Medea Imboden

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.

Follow-up of the Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA 2) 1991–2003: methods and characterization of participants

Summary.Objectives: The Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) was designed to investigate the health effects from long-term exposure to air pollution.Methods: The health assessment at recruitment (1991) and at the first reassessment (2001–3) consisted of an interview about respiratory health, occupational and other exposures, spirometry, a methacholine bronchial challenge test, end-expiratory carbon monoxide (CO) measurement and measurement for atopy. A bio bank for DNA and blood markers was established. Heart rate variability was measured using a 24-hour ECG (Holter) in a random sample of participants aged 50xa0years and older. Concentrations of nitrogen dioxide (NO2), sulphur dioxide (SO2), ozone (O3) and particulates in ambient air have been monitored in all study areas since 1991. Residential histories collected over the 11xa0year follow-up period coupled with GIS modelling will provide individual long-term air pollutant exposure estimates.Results: Of 9651 participants examined in 1991, 8715 could be traced for the cohort study and 283 died. Basic information about health status was obtained for 8047 individuals (86% of alive persons), 6528 individuals (70%) agreed to the health examination and 5973 subjects (62%) completed the entire protocol. Non-participants in the reassessment were on average younger than participants and more likely to have been smokers and to have reported respiratory symptoms in the first assessment. Average weight had increased by 5.5xa0kg in 11xa0years and 28% of smokers in 1991 had quit by the time of the reassessment.Zusammenfassung.Die Schweizer SAPALDIA-Kohortenstudie (SAPALDIA 2) 1991–2003: Methoden und TeilnehmendencharakteristikaFragestellung: Die Schweizer Kohortenstudie Luftverschmutzung und Atemwegserkrankungen bei Erwachsenen (SAPALDIA) untersucht die gesundheitlichen Auswirkungen der Langzeitbelastung durch Luftschadstoffe in der Bevölkerung.Methoden: 1991 und 2002 wurden ein Interview zur respiratorischen Gesundheit und deren Risikofaktoren, eine Spirometrie, ein bronchialer Reagibilitätstest mit Methacholin, eine endexpiratorische Kohlenmonoxidmessung und Tests zur allergischen Sensibilisierung durchgeführt. Für SAPALDIA 2 wurde eine Biobank mit Blut-, Serum-, Plasma- und DNA-Proben eingerichtet. Eine Stichprobe der über 50-jährigen Teilnehmenden erhielt ein 24-Stunden EKG (Holter). Luftschadstoffkonzentrationen von Stickstoffdioxid (NO2), Schwefeldioxid (SO2), Ozon (O3) und Schwebstaub (PM10) wurden in allen acht Studiengebieten seit 1991 gemessen. Die seit SAPALDIA 1 erfassten Adressgeschichten und auf GIS-Technologie beruhenden Schadstoffverteilungsdaten für NO2 und PM10 werden die Schätzung der individuellen Langzeitbelastung jedes SAPALDIA-Teilnehmenden ermöglichen.Ergebnisse: Von der ursprünglichen Kohorte von 9 651 Teilnehmern in 1991 waren 283 verstorben und Adressen konnten von 8715 aufgefunden werden. Basisinformationen zum Gesundheitszustand von 8047 Personen (86% aller lebenden Personen) wurden erfasst, 6528 (70%) nahmen an der Untersuchung teil und für 5973 (62%) liegen vollständige SAPALDIA2-Untersuchungen vor. Nichtteilnehmende waren im Durchschnitt jünger, weniger gut ausgebildet, eher Raucher und hatten eher respiratorische Symptome. Die untersuchten Personen haben in den letzten 11 Jahren durchschnittlich 5,5xa0kg Körpergewicht zugelegt, 28% der RaucherInnen haben aufgehört zu rauchen.Résumé.Etude de cohorte SAPALDIA (Etude Suisse sur la pollution atmosphérique et les maladies respiratoires chez l’adulte): méthodes et caractéristiques des participantsObjectifs: L’étude SAPALDIA a pour objectif de mesurer les effets sur la santé d’une exposition à long terme aux polluants atmosphériques dans la population adulte.Méthodes: Les participants ont été interrogés en 1991 et en 2002 sur leur état de santé respiratoire et ses facteurs de risque. Ils ont passé les examens suivants: spirométrie, test de la réactivité bronchique et de l’atopie, mesure du CO en fin d’expiration. Une banque biologique a été créée. Un ECG (Holter) a été pratiqué auprès d’un échantillon de participants âgés de plus de 50 ans. Les concentrations des polluants atmosphériques (dioxyde d’azote (NO2), dioxyde de soufre (SO2), ozone, particules fines (PM10)) ont été mesurées dans huit régions de Suisse depuis 1991. L’exposition individuelle sur 11 ans sera déterminée à partir des adresses, de la distribution de NO2 et PM10 et les modèles GIS.Résultats: Sur les 9 651 participants examinés en 1991, 283 sont décédés, 87 15 ont été localisés, 8047 ont donné des informations sur leur état de santé (86% des personnes en vie), 6 528 participants (70 %) ont accepté d’effectuer l’examen de santé et 5 973 (62 %) ont réalisé entièrement le protocole. Les non participants étaient en moyenne plus jeunes, moins éduqués, plus fréquemment fumeurs et souffraient plus fréquemment de symptômes respiratoires. Les personnes examinées ont pris en moyenne 5,5xa0kg de poids en 11 ans. 28% des fumeurs ont cessé de fumer.

