6 [1.3-16.6]), but were not different in PRISm relative to COPD GOLD2-3 (HR 0.9 [0.7-1.3] and HR 1.2 [0.6-2.5]). Conclusion: In the general population, PRISm is associated with increased all-cause and CV mortality compared to subjects with normal spirometry and COPD GOLD1.

COPD is associated with a progressive loss of muscle mass and function. However, there is an unmet need to define and standardise methods to estimate the prevalence of sarcopenia in COPD patients.We performed a systematic review and meta-analysis of the prevalence of this extrapulmonary manifestation in COPD patients. We searched Embase, Medline (Ovid), CINAHL (EBSCO), Web of Science, Scopus and Google Scholar for studies published up to January 17, 2019, assessing sarcopenia in COPD patients based on low muscle mass and decreased muscle function. Interventional studies, in vitro experiments, protocols or reviews and meta-analyses were excluded. We estimated heterogeneity (I2) and assessed significance (Q) using a Chi-squared test for estimates obtained from random-effects models.4465 articles were initially identified. After removing the duplicates and applying the selection criteria, we reviewed 62 full-text articles. Finally, 10 articles (n=2565 COPD patients) were included in this systematic review and meta-analyses. Overall, the prevalence of sarcopenia in patients with COPD was 21.6% (95% CI 14.6–30.9%, I2=94%), ranging from 8% in population-based to 21% in clinic-based studies, and 63% in COPD patients residing in nursing homes.Sarcopenia is frequently observed in COPD patients, with varying prevalence across population settings. Sarcopenia in COPD should be assessed using standardised tests and cut-off points from sarcopenia consensus criteria for clinical practice and international comparisons.

Patients with chronic obstructive pulmonary disease (COPD) commonly present with multimorbidity. We aimed to investigate the association between COPD and the development of peripheral arterial disease (PAD) in the general population, and how this might affect mortality among individuals with COPD. We included 3123 participants of the population-based Rotterdam Study without PAD at baseline (mean age 65 years; 57.4% female). The association between COPD at baseline and PAD during follow-up was studied using logistic regression (PAD being indicated by an ankle–brachial index (ABI) of 0.9 or less). Cox regression was used for mortality analysis and interaction terms were used to investigate mortality risk modification by PAD. The presence of COPD was associated with incident PAD (adjusted odds ratio 1.9, 95% CI 1.1–3.2). Mortality rates per 100 000 person-years were as follows: 10.0 in individuals without COPD or PAD, 18.4 in those with COPD only, 16.1 in those with PAD only and 30.1 in individuals with both COPD and PAD. No statistical interaction was found between PAD and COPD on risk of dying. Individuals with COPD have an almost doubled risk of developing PAD. Although PAD does not modify the association between COPD and mortality, people suffering from both diseases have substantially higher mortality rates., Individuals with COPD have an almost doubled risk of developing peripheral arterial disease (PAD). People suffering from both COPD and PAD have substantially higher mortality rates. http://ow.ly/IyOx30m0IBo

COPD is the third leading cause of death in the world and its global burden is predicted to increase further. Even though the prevalence of COPD is well studied, only few studies examined the incidence of COPD in a prospective and standardized manner. In a prospective population-based cohort study (Rotterdam Study) enrolling subjects aged ≥45, COPD was diagnosed based on a pre-bronchodilator obstructive spirometry (FEV1/FVC

Although several genome-wide association studies (GWAS) have investigated the genetics of pulmonary ventilatory function, little is known about the genetic factors that influence gas exchange. The aim of the study was to investigate the heritability of, and genetic variants associated with the diffusing capacity of the lung.GWAS was performed on diffusing capacity of the lung measured by carbon monoxide uptake (DLCO) and per alveolar volume (VA) using the single-breath technique, in 8372 individuals from two population-based cohort studies, the Rotterdam Study and the Framingham Heart Study. Heritability was estimated in related (n=6246) and unrelated (n=3286) individuals.Heritability of DLCO and DLCO/VA ranged between 23% and 28% in unrelated individuals and between 45% and 49% in related individuals. Meta-analysis identified a genetic variant in ADGRG6 that is significantly associated with DLCO/VA. Gene expression analysis of ADGRG6 in human lung tissue revealed a decreased expression in patients with chronic obstructive pulmonary disease (COPD) and subjects with decreased DLCO/VA.DLCO and DLCO/VA are heritable traits, with a considerable proportion of variance explained by genetics. A functional variant in ADGRG6 gene region was significantly associated with DLCO/VA. Pulmonary ADGRG6 expression was decreased in patients with COPD.

