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Find video protocols related to scientific articles indexed in Pubmed.
A multicentre study of air pollution exposure and childhood asthma prevalence: the ESCAPE project.
Eur. Respir. J.
PUBLISHED: 10-18-2014
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The aim of this study was to determine the effect of six traffic-related air pollution metrics (nitrogen dioxide, nitrogen oxides, particulate matter with an aerodynamic diameter <10 ?m (PM10), PM2.5, coarse particulate matter and PM2.5 absorbance) on childhood asthma and wheeze prevalence in five European birth cohorts: MAAS (England, UK), BAMSE (Sweden), PIAMA (the Netherlands), GINI and LISA (both Germany, divided into north and south areas). Land-use regression models were developed for each study area and used to estimate outdoor air pollution exposure at the home address of each child. Information on asthma and current wheeze prevalence at the ages of 4-5 and 8-10 years was collected using validated questionnaires. Multiple logistic regression was used to analyse the association between pollutant exposure and asthma within each cohort. Random-effects meta-analyses were used to combine effect estimates from individual cohorts. The meta-analyses showed no significant association between asthma prevalence and air pollution exposure (e.g. adjusted OR (95%CI) for asthma at age 8-10 years and exposure at the birth address (n = 10377): 1.10 (0.81-1.49) per 10 ?g·m(-3) nitrogen dioxide; 0.88 (0.63-1.24) per 10 ?g·m(-3) PM10; 1.23 (0.78-1.95) per 5 ?g·m(-3) PM2.5). This result was consistently found in initial crude models, adjusted models and further sensitivity analyses. This study found no significant association between air pollution exposure and childhood asthma prevalence in five European birth cohorts.
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A novel common variant in DCST2 is associated with length in early life and height in adulthood.
Ralf J P van der Valk, Eskil Kreiner-Møller, Marjolein N Kooijman, Mònica Guxens, Evangelia Stergiakouli, Annika Sääf, Jonathan P Bradfield, Frank Geller, M Geoffrey Hayes, Diana L Cousminer, Antje Körner, Elisabeth Thiering, John A Curtin, Ronny Myhre, Ville Huikari, Raimo Joro, Marjan Kerkhof, Nicole M Warrington, Niina Pitkänen, Ioanna Ntalla, Momoko Horikoshi, Riitta Veijola, Rachel M Freathy, Yik-Ying Teo, Sheila J Barton, David M Evans, John P Kemp, Beate St Pourcain, Susan M Ring, George Davey Smith, Anna Bergström, Inger Kull, Hakon Hakonarson, Frank D Mentch, Hans Bisgaard, Bo Chawes, Jakob Stokholm, Johannes Waage, Patrick Eriksen, Astrid Sevelsted, Mads Melbye, , Cornelia M van Duijn, Carolina Medina-Gomez, Albert Hofman, Johan C de Jongste, H Rob Taal, André G Uitterlinden, Loren L Armstrong, Johan Eriksson, Aarno Palotie, Mariona Bustamante, Xavier Estivill, Juan R Gonzalez, Sabrina Llop, Wieland Kiess, Anubha Mahajan, Claudia Flexeder, Carla M T Tiesler, Clare S Murray, Angela Simpson, Per Magnus, Verena Sengpiel, Anna-Liisa Hartikainen, Sirkka Keinänen-Kiukaanniemi, Alexandra Lewin, Alexessander Da Silva Couto Alves, Alexandra I Blakemore, Jessica L Buxton, Marika Kaakinen, Alina Rodriguez, Sylvain Sebert, Marja Vaarasmaki, Timo Lakka, Virpi Lindi, Ulrike Gehring, Dirkje S Postma, Wei Ang, John P Newnham, Leo-Pekka Lyytikäinen, Katja Pahkala, Olli T Raitakari, Kalliope Panoutsopoulou, Eleftheria Zeggini, Dorret I Boomsma, Maria Groen-Blokhuis, Jorma Ilonen, Lude Franke, Joel N Hirschhorn, Tune H Pers, Liming Liang, Jinyan Huang, Berthold Hocher, Mikael Knip, Seang-Mei Saw, John W Holloway, Erik Melén, Struan F A Grant, Bjarke Feenstra, William L Lowe, Elisabeth Widén, Elena Sergeyev, Harald Grallert, Adnan Custovic, Bo Jacobsson, Marjo-Riitta Järvelin, Mustafa Atalay, Gerard H Koppelman, Craig E Pennell, Harri Niinikoski, George V Dedoussis, Mark I McCarthy, Timothy M Frayling, Jordi Sunyer, Nicholas J Timpson, Fernando Rivadeneira, Klaus Bønnelykke, Vincent W V Jaddoe.
