Chronic obstructive pulmonary disease (COPD) has seriously impacted the health of individuals and populations. In this study, proton nuclear magnetic resonance (1H NMR)-based metabonomics combined with multivariate pattern recognition analysis was applied to investigate the metabolic signatures of patients with COPD. Serum and urine samples were collected from COPD patients (n = 32) and healthy controls (n = 21), respectively. Samples were analyzed by high resolution 1H NMR (600 MHz), and the obtained spectral profiles were then subjected to multivariate data analysis. Consistent metabolic differences have been found in serum as well as in urine samples from COPD patients and healthy controls. Compared to healthy controls, COPD patients displayed decreased lipoprotein and amino acids, including branched-chain amino acids (BCAAs), and increased glycerolphosphocholine in serum. Moreover, metabolic differences in urine were more significant than in serum. Decreased urinary 1-methylnicotinamide, creatinine and lactate have been discovered in COPD patients in comparison with healthy controls. Conversely, acetate, ketone bodies, carnosine, m-hydroxyphenylacetate, phenylacetyglycine, pyruvate and α-ketoglutarate exhibited enhanced expression levels in COPD patients relative to healthy subjects. Our results illustrate the potential application of NMR-based metabonomics in early diagnosis and understanding the mechanisms of COPD.

Background Long-term exposure to outdoor air pollution increases the risk of cardiovascular disease, but evidence is unclear on the health effects of exposure to pollutant concentrations lower than current EU and US standards and WHO guideline limits. Within the multicentre study Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE), we investigated the associations of long-term exposures to fine particulate matter (PM 2•5 ), nitrogen dioxide (NO 2 ), black carbon, and warm-season ozone (O 3 ) with the incidence of stroke and acute coronary heart disease.Methods We did a pooled analysis of individual data from six population-based cohort studies within ELAPSE, from Sweden, Denmark, the Netherlands, and Germany (recruited 1992-2004), and harmonised individual and area-level variables between cohorts. Participants (all adults) were followed up until migration from the study area, death, or incident stroke or coronary heart disease, or end of follow-up (2011-15). Mean 2010 air pollution concentrations from centrally developed European-wide land use regression models were assigned to participants' baseline residential addresses. We used Cox proportional hazards models with increasing levels of covariate adjustment to investigate the association of air pollution exposure with incidence of stroke and coronary heart disease. We assessed the shape of the concentration-response function and did subset analyses of participants living at pollutant concentrations lower than predefined values. FindingsFrom the pooled ELAPSE cohorts, data on 137 148 participants were analysed in our fully adjusted model. During a median follow-up of 17•2 years (IQR 13•8-19•5), we observed 6950 incident events of stroke and 10 071 incident events of coronary heart disease. Incidence of stroke was associated with PM 2•5 (hazard ratio 1•10 [95% CI 1•01-1•21] per 5 μg/m³ increase), NO 2 (1•08 [1•04-1•12] per 10 µg/m³ increase), and black carbon (1•06 [1•02-1•10] per 0•5 10 -⁵/m increase), whereas coronary heart disease incidence was only associated with NO 2 (1•04 [1•01-1•07]). Warm-season O 3 was not associated with an increase in either outcome. Concentration-response curves indicated no evidence of a threshold below which air pollutant concentrations are not harmful for cardiovascular health. Effect estimates for PM 2•5 and NO 2 remained elevated even when restricting analyses to participants exposed to pollutant concentrations lower than the EU limit values of 25 µg/m³ for PM 2•5 and 40 µg/m³ for NO 2 .Interpretation Long-term air pollution exposure was associated with incidence of stroke and coronary heart disease, even at pollutant concentrations lower than current limit values.

Rationale: Rare genetic variants in telomere-related genes have been identified in familial, idiopathic, and rheumatoid arthritis-associated pulmonary fibrosis. Short peripheral blood leukocyte (PBL) telomere length predicts poor outcomes in chronic hypersensitivity pneumonitis (CHP).Objectives: Determine the prevalence and clinical relevance of rare protein-altering variants in telomere-related genes in patients with CHP.Methods: Next-generation sequences from two CHP cohorts were analyzed to identify variants in TERT (telomerase reverse transcriptase), TERC (telomerase RNA component), DKC1 (dyskerin pseudouridine synthase 1), RTEL1 (regulator of telomere elongation helicase 1), PARN (poly[A]-specific RNase), and TINF2 (TERF1interacting nuclear factor 2). To qualify, variants were required to have a minor allele frequency less than 0.005 and be predicted to be damaging to protein function. Variant status (binary variable) was used in statistical association tests, including Cox proportional hazard models for transplant-free survival. PBL telomere length was measured using quantitative PCR.Measurements and Main Results: Qualifying variants were identified in 16 of 144 patients (11.1%; 95% confidence interval [CI], 6.5-17.4) in the discovery cohort and 17 of 209 patients (8.1%; 95% CI, 4.8-12.7) in the replication cohort. Age-and ancestry-adjusted PBL telomere length was significantly shorter in the presence of a variant in both cohorts (discovery: 2561 bp; 95% CI, 2933 to 2190; P = 0.003; replication: 2612 bp; 95% CI, 2870 to 2354; P = 5.30 3 10 26 ). Variant status was significantly associated with transplant-free survival in both cohorts (discovery: age-, sex-, and ancestry-adjusted hazard ratio, 3.73; 95% CI, 1.92-7.28; P = 0.0001; replication: hazard ratio, 2.72; 95% CI, 1.26-5.88; P = 0.011).Conclusions: A substantial proportion of patients diagnosed with CHP have rare, protein-altering variants in telomere-related genes, which are associated with short peripheral blood telomere length and significantly reduced transplant-free survival.