Background. Chronic obstructive pulmonary disease (COPD) is associated with a progressive loss of muscle mass and function. However, there is an unmet need to define and to standardize methods to estimate the prevalence of sarcopenia in COPD patients. Therefore, we performed a systematic review and meta-analysis of the prevalence of this extra-pulmonary manifestation in patients with COPD. Methods. We searched Embase, Medline (Ovid), CINAHL (EBSCO), Web of Science, Scopus and Google Scholar for studies published until July 2017, assessing lean mass or sarcopenia in COPD patients. Interventional studies, in vitro experiments, protocols or reviews and meta-analyses were excluded. The main outcome was the prevalence of sarcopenia and low lean mass. Risk of bias was assessed by the Hoy scale. We used random-effects models and assessed heterogeneity (I2) by X² test. PROSPERO, registration number CRD42018095480. Findings. 3,915 articles were initially identified, and 253 were unique articles. From 27 articles included in this systematic review, 24 were meta-analyzed (n=13.009). The prevalence of sarcopenia in patients with COPD was 25.7% (95%CI: 12.9-44.8%; I²=88%). Low lean mass based on a low fat free mass index was present in 23.4% (95%CI: 18.6-29.0; I² =96%) of COPD patients, whereas the prevalence of a low appendicular skeletal muscle index was 31.0% (95%CI: 28.0-34.2; I²=65%). Interpretation. Sarcopenia and low lean mass are frequently observed in COPD patients with varying prevalence. Heterogeneity was considerable as a result of wide range of operational definitions, cut-offs, and methods used to diagnose sarcopenia. Assessment of sarcopenia in COPD patients should integrate standardized tests of muscle mass and muscle function. Funding: There was no funding source related to the execution of this study. Declaration of Interest: The authors have no conflicts of interest to declare.

Chronic obstructive pulmonary disease (COPD) is a complex and heritable disease, associated with common genetic variants. Familial types of COPD may be explained by rare variants, which have not been widely studied. We aimed to discover rare genetic variants underlying COPD through genome-wide linkage scan. Affected-only analysis was performed using 6K Illumina Linkage IV Panel in 142 cases clustered in 27 families from a genetic isolate, Erasmus Rucphen Family (ERF) study. Potential causal variants were then selected in exome sequence data from the affected members of the families that contributed the most to the peak. The shared rare variants were further tested for association with COPD in the entire ERF study (N=657). Significant evidence for linkage was observed on chromosomes 15 (log of odds (LOD) score=5.52) and 11 (LOD=3.71). Chromosome 15 is a known COPD locus harbouring nicotinic receptors. In the chromosome 11 locus we identified several rare (minor allele frequency (MAF)

Introduction: COPD patients commonly present with multi-morbidity, including vascular disease. Atherosclerosis is known as the main driver of vascular disease. One of its clinical manifestations is peripheral arterial disease (PAD), which mainly affects the lower limb arteries. Little is known about the association between COPD and PAD in the general population. Our aim was to study the association between COPD and PAD in a population-based setting. Methods: In 3,459 participants of the Rotterdam study (mean age ± standard deviation 65.4 ± 6.7, 57.4% females), PAD (an Ankle Brachial Index (ABI) ≤ 0.9) and COPD (based on obstructive spirometry or clinical presentation) was assessed. The association between COPD and PAD was tested by means of a cox regression analysis. Results: In this study, 13 (13.3%) of individuals with COPD had PAD compared to 323 (9.6%) of individuals without COPD. The incidence of PAD in individuals with COPD was 32.0/1000 person years (PY), compared to 18.4/1000 PY in individuals without COPD. A statistically significant association was found between COPD and PAD, with an Hazard Ratio of 1.78 (95% Confidence Interval 1.13-2.), adjusted for age, sex, smoking history, body mass index, hypertension, statin use, serum HDL to cholesterol ratio and ethnicity. Conclusion: Individuals with COPD have higher risk of developing PAD. This emphasizes the importance of determining ABI for the diagnosis of PAD in the management of patients with COPD.