Hum. Mol. Genet.
PUBLISHED: 10-03-2014
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Common genetic variants have been identified for adult height, but not much is known about the genetics of skeletal growth in early life. To identify common genetic variants that influence fetal skeletal growth, we meta-analyzed 22 genome-wide association studies (Stage 1; N = 28 459). We identified seven independent top single nucleotide polymorphisms (SNPs) (P < 1 × 10(-6)) for birth length, of which three were novel and four were in or near loci known to be associated with adult height (LCORL, PTCH1, GPR126 and HMGA2). The three novel SNPs were followed-up in nine replication studies (Stage 2; N = 11 995), with rs905938 in DC-STAMP domain containing 2 (DCST2) genome-wide significantly associated with birth length in a joint analysis (Stages 1 + 2; ? = 0.046, SE = 0.008, P = 2.46 × 10(-8), explained variance = 0.05%). Rs905938 was also associated with infant length (N = 28 228; P = 5.54 × 10(-4)) and adult height (N = 127 513; P = 1.45 × 10(-5)). DCST2 is a DC-STAMP-like protein family member and DC-STAMP is an osteoclast cell-fusion regulator. Polygenic scores based on 180 SNPs previously associated with human adult stature explained 0.13% of variance in birth length. The same SNPs explained 2.95% of the variance of infant length. Of the 180 known adult height loci, 11 were genome-wide significantly associated with infant length (SF3B4, LCORL, SPAG17, C6orf173, PTCH1, GDF5, ZNFX1, HHIP, ACAN, HLA locus and HMGA2). This study highlights that common variation in DCST2 influences variation in early growth and adult height.
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Dissecting the genetics of chronic mucus hypersecretion in smokers with and without COPD.
Eur. Respir. J.
PUBLISHED: 09-20-2014
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Smoking is a notorious risk factor for chronic mucus hypersecretion (CMH). CMH frequently occurs in chronic obstructive pulmonary disease (COPD). The question arises whether the same single-nucleotide polymorphisms (SNPs) are related to CMH in smokers with and without COPD. We performed two genome-wide association studies of CMH under an additive genetic model in male heavy smokers (?20 pack-years) with COPD (n = 849, 39.9% CMH) and without COPD (n = 1348, 25.4% CMH), followed by replication and meta-analysis in comparable populations, and assessment of the functional relevance of significantly associated SNPs. Genome-wide association analysis of CMH in COPD and non-COPD subjects yielded no genome-wide significance after replication. In COPD, our top SNP (rs10461985, p = 5.43×10(-5)) was located in the GDNF-AS1 gene that is functionally associated with the GDNF gene. Expression of GDNF in bronchial biopsies of COPD patients was significantly associated with CMH (p = 0.007). In non-COPD subjects, four SNPs had a p-value <10(-5) in the meta-analysis, including a SNP (rs4863687) in the MAML3 gene, the T-allele showing modest association with CMH (p = 7.57×10(-6), OR 1.48) and with significantly increased MAML3 expression in lung tissue (p = 2.59×10(-12)). Our data suggest the potential for differential genetic backgrounds of CMH in individuals with and without COPD.
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Susceptibility loci for lung cancer are associated with mRNA levels of nearby genes in the lung.
Carcinogenesis
PUBLISHED: 09-03-2014
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Recent studies identified three genetic loci reproducibly associated with lung cancer in populations of European ancestry, namely 15q25, 5p15 and 6p21. The goals of this study are first to confirm whether these loci are associated with lung cancer in a French Canadian population and second to identify disease-associated single nucleotide polymorphisms (SNPs) influencing messenger RNA (mRNA) expression levels of genes in the lung, that is expression quantitative trait loci (eQTLs). SNPs were genotyped in 420 patients undergoing lung cancer surgery and compared with 3151 controls of European ancestry. Genome-wide gene expression levels in non-tumor lung tissues of the same 420 patients were also measured to identify eQTLs. Significant eQTLs were then followed-up in two replication sets (n = 339 and 363). SNPs found in the three susceptibility loci were associated with lung cancer in the French Canadian population. Strong eQTLs were found on chromosome 15q25 with the expression levels of CHRNA5 (P = 2.23 × 10(-) (22) with rs12907966). The CHRNA5-rs12907966 eQTL was convincingly validated in the two replication sets (P = 3.46 × 10(-) (16) and 2.01 × 10(-) (15)). On 6p21, a trend was observed for rs3131379 to be associated with the expression of APOM (P = 3.58 × 10(-) (4)) and validated in the replication sets (P = 1.11 × 10(-) (8) and 6.84 × 10(-) (4)). On 5p15, no significant eQTLs were found. This study confirmed that chromosomes 15q25, 5p15 and 6p21 harbored susceptibility loci for lung cancer in French Canadians. Most importantly, this study suggests that the risk alleles at 15q25 and 6p21 may mediate their effect by regulating the mRNA expression levels of CHRNA5 and APOM in the lung.