SERPINA1 Gene Variants in Individuals from the General Population with Reduced α1-Antitrypsin Concentrations

BACKGROUNDnIndividuals with severe deficiency in serum alpha(1)-antitrypsin (AAT) concentrations are at high risk for developing chronic obstructive pulmonary disease (COPD), whereas those carrying the PI*MZ genotype are at slightly increased risk. Testing appropriate subgroups of the population for AAT deficiency (AATD) is therefore an important aspect of COPD prevention and timely treatment. We decided to perform an exhaustive investigation of SERPINA1 gene variants in individuals from the general population with a moderately reduced serum AAT concentration, because such information is currently unavailable.nnnMETHODSnWe determined the Z and S alleles of 1399 individuals enrolled in the Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) with serum AAT concentrations < or = 1.13 g/L and submitted 423 of these samples for complete exon 2-->5 sequencing.nnnRESULTSnWe found that 900 of 1399 samples (64%), carried the normal PI*MM genotype, whereas 499 samples (36%) carried at least 1 SERPINA1 deficiency variant. In the subpopulations in which AAT concentrations ranged from > 1.03 to < or = 1.13 and from > 0.93 to < or = 1.03 g/L, individuals with the PI*MM genotype represented the majority (86.5% and 53.8%, respectively). The PI*MS genotype was predominant (54.9%) in the AAT range of 0.83 to 0.93 g/L, whereas PI*MZ represented 76.4% in the AAT range of > 0.73 to < or = 0.83 g/L.nnnCONCLUSIONSnThis analysis provided a detailed molecular definition of intermediate AATD, which would be helpful in the diagnostic setting.

The common G-allele of interleukin-18 single-nucleotide polymorphism is a genetic risk factor for atopic asthma. The SAPALDIA Cohort Study.

Background IL‐18 is a pleiotrophic cytokine involved in both, T‐helper type 1 (Th1) and Th2 differentiation. Recently genetic variants in the IL‐18 gene have been associated with increased risk of atopy and asthma.

Circulating alpha1-antitrypsin in the general population: Determinants and association with lung function

BackgroundSevere alpha1-antitrypsin (AAT) deficiency associated with low AAT blood concentrations is an established genetic COPD risk factor. Less is known about the respiratory health impact of variation in AAT serum concentrations in the general population. We cross-sectionally investigated correlates of circulating AAT concentrations and its association with FEV1.MethodsIn 5187 adults (2669 females) with high-sensitive c-reactive protein (CRP) levels ≤ 10 mg/l from the population-based Swiss SAPALDIA cohort, blood was collected at the time of follow-up examination for measuring serum AAT and CRP.ResultsFemale gender, hormone intake, systolic blood pressure, age in men and in postmenopausal women, as well as active and passive smoking were positively, whereas alcohol intake and BMI inversely correlated with serum AAT levels, independent of CRP adjustment. We observed an inverse association of AAT with FEV1 in the total study population (p < 0.001), that disappeared after adjustment for CRP (p = 0.28). In addition, the AAT and FEV1 association was modified by gender, menopausal status in women, and smoking.ConclusionThe results of this population-based study reflect a complex interrelationship between tobacco exposure, gender related factors, circulating AAT, systemic inflammatory status and lung function.

Joint effect of obesity and TNFA variability on asthma: two international cohort studies

Obesity is a risk factor for asthma. Adipose tissue expresses pro-inflammatory molecules including tumour necrosis factor (TNF), and levels of TNF are also related to polymorphisms in the TNF-α (TNFA) gene. The current authors examined the joint effect of obesity and TNFA variability on asthma in adults by combining two population-based studies. The European Community Respiratory Health Survey and the Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults used comparable protocols, questionnaires and measures of lung function and atopy. DNA samples from 9,167 participants were genotyped for TNFA -308 and lymphotoxin-α (LTA) +252 gene variants. Obesity and TNFA were associated with asthma when mutually adjusting for their independent effects (odds ratio (OR) for obesity 2.4, 95% confidence interval (CI) 1.7–3.2; OR for TNFA -308 polymorphism 1.3, 95% CI 1.1–1.6). The association of obesity with asthma was stronger for subjects carrying the G/A and A/A TNFA -308 genotypes compared with the more common G/G genotype, particularly among nonatopics (OR for G/A and A/A genotypes 6.1, 95% CI 2.5–14.4; OR for G/G genotype 1.7, 95% CI 0.8–3.3). The present findings provide, for the first time, evidence for a complex pattern of interaction between obesity, a pro-inflammatory genetic factor and asthma.

