Nicole Probst-Hensch

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.

Prognostic Significance of Epithelial-Mesenchymal and Mesenchymal-Epithelial Transition Protein Expression in Non–Small Cell Lung Cancer

Purpose: In carcinomas, invasive tumor growth is accompanied by desmoplastic stroma reaction and facilitated by epithelial-mesenchymal transition (EMT) of cancer cells. We investigated the prognostic significance of the EMT indicator proteins periostin and vimentin in comparison with versican, a putative indicator of the opposite mechanism mesenchymal-epithelial transition (MET), and to the desmoplasia proteins collagen and elastin in non-small cell lung cancer (NSCLC). Experimental Design: Tumor of 533 patients with surgically resected NSCLC was used for analysis of stromal and epithelial protein expression by immunohistochemistry (EMT-MET proteins) and Elastica van Gieson histochemical staining (collagen and elastin). A semiquantitative sum scoring system was done on three tissue microarrays. Results: Of the 533 patients, 48% had squamous cell carcinoma, 47% adenocarcinoma, and 5% adenosquamous carcinoma. High expression of periostin in either stroma or tumor epithelia, independently scored by two pathologists, correlated with male gender, higher stage, higher pT category, and larger tumor size, and in only stroma with tumor relapse. High expression of versican in either stroma or epithelia as well as of stromal collagen had fewer but concordant associations with advanced tumor and periostin, respectively. High expression of elastin was oppositely associated with less advanced disease. Associations of high vimentin were inconsistent (all P values <0.05). High stromal periostin was found to be a prognostic factor for decreased progression-free survival on univariate analysis (P = 0.007). Conclusions: Because up-regulation is frequently observed in the stromal and epithelial tumor compartment, EMT-MET indicator proteins may be integrated in progression models of NSCLC.

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.

Non-Hodgkin lymphoma incidence in the Swiss HIV Cohort Study before and after highly active antiretroviral therapy

Objective:To assess the long-term effect of HAART on non-Hodgkin lymphoma (NHL) incidence in people with HIV (PHIV). Design:Follow-up of the Swiss HIV Cohort Study (SHCS). Methods:Between 1984 and 2006, 12 959 PHIV contributed a total of 75 222 person-years (py), of which 36 787 were spent under HAART. Among these PHIV, 429 NHL cases were identified from the SHCS dataset and/or by record linkage with Swiss Cantonal Cancer Registries. Age- and gender-standardized incidence was calculated and Cox regression was used to estimate hazard ratios (HR). Results:NHL incidence reached 13.6 per 1000 py in 1993–1995 and declined to 1.8 in 2002–2006. HAART use was associated with a decline in NHL incidence [HR = 0.26; 95% confidence interval (CI), 0.20–0.33], and this decline was greater for primary brain lymphomas than other NHL. Among non-HAART users, being a man having sex with men, being 35 years of age or older, or, most notably, having low CD4 cell counts at study enrolment (HR = 12.26 for < 50 versus ≥ 350 cells/μl; 95% CI, 8.31–18.07) were significant predictors of NHL onset. Among HAART users, only age was significantly associated with NHL risk. The HR for NHL declined steeply in the first months after HAART initiation (HR = 0.46; 95% CI, 0.27–0.77) and was 0.12 (95% CI, 0.05–0.25) 7 to10 years afterwards. Conclusions:HAART greatly reduced the incidence of NHL in PHIV, and the influence of CD4 cell count on NHL risk. The beneficial effect remained strong up to 10 years after HAART initiation.

Influence of HIV-related immunodeficiency on the risk of hepatocellular carcinoma.