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Genetic regulation of gene expression in the lung identifies CST3 and CD22 as potential causal genes for airflow obstruction.
Thorax
PUBLISHED: 09-02-2014
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COPD is a complex chronic disease with poorly understood pathogenesis. Integrative genomic approaches have the potential to elucidate the biological networks underlying COPD and lung function. We recently combined genome-wide genotyping and gene expression in 1111 human lung specimens to map expression quantitative trait loci (eQTL).
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Nocturnal dry cough in the first 7 years of life is associated with asthma at school age.
Pediatr. Pulmonol.
PUBLISHED: 08-26-2014
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Childhood wheeze is an important, well-known risk factor for asthma, yet little is known about the contribution of nocturnal dry cough. We investigated the association of nocturnal dry cough at ages 1-7 years with doctor-diagnosed asthma at 8 years of age, both in the presence and absence of wheeze.
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Risk factors and early origins of chronic obstructive pulmonary disease.
Lancet
PUBLISHED: 08-11-2014
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Chronic obstructive pulmonary disease is mainly a smoking-related disorder and affects millions of people worldwide, with a large effect on individual patients and society as a whole. Although the disease becomes clinically apparent around the age of 40-50 years, its origins can begin very early in life. Different risk factors in very early life-ie, in utero and during early childhood-drive the development of clinically apparent chronic obstructive pulmonary disease in later life. In discussions of which risk factors drive chronic obstructive pulmonary disease, it is important to realise that the disease is very heterogeneous and at present is largely diagnosed by lung function only. In this Review, we will discuss the evidence for risk factors for the various phenotypes of chronic obstructive pulmonary disease during different stages of life.
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Objective allergy markers and risk of cancer mortality and hospitalization in a large population-based cohort.
Cancer Causes Control
PUBLISHED: 07-08-2014
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There are indications that a history of allergy may offer some protection against cancer. We studied the relation of three objectively determined allergy markers with cancer mortality and hospitalization risk.
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A large lung gene expression study identifying fibulin-5 as a novel player in tissue repair in COPD.
Thorax
PUBLISHED: 07-04-2014
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Chronic obstructive pulmonary disease (COPD) is a progressive, incurable lung disease characterised by abnormal tissue repair causing emphysema and small airways fibrosis. Since current therapy cannot modify this abnormal repair, it is crucial to unravel its underlying molecular mechanisms. Unbiased analysis of genome-wide gene expression profiles in lung tissue provides a powerful tool to investigate this.
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Common genes underlying asthma and COPD? Genome-wide analysis on the Dutch hypothesis.
Eur. Respir. J.
PUBLISHED: 07-03-2014
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Asthma and chronic obstructive pulmonary disease (COPD) are thought to share a genetic background ("Dutch hypothesis"). We investigated whether asthma and COPD have common underlying genetic factors, performing genome-wide association studies for both asthma and COPD and combining the results in meta-analyses. Three loci showed potential involvement in both diseases: chr2p24.3, chr5q23.1 and chr13q14.2, containing DDX1, COMMD10 (both participating in the nuclear factor (NF) ?? pathway) and GNG5P5, respectively. Single nucleotide polymorphisms (SNPs) rs9534578 in GNG5P5 reached genome-wide significance after first replication phase (p=9.96×10(-9)). The second replication phase, in seven independent cohorts, provided no significant replication. Expression quantitative trait loci (eQTL) analysis in blood cells and lung tissue on the top 20 associated SNPs identified two SNPs in COMMD10 that influenced gene expression. Inflammatory processes differ in asthma and COPD and are mediated by NF-??, which could be driven by the same underlying genes, COMMD10 and DDX1. None of the SNPs reached genome-wide significance. Our eQTL studies support a functional role for two COMMD10 SNPs, since they influence gene expression in both blood cells and lung tissue. Our findings suggest that there is either no common genetic component in asthma and COPD or, alternatively, different environmental factors, e.g. lifestyle and occupation in different countries and continents, which may have obscured the genetic common contribution.
