Sven Gläser

Cohort Profile: The Study of Health in Pomerania

Henry Volzke, y Dietrich Alte,1y Carsten Oliver Schmidt, Dorte Radke, Roberto Lorbeer, Nele Friedrich, Nicole Aumann, Katharina Lau, Michael Piontek, Gabriele Born, Christoph Havemann, Till Ittermann, Sabine Schipf, Robin Haring, Sebastian E Baumeister, Henri Wallaschofski, Matthias Nauck, Stephanie Frick, Andreas Arnold, Michael Junger, Julia Mayerle, Matthias Kraft, Markus M Lerch, Marcus Dorr, Thorsten Reffelmann, Klaus Empen, Stephan B Felix, Anne Obst, Beate Koch, Sven Glaser, Ralf Ewert, Ingo Fietze, Thomas Penzel, Martina Doren, Wolfgang Rathmann, Johannes Haerting, Mario Hannemann, Jurgen Ropcke, Ulf Schminke, Clemens Jurgens, Frank Tost, Rainer Rettig, Jan A Kors, Saskia Ungerer, Katrin Hegenscheid, Jens-Peter Kuhn, Julia Kuhn, Norbert Hosten, Ralf Puls, Jorg Henke, Oliver Gloger, Alexander Teumer, Georg Homuth, Uwe Volker, Christian Schwahn, Birte Holtfreter, Ines Polzer, Thomas Kohlmann, Hans J Grabe, Dieter Rosskopf, Heyo K Kroemer, Thomas Kocher, Reiner Biffar,17,y Ulrich John20y and Wolfgang Hoffmann1y

Genome-wide association study identifies five loci associated with lung function

Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease (COPD). We tested genome-wide association with forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) in the SpiroMeta consortium (n = 20,288 individuals of European ancestry). We conducted a meta-analysis of top signals with data from direct genotyping (n ≤ 32,184 additional individuals) and in silico summary association data from the CHARGE Consortium (n = 21,209) and the Health 2000 survey (n ≤ 883). We confirmed the reported locus at 4q31 and identified associations with FEV1 or FEV1/FVC and common variants at five additional loci: 2q35 in TNS1 (P = 1.11 × 10−12), 4q24 in GSTCD (2.18 × 10−23), 5q33 in HTR4 (P = 4.29 × 10−9), 6p21 in AGER (P = 3.07 × 10−15) and 15q23 in THSD4 (P = 7.24 × 10−15). mRNA analyses showed expression of TNS1, GSTCD, AGER, HTR4 and THSD4 in human lung tissue. These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease.

Impairment of Ventilatory Efficiency in Heart Failure Prognostic Impact

BACKGROUND Impairment of ventilatory efficiency in congestive heart failure (CHF) correlates well with symptomatology and contributes importantly to dyspnea. METHODS AND RESULTS We investigated 142 CHF patients (mean NYHA class, 2.6; mean maximum oxygen consumption [VO(2)max], 15.3 mL O(2) x kg(-1) x min(-1); mean left ventricular ejection fraction [LVEF], 27%). Patients were compared with 101 healthy control subjects. Cardiopulmonary exercise testing was performed, and ventilatory efficiency was defined as the slope of the linear relationship of V(CO(2)) and ventilation (VE). Results are presented in percent of age- and sex-adjusted mean values. Forty-four events (37 deaths and 7 instances of heart transplantation, cardiomyoplasty, or left ventricular assist device implantation) occurred. Among VO(2)max, NYHA class, LVEF, total lung capacity, and age, the most powerful predictor of event-free survival was the VE versus V(CO(2)) slope; patients with a slope </=130% of age- and sex-adjusted normal values had a significantly better 1-year event-free survival (88.3%) than patients with a slope >130% (54.7%; P<0.001). CONCLUSIONS The VE versus V(CO(2)) slope is an excellent prognostic parameter. It is easier to obtain than parameters of maximal exercise capacity and is of higher prognostic importance than VO(2)max.