Objective:To investigate HIV-related immunodeficiency as a risk factor for hepatocellular carcinoma (HCC) among persons infected with HIV, while controlling for the effect of frequent coinfection with hepatitis C and B viruses. Design:A case–control study nested in the Swiss HIV Cohort Study. Methods:Twenty-six HCC patients were identified in the Swiss HIV Cohort Study or through linkage with Swiss Cancer Registries, and were individually matched to 251 controls according to Swiss HIV Cohort Study centre, sex, HIV-transmission category, age and year at enrolment. Odds ratios and corresponding confidence intervals were estimated by conditional logistic regression. Results:All HCC patients were positive for hepatitis B surface antigen or antibodies against hepatitis C virus. HCC patients included 14 injection drug users (three positive for hepatitis B surface antigen and 13 for antibodies against hepatitis C virus) and 12 men having sex with men/heterosexual/other (11 positive for hepatitis B surface antigen, three for antibodies against hepatitis C virus), revealing a strong relationship between HIV transmission route and hepatitis viral type. Latest CD4+ cell count [Odds ratio (OR) per 100 cells/μl decrease = 1.33, 95% confidence interval (CI) 1.06–1.68] and CD4+ cell count percentage (OR per 10% decrease = 1.65, 95% CI 1.01–2.71) were significantly associated with HCC. The effects of CD4+ cell count were concentrated among men having sex with men/heterosexual/other rather than injecting drug users. Highly active antiretroviral therapy use was not significantly associated with HCC risk (OR for ever versus never = 0.59, 95% confidence interval 0.18–1.91). Conclusion:Lower CD4+ cell counts increased the risk for HCC among persons infected with HIV, an effect that was particularly evident for hepatitis B virus-related HCC arising in non-injecting drug users.

Golgi phosphoprotein 2 (GOLPH2) expression in liver tumors and its value as a serum marker in hepatocellular carcinomas.

Hepatocellular carcinomas (HCCs) and bile duct carcinomas (BDCs) have a poor prognosis. Therefore, surveillance strategies including sensitive and specific serum markers for early detection are needed. Recently, Golgi Phosphoprotein 2 (GOLPH2) has been proposed as a serum marker for HCC, but GOLPH2 expression data in liver tissues was not available. Using tissue microarrays and immunohistochemistry, we semiquantitatively analyzed GOLPH2 protein expression in patients with HCC (n = 170), benign liver tumors (n = 22), BDC (n = 114) and normal liver tissue (n = 105). A newly designed sandwich enzyme‐linked immunoassay (ELISA) was used to analyze GOLPH2 levels in the sera of patients with HCC (n = 62), hepatitis C virus (HCV) (n = 29), BDC (n = 10), and healthy control persons (n = 12). By immunohistochemistry 121/170 (71%) of HCC showed strong GOLPH2 expression, which was significantly associated with a higher tumor grade (P = 0.01). A total of 97/114 (85%) BDCs showed a strong GOLPH2 expression which proved to be an independent prognostic factor for overall survival (P < 0.05). Serum levels of GOLPH2 measured by ELISA were significantly elevated in patients with HCC with underlying HCV infection (median 18 mg/L, P < 0.05) and patients with BDC (median = 14.5 mg/L, P < 0.01) in comparison to healthy controls (median 4 mg/L). Conclusion: GOLPH2 protein is highly expressed in tissues of HCC and BDC. GOLPH2 protein levels are detectable and quantifiable in sera by ELISA. In patients with hepatitis C, serial ELISA measurements in the course of the disease appear to be a promising complementary serum marker in the surveillance of HCC. GOLPH2 should be further evaluated as a serum tumor marker in BDC on a larger scale. (HEPATOLOGY 2009.)

Prevalence of airflow obstruction in smokers and never-smokers in Switzerland

The aim of the present study was to measure age-specific prevalence of airflow obstruction in Switzerland in smokers and never-smokers using pulmonary function tests and respiratory symptoms from 6,126 subjects participating in the Swiss Cohort Study on Air Pollution and Lung Diseases in Adults. The lower limit of normal of the forced expiratory volume in 1 s/forced vital capacity ratio was used to define airflow obstruction. Severity of airflow obstruction was graded according to the recommendations of the Global Initiative for Chronic Obstructive Lung Disease. Prevalence of airflow obstruction ranged from 2.5% in subjects aged 30–39 yrs to 8.0% in those aged ≥70 yrs. In multivariate analysis, age (OR 2.8, ≥70 yrs versus 30–39 yrs), smoking (OR 1.8) and asthma (OR 6.7) were associated with airflow obstruction. Never-smokers constituted 29.3% of subjects with airflow obstruction. Never-smokers with airflow obstruction were younger, more likely to be male and reported asthma more frequently than obstructive smokers. Obstructive smokers and never-smokers had similar level of symptoms and quality of life impairment. The prevalence of airflow obstruction in Switzerland is similar to other developed countries. Never-smokers account for a third of the prevalence, which is higher proportion than elsewhere. Airflow obstruction in never-smokers deserves attention because of its frequency and its similar health impact to that in smokers.