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Increased activation of blood neutrophils after cigarette smoking in young individuals susceptible to COPD.
Respir. Res.
PUBLISHED: 06-25-2014
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BackgroundCigarette smoking is the most important risk factor for Chronic Obstructive Pulmonary Disease (COPD). Only a subgroup of smokers develops COPD and it is unclear why these individuals are more susceptible to the detrimental effects of cigarette smoking. The risk to develop COPD is known to be higher in individuals with familial aggregation of COPD. This study aimed to investigate if acute systemic and local immune responses to cigarette smoke differentiate between individuals susceptible or non-susceptible to develop COPD, both at young (18-40 years) and old (40-75 years) age.MethodsAll participants smoked three cigarettes in one hour. Changes in inflammatory markers in peripheral blood (at 0 and 3 hours) and in bronchial biopsies (at 0 and 24 hours) were investigated. Acute effects of smoking were analyzed within and between susceptible and non-susceptible individuals, and by multiple regression analysis.ResultsYoung susceptible individuals showed significantly higher increases in the expression of Fc¿RII (CD32) in its active form on neutrophils after smoking (p¿=¿0.016 and 0.028 respectively), independently of age, smoking status and expression of the respective markers at baseline. Smoking had no significant effect on mediators in blood or inflammatory cell counts in bronchial biopsies. In the old group, acute effects of smoking were comparable between healthy controls and COPD patients.ConclusionsWe show for the first time that COPD susceptibility at young age associates with an increased systemic innate immune response to cigarette smoking. This suggests a role of systemic inflammation in the early induction phase of COPD.Trial registrationClinicaltrials.gov: NCT00807469.
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Effects of cigarette smoke extract on human airway smooth muscle cells in COPD.
Eur. Respir. J.
PUBLISHED: 06-25-2014
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We hypothesised that the response to cigarette smoke in airway smooth muscle (ASM) cells from smokers with chronic obstructive pulmonary disease (COPD) would be intrinsically different from smokers without COPD, producing greater pro-inflammatory mediators and factors relating to airway remodelling. ASM cells were obtained from smokers with or without COPD, and then stimulated with cigarette smoke extract (CSE) or transforming growth factor-?1. The production of chemokines and matrix metalloproteinases (MMPs) were measured by ELISA, and the deposition of collagens by extracellular matrix ELISA. The effects of CSE on cell attachment and wound healing were measured by toluidine blue attachment and cell tracker green wound healing assays. CSE increased the release of CXCL8 and CXCL1 from human ASM cells, and cells from smokers with COPD produced more CSE-induced CXCL1. The production of MMP-1, -3 and -10, and the deposition of collagen VIII alpha 1 (COL8A1) were increased by CSE, especially in the COPD group which had higher production of MMP-1 and deposition of COL8A1. CSE decreased ASM cell attachment and wound healing in the COPD group only. ASM cells from smokers with COPD were more sensitive to CSE stimulation, which may explain, in part, why some smokers develop COPD.
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Pharmacogenetic analysis of GLCCI1 in three north European pediatric asthma populations with a reported use of inhaled corticosteroids.
Pharmacogenomics
PUBLISHED: 06-05-2014
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GLCCI1 rs37972 has previously been associated with decreased lung function improvement upon treatment with inhaled corticosteroids (ICS) in asthmatics.
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Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.