A Comprehensive Evaluation of Potential Lung Function Associated Genes in the SpiroMeta General Population Sample

Rationale Lung function measures are heritable traits that predict population morbidity and mortality and are essential for the diagnosis of chronic obstructive pulmonary disease (COPD). Variations in many genes have been reported to affect these traits, but attempts at replication have provided conflicting results. Recently, we undertook a meta-analysis of Genome Wide Association Study (GWAS) results for lung function measures in 20,288 individuals from the general population (the SpiroMeta consortium). Objectives To comprehensively analyse previously reported genetic associations with lung function measures, and to investigate whether single nucleotide polymorphisms (SNPs) in these genomic regions are associated with lung function in a large population sample. Methods We analysed association for SNPs tagging 130 genes and 48 intergenic regions (+/−10 kb), after conducting a systematic review of the literature in the PubMed database for genetic association studies reporting lung function associations. Results The analysis included 16,936 genotyped and imputed SNPs. No loci showed overall significant association for FEV1 or FEV1/FVC traits using a carefully defined significance threshold of 1.3×10−5. The most significant loci associated with FEV1 include SNPs tagging MACROD2 (P = 6.81×10−5), CNTN5 (P = 4.37×10−4), and TRPV4 (P = 1.58×10−3). Among ever-smokers, SERPINA1 showed the most significant association with FEV1 (P = 8.41×10−5), followed by PDE4D (P = 1.22×10−4). The strongest association with FEV1/FVC ratio was observed with ABCC1 (P = 4.38×10−4), and ESR1 (P = 5.42×10−4) among ever-smokers. Conclusions Polymorphisms spanning previously associated lung function genes did not show strong evidence for association with lung function measures in the SpiroMeta consortium population. Common SERPINA1 polymorphisms may affect FEV1 among smokers in the general population.

Reference values for cardiopulmonary exercise testing in healthy volunteers: the SHIP study

Cardiopulmonary exercise testing (CPET) is a widely applied clinical procedure. The aim of the present study was to acquire a comprehensive set of reference values for cardiopulmonary responses to exercise and to evaluate possible associations with sex, age and body mass index (BMI). A standardised progressive incremental exercise protocol on a cycle ergometer was applied to 1,708 volunteers of a cross-sectional epidemiologic survey, called “Study of Health in Pomerania”. Individuals with cardiopulmonary disorders, or echocardiographic or lung function pathologies, were excluded. The influence of potential confounding factors, such as smoking, taking β-blockers, hypertension, diastolic dysfunction, BMI and physical activity, were analysed for their influencing power. Reference values of CPET parameters were determined by regression analyses. Of the volunteers, 542 current smokers and obese individuals were excluded for not being representative of a healthy population. The final sample size was 534 (253 males), with age 25–80 yrs. The current study provides a representative set of reference values for CPET parameters based on age and weight. Sex and age have a significant influence on exercise parameters. While addressing the problem of a selection bias, the current study provides the first comprehensive set of reference values obtained in a large number of healthy volunteers within a population-based survey.

Ventilatory efficiency and exercise tolerance in 101 healthy volunteers

Abstract The ventilatory equivalent for CO2 defines ventilatory efficiency largely independent of metabolism. An impairment of ventilatory efficiency may be caused by an increase in either anatomical or physiological dead space, the latter being the most important mechanism in the hyperpnoea of heart failure, pulmonary embolism, pulmonary hypertension and the former in restrictive lung disease. However, normal values for ventilatory efficiency have not yet been established. We investigated 101 (56 men) healthy volunteers, aged 16–75 years, measuring ventilation and gas exchange at rest (n = 64) and on exercise (modified Naughton protocol, n = 101). Age and sex dependent normal values for ventilatory efficiency at rest defined as the ratio ventilation:carbon dioxide output (V˙E:V˙CO2), exercise ventilatory efficiency during exercise, defined as the slope of the linear relationship between ventilation and carbon dioxide output (V˙E vs V˙CO2 slope), oxygen uptake at the anaerobic threshold and at maximum (V˙O2AT,V˙O2max, respectively) and breathing reserve were established. Ventilatory efficiency at rest was largely independent of age, but was smaller in the men than in the women [V˙E:V˙CO2 50.5 (SD 8.8) vs 57.6 (SD 12.6) P<0.05]. Ventilatory efficiency during exercise declined significantly with age and was smaller in the men than in the women (men: (V˙E vs V˙CO2 slope = 0.13 × age + 19.9; women: V˙E vs V˙CO2 slope = 0.12 × age + 24.4). The V˙O2AT and V˙O2max were 23 (SD 5) and 39 (SD 7) ml O2 · kg · min−1 in the men and 18 (SD 4) and 32 (SD 7) in the women, respectively, and declined significantly with age. The V˙O2AT was reached at 58 (SD 9)% V˙O2max. Breathing reserve at the end of exercise was 41% and was independent of sex and age. It was concluded from this study that ventilatory efficiency as well as peak oxygen uptake are age and sex dependent in adults.