PTEN expression is a strong predictor of survival in mesothelioma patients

BACKGROUNDnMalignant pleural mesothelioma (MPM) is a highly aggressive tumour with poor prognosis and limited response to therapy. MPM is characterised by complex chromosomal aberrations, including chromosome 10 losses. The tumour suppressor gene phosphatase and tensin homologue deleted from chromosome 10 (PTEN) located on chromosome 10q23 plays an important role in different cancer, but its relevance for MPM is unclear.nnnPATIENTS AND METHODSnIn the present tissue microarray-based study, 341 MPM were studied for PTEN expression by immunohistochemistry using a monoclonal mouse PTEN antibody. Expression levels were semiquantitatively scored (negative, weak, moderate, strong). Expression of PTEN was correlated to overall survival.nnnRESULTSnClinical data from 206 patients were available. One hundred and five patients were stage T4 and 92 patients presented with regional and mediastinal lymph node metastasis. Loss of PTEN expression was observed in 62% of the cases. The survival time was correlated to PTEN expression in 126 cases with complete follow-up data. Comparing any PTEN expression versus no expression, median survival time was significantly longer (log rank test p=0.0001) in patients with PTEN expression (15.5 months; 95% CI: 3.8; 27.2 vs 9.7 months; 95% CI: 7.9; 11.7). Cox regression analysis revealed an association between PTEN expression and survival (p=0.003) independently from the histological subtype (p=0.7).nnnCONCLUSIONnPTEN is an independent prognostic biomarker in mesothelioma patients. The frequent loss of expression of the tumour suppressor gene PTEN suggests involvement of the PI3K-AKT/protein kinase B (PKB) pathway in MPMs, which may be relevant for future mesothelioma treatment.

IMP3 expression in lesions of the biliary tract: a marker for high-grade dysplasia and an independent prognostic factor in bile duct carcinomas

The oncofetal protein IMP3 (insulin-like growth factor II mRNA binding protein 3) is expressed during embryogenesis and carcinogenesis. Various tumor types have been analyzed for IMP3 expression, which was exclusively found in tumor cells and correlated with increased tumor aggressiveness and reduced overall survival. To our knowledge, IMP3 expression has not been investigated in bile duct carcinomas. Using large tissue sections from resection specimens of the extrahepatic biliary tract, we analyzed IMP3 in normal bile ducts (n = 36), bile ducts with acute inflammation and reactive epithelial changes (n = 26), low-grade dysplasia (n = 9), and high-grade dysplasia (n = 11). Furthermore, IMP3 expression was assessed in bile duct carcinoma (n = 115) using clinically well-characterized tissue microarrays. The findings were correlated with clinical-pathologic parameters including survival. High-grade dysplasia was strongly positive for IMP3 in all cases studied compared with no or weak expression in normal, inflamed, and low-grade dysplastic bile ducts. Of the bile duct carcinomas 58.3% (67/115) were strongly positive for IMP3, which was associated with a higher proliferation rate (P = .004) and p53 positivity (P = .022). Patients with strong IMP3 expression had significantly reduced overall survival (P = .037) similarly to the subgroup of pT3 carcinomas (P = .007). In multivariate analysis, IMP3 expression was an independent prognostic factor for overall survival (P = .040, RR = 1.809). This comprehensive study shows that IMP3 is an independent prognostic biomarker in bile duct carcinoma. In addition, it may be a marker for high-grade dysplasia in the extrahepatic biliary tract.

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.