The role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for the association of serum 25-hydroxyvitamin D [25(OH)D] and pulmonary function. We conducted the largest cross-sectional meta-analysis of the 25(OH)D– pulmonary function association to date, based on nine European ancestry (EA) cohorts (n=22,838) and five African ancestry (AA) cohorts (n=4,290) in the CHARGE Consortium. Data were analyzed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean (SD) serum 25(OH)D was 68 (29) nmol/L for EAs and 49 (21) nmol/L for AAs. For each 1 nmol/L higher 25(OH)D, forced expiratory volume in the first second (FEV1) was higher by 1.1 mL in EAs (95% CI: 0.9,1.3; P=2.5×10-21) and 1.8 mL (95% CI: 1.1,2.5; P=1.6×10-7) in Aas (Prace difference=0.06), and forced vital capacity (FVC) was higher by 1.3 mL in EAs (95% CI: 1.0,1.6; P=1.1×10-20) and 1.5 mL (95% CI: 0.8,2.3; P=1.2×10-4) in AAs (Prace difference=0.56). Among EAs, the 25(OH)D–FVC association was stronger in smokers: per 1nmol/L higher 25(OH)D, FVC was higher by 1.7 mL (95% CI: 1.1,2.3) for current smokers and 1.7 mL (95% CI: 1.2,2.1) for former smokers, compared to 0.8 mL (95% CI: 0.4,1.2) for never smokers. In summary, the 25(OH)D associations with FEV1 and FVC were positive in both ancestries. In EAs, a stronger association was observed for smokers compared to never smokers, which supports the importance of vitamin D in vulnerable populations.Cohort FundingThis work was supported by National Institutes of Health (NIH) grant number R21 HL125574 funded by the National Heart, Lung, and Blood Institute (NHLBI) and the NIH Office of Dietary Supplements (ODS) (co-Principal Investigators [co-PIs]: DBH and PAC). The corresponding author (PAC) had full access to the data for the meta-analysis, and had final responsibility for the decision to submit for publication. No funding source had any role in the analysis of the data, the writing of the manuscript, or the decision to submit it. This work was also supported in part by R01HL077612 (PI: RGB) and by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (ZO1 ES043012, PI: SJL). SJL is supported by the Intramural Research Program of NIH, National Institute of Environmental Health Sciences. Infrastructure for the CHARGE Consortium is supported in part by the NHLBI grant R01HL105756.The Age, Gene/Environment Susceptibility (AGES)–Reykjavik Study has been funded by NIH contracts N01-AG-1-2100 and 271201200022C, the National Institute on Aging (NIA) Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, VSN: 00-063. The researchers are indebted to the participants for their willingness to participate in the study.The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by NHLBI contracts HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C. 25(OH)D measurements were conducted with the support of R01 HL103706 from the NHLBI and R01 HL103706-S1 from the NIH ODS. The authors thank the staff and participants of the ARIC study for their important contributions.This Cardiovascular Health Study (CHS) research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL085251, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and R01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from NIA. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Vitamin D measurements were made possible by NHLBI (R01HL084443-01A2).This work in Framingham Heart Study was supported by NHLBI’s Framingham Heart Study contract (N01-HC-25195 and HHSN268201500001I). Vitamin D measurements in the Framingham study were made possible by NIA (R01 AG14759 to SLB.).The Health Aging and Body Composition cohort study was supported by NIA contracts N01AG62101, N01AG2103, and N01AG62106, NIA grant R01-AG028050, NINR grant R01-NR012459, and in part by the Intramural Research Program of the NIA, NIH. This research was further supported by RC1AG035835, and the serum vitamin D assays were supported by R01AG029364.The Multi-Ethnic Study of Atherosclerosis (MESA) study is conducted and supported by NHLBI in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from NHLBI, UL1-TR-000040, UL1-TR-001079, and UL1-TR-001881 from NCRR, and DK063491 from the NIDDK. The MESA Lung study was supported by grants R01 HL077612, RC1 HL100543 and R01 HL093081 from NHLBI. Support for the Mineral Metabolite dataset was provided by grant HL096875.The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands; the Organization for the Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Dutch Ministry of Education, Culture, and Science; the Dutch Ministry for Health, Welfare, and Sports; the European Commission (DG XII), and the Municipality of Rotterdam. LL was a postdoctoral fellow of the Research Foundation—Flanders (FWO) in Brussels, Belgium. Part of this work was supported by a FWO-grant G035014N. DSM Nutritional Products AG, Kaiseraugst, Switzerland, sponsored the Vitamin D serum analyses. The authors are grateful to the study participants, the staff from the Rotterdam Study, and the participating general practitioners and pharmacists.The Coronary Artery Risk Development in Young Adults Study (CARDIA) is supported by contracts HHSN268201300025C, HHSN268201300026C, HHSN268201300027C, HHSN268201300028C, HHSN268201300029C, and HHSN268200900041C from the National Heart, Lung, and Blood Institute (NHLBI), the Intramural Research Program of the National Institute on Aging (NIA), and an intra-agency agreement between NIA and NHLBI (AG0005).Author DisclosureDr. Psaty serves on the DSMB of a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson.All other authors have no conflicts of interest. There is no commercial support or financial interest from the tobacco industry for the research presented.The study sponsors were not involved in study design, data collection, data analysis, data interpretation, report writing, or decisions to submit the paper for publication. PAC and DBH had final responsibility for the decision to submit for publication.Online Supporting MaterialSupplemental table, figures, and methods are available.Abbreviation Footnote25(OH)D25-Hydroxyvitamin DAAAfrican AncestryAGESAge, Gene, Environment, Susceptibility Study—Reykjavik, IcelandARICAtherosclerosis Risk in Communities StudyCARDIACoronary Artery Risk Development in Young Adults StudyCHARGECohorts for Heart and Aging Research in Genomic Epidemiology ConsortiumCHSCardiovascular Health StudyCLIAChemiluminescence ImmunoassayCOPDChronic Obstructive Pulmonary DiseaseEAEuropean AncestryFEV1Forced Expiratory Volume in the First SecondFHS (Offspring)Framingham Heart Study—Offspring CohortFHS (Gen3)Framingham Heart Study—Generation 3 CohortFVCForced Vital CapacityHABCHealth, Aging, and Body Composition StudyLC-MS/MSLiquid Chromatography in Tandem with Mass SpectrometryMESAMulti-Ethnic Study of AtherosclerosisNHANESNational Health and Nutrition Examination SurveyPFTPulmonary Function TestRIARadioimmunoassayRSRotterdam (Netherlands) Study