Impact of pulmonary hypertension on gas exchange and exercise capacity in patients with pulmonary fibrosis

Pulmonary hypertension is a relevant interceding morbidity in patients with pulmonary fibrosis that has significant impact on exercise tolerance and outcome. The aim of this study was to further characterize the exercise intolerance, dyspnoea and ventilatory inefficiency of patients with pulmonary fibrosis in the presence or absence of pulmonary hypertension via cardiopulmonary exercise testing. Thirty-four patients underwent pulmonary function testing, symptom-limited exercise testing on a bicycle and dyspnoea evaluation according to the BORG scale. Pulmonary hypertension was assessed by echocardiography and in a subset of patients right heart catheterization. Sixteen of 34 patients with pulmonary fibrosis revealed pulmonary hypertension. While all study patients did not differ in lung functions and demographic characteristics, patients suffering from pulmonary hypertension showed a significantly impaired exercise tolerance and worsened ventilatory inefficiency. The extent of pulmonary artery pressure elevation impacted significantly on ventilatory inefficiency. In addition, the increased ventilatory requirements significantly influenced the extent of dyspnoea in patients with pulmonary hypertension. We conclude that pulmonary hypertension has a significant impact on exercise capacity and dyspnoea in patients with interstitial lung disease (ILD). The further impairment of exercise capacity as well as the extent of dyspnoea in patients with interceding PHT is attributable to a significantly impaired ventilatory inefficiency.

Incremental prognostic value of cardiopulmonary exercise testing and resting haemodynamics in pulmonary arterial hypertension

BACKGROUND Pulmonary arterial hypertension (PAH) is a fatal disease despite recent treatment advances. Individual risk stratification is important. Exercise capacity and invasive haemodynamic data are both relevant, but data on the combined prognostic power are lacking. METHODS 226 consecutive patients with idiopathic or familial PAH were included at seven specialised tertiary centres. All patients underwent right heart catheterization and cardiopulmonary exercise testing (CPET). RESULTS During follow-up (1508 ± 1070 days) 72 patients died and 30 underwent transplantation. On multivariate analysis percentage of predicted peak oxygen uptake (%predicted peak VO2 [risk ratio 0.95]), pulmonary vascular resistance (PVR [1.105,]) and increase in heart rate during exercise (ΔHR [0.974]) were independent prognostic predictors (all p<0.0001). Peak VO2 allowed for risk stratification with a survival of 100, 92.9, 87.4 and 69.6% at 1 year and 97.7, 63.2, 41 and 23% at 5 years for the 4th, 3rd, 2nd and 1st quartiles, respectively. Dichotomizing by median peak VO2 and intra-group median PVR showed a worse 1-year survival for patients with low peak VO2/higher PVR compared to patients with low peak VO2/low PVR, high peak VO2/high PVR and high peak VO2/low PVR (65 vs. 93, 93, 100%, p<0.001). At 10 years survival was different for all 4 subgroups (19 vs. 25 vs. 48 vs. 75%, adjusted p<0.05). CONCLUSIONS Peak VO2, PVR and ΔHR independently predict prognosis in patients with PAH. Low peak VO2, high PVR and low ΔHR refer to poor prognosis. Combined use of peak VO2 and PVR provides accurate risk stratification underlining the complementary prognostic information from cardiopulmonary exercise testing and resting invasive haemodynamic data.

Sixteen new lung function signals identified through 1000 Genomes Project reference panel imputation.

Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC with 1000 Genomes Project (phase 1)-imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci (P<5 × 10−8) in or near ENSA, RNU5F-1, KCNS3, AK097794, ASTN2, LHX3, CCDC91, TBX3, TRIP11, RIN3, TEKT5, LTBP4, MN1 and AP1S2, and two novel signals at known loci NPNT and GPR126, providing a basis for new understanding of the genetic determinants of these traits and pulmonary diseases in which they are altered.

Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function

Background Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. Methods We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. Results The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10-7). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10-8) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. Conclusions In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.