α1-Antitrypsin deficiency and lung disease: risk modification by occupational and environmental inhalants

Chronic obstructive pulmonary disease (COPD) is a prevalent and preventable disease associated with high morbidity and mortality. Severe and intermediate α1-antitrypsin (AAT) deficiency (serum levels <11 and 11–20u2005µmol·L−1, respectively) increase the risk of COPD in active smokers. However, little is known about the interaction of severe and intermediate AAT deficiency with modifiable COPD risk factors other than active smoking. In this study, a MEDLINE search was carried out for studies investigating the combined effect of environmental inhalants (occupation and passive smoking) and AAT deficiency in the lung. A total of 18 studies using established methods for the assessment of AAT deficiency were included in this review. Occupational exposures and passive smoking affected lung function decline or prevalence of respiratory symptoms in four out of five studies investigating subjects with severe AAT deficiency, and in eight out of 13 studies with a focus on intermediate AAT deficiency. While study designs mostly prohibited formal assessment of effect modification, an interaction between intermediate AAT deficiency and passive smoking was identified in two studies with children. Additional study limitations included small sample size, poor adjustment for confounding and misclassification of environmental exposure as well as AAT activity. In conclusion, population-based epidemiological studies with associated biobanks are needed to identify gene–environment interactions and population subgroups susceptible to α1-antitrypsin deficiency.

Cytokine gene polymorphisms and atopic disease in two European cohorts. (ECRHS-Basel and SAPALDIA)

BackgroundAtopy and allergic phenotypes are biologically characterized by an imbalanced T helper cell response skewed towards a type 2 (TH2) immune response associated with elevated serum immunoglobulin E (IgE) levels. Polymorphisms in cytokine genes might modulate regulation of the TH1/TH2 balance. We thus aimed at reproducing our previous findings from a European study population on the association of various cytokine polymorphisms with self-reported hay fever as well as increased total and specific IgE levels in two comparable study populations.MethodsTwo prospective Caucasian cohorts were used. In the Basel center of the European Community Respiratory Health Survey (ECRHS, n = 418) ten distinct cytokine polymorphisms of putative functional relevance were genotyped. In the Swiss cohort Study on Air Pollution And Lung Disease In Adults (SAPALDIA, n = 6003) two cytokine polymorphisms were genotyped. The associations of these polymorphisms with atopy were estimated by covariance and logistic regression analysis.ResultsWe confirmed IL4, IL10, IL6 and IL18 as candidate genes for atopic health outcomes. In the large, well-characterized SAPALDIA cohort the IL6(-174G>C) and IL18(-137G>C) polymorphisms were associated with circulating total IgE concentrations in subjects with hay fever. The IL18(-137G>C) polymorphism was also associated with the prevalence of hay fever.ConclusionComprehensive characterization of genetic variation in extended cytokine candidate gene regions is now needed. Large study networks must follow to investigate the association of risk patterns defined by genetic predisposing and environmental risk factors with specific atopic phenotypes.

HMOX1 and GST variants modify attenuation of FEF25–75% decline due to PM10 reduction

Reduced exposure to particulate matter with a 50% cut-off aerodynamic diameter of 10 microm (PM(10)) attenuated age-related lung function decline in our cohort, particularly in the small airways. We hypothesised that polymorphisms in glutathione S-transferase (GST) and haem oxygenase-1 (HMOX1) genes, important for oxidative stress defence, modify these beneficial effects. A population-based sample of 4,365 adults was followed up after 11 yrs, including questionnaire, spirometry and DNA blood sampling. PM(10) exposure was estimated by dispersion modelling and temporal interpolation. The main effects on annual decline in forced expiratory flow at 25-75% of forced vital capacity (FEF(25-75%)) and interactions with PM(10) reduction were investigated for polymorphisms HMOX1 rs2071746 (T/A), rs735266 (T/A) and rs5995098 (G/C), HMOX1 (GT)(n) promoter repeat, GSTM1 and GSTT1 deletions, and GSTP1 p.Ile105Val, using mixed linear regression models. HMOX1 rs5995098, HMOX1 haplotype TTG and GSTP1 showed significant genetic main effects. Interactions with PM(10) reduction were detected: a 10 microg.m(-3) reduction significantly attenuated annual FEF(25-75%) decline by 15.3 mL.s(-1) only in the absence of HMOX1 haplotype ATC. Similarly, carriers of long (GT)(n) promoter repeat alleles or the GSTP1 Val/Val genotype profited significantly more from a 10 microg.m(-3) reduction (26.5 mL.s(-1) and 27.3 mL.s(-1) respectively) than non-carriers. Benefits of a reduction in PM(10) exposure are not equally distributed across the population but are modified by the individual genetic make-up determining oxidative stress defence.

Additional file 1: Table S1. of A common functional variant on the pro-inflammatory Interleukin-6 gene may modify the association between long-term PM10 exposure and diabetes

Characteristics of included and excluded participants. Table S2. Association between functional IL6 polymorphisms and diabetes. (DOCX 27 kb)