The role of the &beta, 2-adrenergic receptor (ADRB2) gene in patients with chronic obstructive pulmonary disease (COPD) is unclear. We investigated the association between ADRB2 variants and the risk of exacerbations in COPD patients treated with inhaled &beta, 2-agonists. Within the Rotterdam Study, a population-based cohort study, we followed 1,053 COPD patients until the first COPD exacerbation or end of follow-up and extracted rs1042713 (16Arg &gt, Gly) and rs1042714 (27Gln &gt, Glu) in ADRB2. Exposure to inhaled &beta, 2-agonists was categorised into current, past or non-use on the index date (date of COPD exacerbation for cases and on the same day of follow-up for controls). COPD exacerbations were defined as acute episodes of worsening symptoms requiring systemic corticosteroids and/or antibiotics (moderate exacerbations), or hospitalization (severe exacerbations). The associations between ADRB2 variants and COPD exacerbations were assessed using Cox proportional hazards models, adjusting for age, sex, use of inhaled corticosteroids, daily dose of &beta, 2-agonists, and smoking. In current users of &beta, 2-agonists, the risk of COPD exacerbation decreased by 30% (hazard ratio (HR), 0.70, 95% CI: 0.59&ndash, 0.84) for each copy of the Arg allele of rs1042713 and by 20% (HR, 0.80, 95% CI: 0.69&ndash, 0.94) for each copy of the Gln allele of rs1042714. Furthermore, current users carrying the Arg16/Gln27 haplotype had a significantly lower risk (HR, 0.85) of COPD exacerbation compared to the Gly16/Glu27 haplotype. In conclusion, we observed that the Arg16/Gln27 haplotype in ADRB2 was associated with a reduced risk of COPD exacerbation in current users of inhaled &beta, 2-agonists.

Preserved ratio impaired spirometry (PRISm) is a heterogeneous condition but its course and disease progression remain to be elucidated. We aimed to examine its prevalence, trajectories and prognosis in the general population.In the Rotterdam Study (population-based prospective cohort) we examined prevalence, trajectories and prognosis of subjects with normal spirometry (controls; forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ≥0.7, FEV1 ≥80%), PRISm (FEV1/FVC ≥0.7, FEV1 1/FVC Of 5487 subjects (age 69.1±8.9 years; 7.1% PRISm), 1603 were re-examined after 4.5 years. Of the re-examined PRISm subjects, 15.7% transitioned to normal spirometry and 49.4% to COPD. Median lung function decline was highest in subjects with incident PRISm (FEV1 −92.8 mL·year−1, interquartile range (IQR) −131.9– −65.8 mL·year−1; FVC −93.3 mL·year−1, IQR −159.8– −49.1 mL·year−1), but similar in persistent PRISm (FEV1 −30.2 mL·year−1, IQR −67.9– −7.5 mL·year−1; FVC −20.1 mL·year−1, IQR −47.7–21.7 mL·year−1) and persistent controls (FEV1 −39.6 mL·year−1, IQR −64.3–−12.7 mL·year−1; FVC −20.0 mL·year−1, IQR −55.4–18.8 mL·year−1). Of 5459 subjects with informed consent for follow-up, 692 (12.7%) died during 9.3 years (maximum) follow-up: 10.3% of controls, 18.7% of PRISm subjects and 20.8% of COPD subjects. Relative to controls, subjects with PRISm and COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2–4 had increased all-cause mortality (PRISm: HR 1.6, 95% CI 1.2–2.0; COPD GOLD 2–4: HR 1.7, 95% CI 1.4–2.1) and cardiovascular mortality (PRISm: HR 2.8, 95% CI 1.5–5.1; COPD 2–4: HR 2.1, 95% CI 1.2–3.6). Mortality within PRISm is associated with increased mortality and this population encompasses at least three distinct subsets: one that develops COPD during follow-up, a second with high cardiovascular burden and early mortality, and a third with persistent PRISm and normal age-related lung function decline.