John R B Perry, Felix Day, Cathy E Elks, Patrick Sulem, Deborah J Thompson, Teresa Ferreira, Chunyan He, Daniel I Chasman, Tonu Esko, Gudmar Thorleifsson, Eva Albrecht, Wei Q Ang, Tanguy Corre, Diana L Cousminer, Bjarke Feenstra, Nora Franceschini, Andrea Ganna, Andrew D Johnson, Sanela Kjellqvist, Kathryn L Lunetta, George McMahon, Ilja M Nolte, Lavinia Paternoster, Eleonora Porcu, Albert V Smith, Lisette Stolk, Alexander Teumer, Natalia Tšernikova, Emmi Tikkanen, Sheila Ulivi, Erin K Wagner, Najaf Amin, Laura J Bierut, Enda M Byrne, Jouke-Jan Hottenga, Daniel L Koller, Massimo Mangino, Tune H Pers, Laura M Yerges-Armstrong, Jing Hua Zhao, Irene L Andrulis, Hoda Anton-Culver, Femke Atsma, Stefania Bandinelli, Matthias W Beckmann, Javier Benitez, Carl Blomqvist, Stig E Bojesen, Manjeet K Bolla, Bernardo Bonanni, Hiltrud Brauch, Hermann Brenner, Julie E Buring, Jenny Chang-Claude, Stephen Chanock, Jinhui Chen, Georgia Chenevix-Trench, J Margriet Collée, Fergus J Couch, David Couper, Andrea D Coviello, Angela Cox, Kamila Czene, Adamo Pio D'adamo, George Davey Smith, Immaculata De Vivo, Ellen W Demerath, Joe Dennis, Peter Devilee, Aida K Dieffenbach, Alison M Dunning, Gudny Eiriksdottir, Johan G Eriksson, Peter A Fasching, Luigi Ferrucci, Dieter Flesch-Janys, Henrik Flyger, Tatiana Foroud, Lude Franke, Melissa E Garcia, Montserrat Garcia-Closas, Frank Geller, Eco E J de Geus, Graham G Giles, Daniel F Gudbjartsson, Vilmundur Gudnason, Pascal Guénel, Suiqun Guo, Per Hall, Ute Hamann, Robin Haring, Catharina A Hartman, Andrew C Heath, Albert Hofman, Maartje J Hooning, John L Hopper, Frank B Hu, David J Hunter, David Karasik, Douglas P Kiel, Julia A Knight, Veli-Matti Kosma, Zoltan Kutalik, Sandra Lai, Diether Lambrechts, Annika Lindblom, Reedik Mägi, Patrik K Magnusson, Arto Mannermaa, Nicholas G Martin, Gisli Masson, Patrick F McArdle, Wendy L McArdle, Mads Melbye, Kyriaki Michailidou, Evelin Mihailov, Lili Milani, Roger L Milne, Heli Nevanlinna, Patrick Neven, Ellen A Nohr, Albertine J Oldehinkel, Ben A Oostra, Aarno Palotie, Munro Peacock, Nancy L Pedersen, Paolo Peterlongo, Julian Peto, Paul D P Pharoah, Dirkje S Postma, Anneli Pouta, Katri Pylkäs, Paolo Radice, Susan Ring, Fernando Rivadeneira, Antonietta Robino, Lynda M Rose, Anja Rudolph, Veikko Salomaa, Serena Sanna, David Schlessinger, Marjanka K Schmidt, Mellissa C Southey, Ulla Sovio, Meir J Stampfer, Doris Stöckl, Anna M Storniolo, Nicholas J Timpson, Jonathan Tyrer, Jenny A Visser, Peter Vollenweider, Henry Völzke, Gérard Waeber, Melanie Waldenberger, Henri Wallaschofski, Qin Wang, Gonneke Willemsen, Robert Winqvist, Bruce H R Wolffenbuttel, Margaret J Wright, , Dorret I Boomsma, Michael J Econs, Kay-Tee Khaw, Ruth J F Loos, Mark I McCarthy, Grant W Montgomery, John P Rice, Elizabeth A Streeten, Unnur Thorsteinsdottir, Cornelia M van Duijn, Behrooz Z Alizadeh, Sven Bergmann, Eric Boerwinkle, Heather A Boyd, Laura Crisponi, Paolo Gasparini, Christian Gieger, Tamara B Harris, Erik Ingelsson, Marjo-Riitta Järvelin, Peter Kraft, Debbie Lawlor, Andres Metspalu, Craig E Pennell, Paul M Ridker, Harold Snieder, Thorkild I A Sørensen, Tim D Spector, David P Strachan, André G Uitterlinden, Nicholas J Wareham, Elisabeth Widén, Marek Zygmunt, Anna Murray, Douglas F Easton, Kari Stefansson, Joanne M Murabito, Ken K Ong.
Nature
PUBLISHED: 05-30-2014
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Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P?
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Untargeted lipidomic analysis in chronic obstructive pulmonary disease. Uncovering sphingolipids.
Am. J. Respir. Crit. Care Med.
PUBLISHED: 05-30-2014
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Cigarette smoke is the major risk factor in the development of chronic obstructive pulmonary disease (COPD). Lipidomics is a novel and emerging research field that may provide new insights in the origins of chronic inflammatory diseases, such as COPD.
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Co-morbidities are the key nominators of the health related quality of life in mild and moderate COPD.
BMC Pulm Med
PUBLISHED: 05-23-2014
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Co-morbidities are common in chronic obstructive pulmonary disease (COPD). We assessed the contribution of common co-morbidities on health related quality of life (HRQoL) among COPD patients.
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Genome-wide association analysis identifies six new loci associated with forced vital capacity.
Daan W Loth, María Soler Artigas, Sina A Gharib, Louise V Wain, Nora Franceschini, Beate Koch, Tess D Pottinger, Albert Vernon Smith, Qing Duan, Chris Oldmeadow, Mi Kyeong Lee, David P Strachan, Alan L James, Jennifer E Huffman, Veronique Vitart, Adaikalavan Ramasamy, Nicholas J Wareham, Jaakko Kaprio, Xin-Qun Wang, Holly Trochet, Mika Kähönen, Claudia Flexeder, Eva Albrecht, Lorna M Lopez, Kim de Jong, Bharat Thyagarajan, Alexessander Couto Alves, Stefan Enroth, Ernst Omenaas, Peter K Joshi, Tove Fall, Ana Viñuela, Lenore J Launer, Laura R Loehr, Myriam Fornage, Guo Li, Jemma B Wilk, Wenbo Tang, Ani Manichaikul, Lies Lahousse, Tamara B Harris, Kari E North, Alicja R Rudnicka, Jennie Hui, Xiangjun Gu, Thomas Lumley, Alan F Wright, Nicholas D Hastie, Susan Campbell, Rajesh Kumar, Isabelle Pin, Robert A Scott, Kirsi H Pietiläinen, Ida Surakka, Yongmei Liu, Elizabeth G Holliday, Holger Schulz, Joachim Heinrich, Gail Davies, Judith M Vonk, Mary Wojczynski, Anneli Pouta, Asa Johansson, Sarah H Wild, Erik Ingelsson, Fernando Rivadeneira, Henry Völzke, Pirro G Hysi, Gudny Eiriksdottir, Alanna C Morrison, Jerome I Rotter, Wei Gao, Dirkje S Postma, Wendy B White, Stephen S Rich, Albert Hofman, Thor Aspelund, David Couper, Lewis J Smith, Bruce M Psaty, Kurt Lohman, Esteban G Burchard, André G Uitterlinden, Melissa Garcia, Bonnie R Joubert, Wendy L McArdle, A Bill Musk, Nadia Hansel, Susan R Heckbert, Lina Zgaga, Joyce B J van Meurs, Pau Navarro, Igor Rudan, Yeon-Mok Oh, Susan Redline, Deborah L Jarvis, Jing Hua Zhao, Taina Rantanen, George T O'Connor, Samuli Ripatti, Rodney J Scott, Stefan Karrasch, Harald Grallert, Nathan C Gaddis, John M Starr, Cisca Wijmenga, Ryan L Minster, David J Lederer, Juha Pekkanen, Ulf Gyllensten, Harry Campbell, Andrew P Morris, Sven Gläser, Christopher J Hammond, Kristin M Burkart, John Beilby, Stephen B Kritchevsky, Vilmundur Gudnason, Dana B Hancock, O Dale Williams, Ozren Polašek, Tatijana Zemunik, Ivana Kolčić, Marcy F Petrini, Matthias Wjst, Woo Jin Kim, David J Porteous, Generation Scotland, Blair H Smith, Anne Viljanen, Markku Heliövaara, John R Attia, Ian Sayers, Regina Hampel, Christian Gieger, Ian J Deary, H Marike Boezen, Anne Newman, Marjo-Riitta Järvelin, James F Wilson, Lars Lind, Bruno H Stricker, Alexander Teumer, Timothy D Spector, Erik Melén, Marjolein J Peters, Leslie A Lange, R Graham Barr, Ken R Bracke, Fien M Verhamme, Joohon Sung, Pieter S Hiemstra, Patricia A Cassano, Akshay Sood, Caroline Hayward, Josée Dupuis, Ian P Hall, Guy G Brusselle, Martin D Tobin, Stephanie J London.
Nat. Genet.
PUBLISHED: 05-22-2014
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Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.
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Association of occupational pesticide exposure with accelerated longitudinal decline in lung function.
Am. J. Epidemiol.