Background: The pulmonary artery to aorta ratio (PA:A) is often used as a proxy for pulmonary hypertension. In smokers with COPD, PA:A > 1 has also been associated with an increased risk of severe exacerbations of COPD (i.e. hospitalizations). The aim of this study was to investigate the association between PA:A and mortality in the general population and in patients with COPD. Methods: In 2,197 participants from the population-based Rotterdam Study (mean age ± standard deviation (SD) 69.7 ± 6.7, 51.3% females), PA:A was measured using a cardiac CT scan performed between 2003 and 2006 . PA:A was defined as the ratio between the diameter of the pulmonary artery and the aorta. Multivariable Cox regression models (adjusted for age, sex, weight, smoking, and diabetes) were used to investigate the relationship between PA:A and the risk of mortality. Results: We found that PA:A was associated with a higher risk of mortality in the general population [Hazard Ratio (HR) for mortality per SD increase in PA:A: 1.11 (95% CI: 1.01-1.23)]. The association was more pronounced in participants with moderate to severe COPD (n=107) [HR adj : 1.62 (95% CI: 1.05-2.49)]. Investigating PA:A quartiles in moderate to severe COPD cases, the highest quartile of the PA:A showed the lowest survival using the lowest quartile as reference [HR adj 10.60 (95% CI: 1.83-61.37)]. Conclusion: PA:A is associated with increased mortality in the general population and in subjects with moderate to severe COPD.

Background: COPD is the third leading cause of death in the world and its global burden is predicted to increase. Although the prevalence of COPD is well documented, only few studies examined its incidence. Methods: In a prospective population-based cohort study (Rotterdam Study) enrolling subjects aged 45 and older, COPD was diagnosed based on an obstructive spirometry (FEV1/FVC Results: In this cohort of 14.926 participants, 692 COPD subjects were identified as prevalent cases and 1.304 cases as incident. The median follow up time was 7.6 years (with a maximum follow up time up to 25 years). The overall incidence rate (IR) was 9.4/1000 person-years (PY) with 95% Confidence Interval (CI) 8.9 to 9.9. The IR was higher in men [14.0/1000 PY, 95% CI 13.0-15.1] than in women [6.5/1000 PY, 95% CI 5.9-7.0], and higher in smokers compared with never-smokers [12.6/1000 PY, 95% CI 11.8-13.3 and 4.3/1000 PY, 95% CI 3.7-4.9, respectively]. Age specific IR ranged between 9.2 and 18.5/1000 PY in males and 3.2 to 8.4/1000 PY in females. The overall incidence increased from the age of 45 to the age of 80 in men and 75 in women. The incidence of COPD in never smokers showed to be stable over a broad age range (from 55 till >80 years old). Conclusion: The overall incidence of COPD in the Rotterdam Study was 9.4/1000 PY, with a higher incidence in males and in smokers.

A pulmonary artery to aorta ratio (PA:A) >1 is a proxy of pulmonary hypertension. It is not known whether this measure carries prognostic information in the general population and in individuals with chronic obstructive pulmonary disease (COPD).Between 2003 and 2006, 2197 participants from the population-based Rotterdam Study (mean±sd age 69.7±6.7 years; 51.3% female), underwent cardiac computed tomography (CT) scanning with PA:A quantification, defined as the ratio between the diameters of the pulmonary artery and the aorta. COPD was diagnosed based on spirometry or clinical presentation and obstructive lung function measured by a treating physician. Cox regression was used to investigate the risk of mortality.We observed no association between 1-sd increase of PA:A and mortality in the general population. Larger PA:A was associated with an increased risk of mortality in individuals with COPD, particularly in moderate-to-severe COPD (hazard ratio 1.36, 95% CI 1.03–1.79). We demonstrated that the risk of mortality in COPD was driven by severe COPD, and that this risk increased with decreasing diffusing capacity.Larger PA:A is not associated with mortality in an older general population, but is an independent determinant of mortality in moderate-to-severe COPD. Measuring PA:A in CT scans obtained for other indications may yield important prognostic information in individuals with COPD.