PUBLISHED: 04-29-2014
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Cross-sectional studies have shown that occupational exposure to vapors, gases, dusts, and fumes (VGDF) and pesticides is associated with a lower level of lung function. These associations seem to be stronger in ever smokers. In the current study, we aimed to assess whether occupational exposure to VGDF and pesticides is associated with longitudinal decline in lung function. We used 12,772 observations from 2,527 participants in the Vlagtwedde-Vlaardingen Study, a general-population-based cohort study that followed subjects for 25 years, from 1965 to the last survey in 1989/1990. Job-specific exposure was estimated with the ALOHA+ job exposure matrix. Associations between exposures and annual changes in forced expiratory volume in 1 second (FEV1) and FEV1 as a percentage of inspiratory vital capacity (FEV1%VC) were assessed with linear mixed-effect models including sex, age, and level of lung function at the first measurement and pack-years of smoking at the last measurement. We tested for interaction between smoking and occupational exposure and assessed associations separately for never smokers and ever smokers. Exposure to VGDF was not associated with accelerated lung function decline after adjustment for co-exposure to pesticides. Exposure to pesticides, both in the last-held job and as a cumulative measure, was associated with accelerated decline in FEV1 and FEV1%VC, especially among ever smokers, where we found an excess change in FEV1 of -6.9 mL/year (95% confidence interval: -10.2, -3.7) associated with high pesticide exposure.
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Advanced glycation end products in the skin are enhanced in COPD.
Metab. Clin. Exp.
PUBLISHED: 04-15-2014
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Cigarette smoking is the main cause of chronic obstructive pulmonary disease (COPD) inducing oxidative stress and local tissue injury, resulting in pulmonary inflammation. Advanced glycation end products (AGEs) are produced by glycation and oxidation processes and their formation is accelerated in inflammatory conditions. In this study we assessed whether AGE accumulation in the skin is elevated in COPD and associates with disease severity.
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Risk factors for chronic mucus hypersecretion in individuals with and without COPD: influence of smoking and job exposure on CMH.
Occup Environ Med
PUBLISHED: 03-18-2014
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Chronic mucus hypersecretion (CMH) is highly prevalent in smokers and associated with an accelerated lung function decline and chronic obstructive pulmonary disease (COPD). Several risk factors contribute to CMH and to COPD. It is, however, unknown if risk factors for CMH are similar in persons with and without COPD.
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Associations between particulate matter elements and early-life pneumonia in seven birth cohorts: results from the ESCAPE and TRANSPHORM projects.
Int J Hyg Environ Health
PUBLISHED: 03-10-2014
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Evidence for a role of long-term particulate matter exposure on acute respiratory infections is growing. However, which components of particulate matter may be causative remains largely unknown. We assessed associations between eight particulate matter elements and early-life pneumonia in seven birth cohort studies (N total=15,980): BAMSE (Sweden), GASPII (Italy), GINIplus and LISAplus (Germany), INMA (Spain), MAAS (United Kingdom) and PIAMA (The Netherlands). Annual average exposure to copper, iron, potassium, nickel, sulfur, silicon, vanadium and zinc, each respectively derived from particles with aerodynamic diameters ? 10 ?m (PM10) and 2.5 ?m (PM2.5), were estimated using standardized land use regression models and assigned to birth addresses. Cohort-specific associations between these exposures and parental reports of physician-diagnosed pneumonia between birth and two years were assessed using logistic regression models adjusted for host and environmental covariates and total PM10 or PM2.5 mass. Combined estimates were calculated using random-effects meta-analysis. There was substantial within and between-cohort variability in element concentrations. In the adjusted meta-analysis, pneumonia was weakly associated with zinc derived from PM10 (OR: 1.47 (95% CI: 0.99, 2.18) per 20 ng/m(3) increase). No other associations with the other elements were consistently observed. The independent effect of particulate matter mass remained after adjustment for element concentrations. In conclusion, associations between particulate matter mass exposure and pneumonia were not explained by the elements we investigated. Zinc from PM10 was the only element which appeared independently associated with a higher risk of early-life pneumonia. As zinc is primarily attributable to non-tailpipe traffic emissions, these results may suggest a potential adverse effect of non-tailpipe emissions on health.
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Association of IL33-IL-1 receptor-like 1 (IL1RL1) pathway polymorphisms with wheezing phenotypes and asthma in childhood.
J. Allergy Clin. Immunol.
PUBLISHED: 02-22-2014
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Genome-wide association studies identified IL33 and IL-1 receptor-like 1 (IL1RL1)/IL18R1 as asthma susceptibility loci. IL33 and IL1RL1 constitute a single ligand-receptor pathway.
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Asthma and chronic obstructive pulmonary disease: similarities and differences.
Clin. Chest Med.
PUBLISHED: 02-11-2014
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Asthma and COPD are both heterogeneous lung diseases including many different phenotypes. The classical asthma and COPD phenotypes are easy to discern because they reflect extremes of a phenotypical spectrum. Thus asthma in childhood and COPD in smokers have their own phenotypic expression with underlying pathophysiological mechanisms that differ importantly. In older adults, asthma and COPD are more difficult to differentiate and there exists a bronchodilator response in most but not all patients with asthma and persistent airway obstruction in most but not all patients with COPD where even up to 50% have been reported to have some bronchodilator response as assessed with FEV1. Airway obstruction is generated in the large and small airways both in asthma and COPD, and this small airway obstruction is located more proximally in asthma, yet is found more distally in severe and older individuals with asthma, comparable to COPD. Though the underlying inflammation and remodelling processes in asthma and COPD are different in their extreme phenotypes, there are overlap phenotypes with eosinophilic inflammation even in stable COPD and neutrophilic inflammation in longstanding and severe asthma.
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Comparing the effectiveness of small-particle versus large-particle inhaled corticosteroid in COPD.
Int J Chron Obstruct Pulmon Dis
PUBLISHED: 01-01-2014
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Small airway changes and dysfunction contribute importantly to airway obstruction in chronic obstructive pulmonary disease (COPD), which is currently treated with inhaled corticosteroids (ICS) and long-acting bronchodilators at Global initiative for Obstructive Lung Disease (GOLD) grades 2-4. This retrospective matched cohort analysis compared effectiveness of a representative small-particle ICS (extrafine beclomethasone) and larger-particle ICS (fluticasone) in primary care patients with COPD.
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Susceptibility to COPD: differential proteomic profiling after acute smoking.
PLoS ONE
PUBLISHED: 01-01-2014
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Cigarette smoking is the main risk factor for COPD (Chronic Obstructive Pulmonary Disease), yet only a subset of smokers develops COPD. Family members of patients with severe early-onset COPD have an increased risk to develop COPD and are therefore defined as "susceptible individuals". Here we perform unbiased analyses of proteomic profiles to assess how "susceptible individuals" differ from age-matched "non-susceptible individuals" in response to cigarette smoking. Epithelial lining fluid (ELF) was collected at baseline and 24 hours after smoking 3 cigarettes in young individuals susceptible or non-susceptible to develop COPD and older subjects with established COPD. Controls at baseline were older healthy smoking and non-smoking individuals. Five samples per group were pooled and analysed by stable isotope labelling (iTRAQ) in duplicate. Six proteins were selected and validated by ELISA or immunohistochemistry. After smoking, 23 proteins increased or decreased in young susceptible individuals, 7 in young non-susceptible individuals, and 13 in COPD in the first experiment; 23 proteins increased or decreased in young susceptible individuals, 32 in young non-susceptible individuals, and 11 in COPD in the second experiment. SerpinB3 and Uteroglobin decreased after acute smoke exposure in young non-susceptible individuals exclusively, whereas Peroxiredoxin I, S100A9, S100A8, ALDH3A1 (Aldehyde dehydrogenase 3A1) decreased both in young susceptible and non-susceptible individuals, changes being significantly different between groups for Uteroglobin with iTRAQ and for Serpin B3 with iTRAQ and ELISA measures. Peroxiredoxin I, SerpinB3 and ALDH3A1 increased in COPD patients after smoking. We conclude that smoking induces a differential protein response in ELF of susceptible and non-susceptible young individuals, which differs from patients with established COPD. This is the first study applying unbiased proteomic profiling to unravel the underlying mechanisms that induce COPD. Our data suggest that SerpinB3 and Uteroglobin could be interesting proteins in understanding the processes leading to COPD.
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Susceptibility to chronic mucus hypersecretion, a genome wide association study.
PLoS ONE
PUBLISHED: 01-01-2014
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Chronic mucus hypersecretion (CMH) is associated with an increased frequency of respiratory infections, excess lung function decline, and increased hospitalisation and mortality rates in the general population. It is associated with smoking, but it is unknown why only a minority of smokers develops CMH. A plausible explanation for this phenomenon is a predisposing genetic constitution. Therefore, we performed a genome wide association (GWA) study of CMH in Caucasian populations.
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Lower corticosteroid skin blanching response is associated with severe COPD.
PLoS ONE
PUBLISHED: 01-01-2014
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Chronic obstructive pulmonary disease (COPD) is characterized by chronic airflow limitation caused by ongoing inflammatory and remodeling processes of the airways and lung tissue. Inflammation can be targeted by corticosteroids. However, airway inflammation is generally less responsive to steroids in COPD than in asthma. The underlying mechanisms are yet unclear. This study aimed to assess whether skin corticosteroid insensitivity is associated with COPD and COPD severity using the corticosteroid skin blanching test.
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Steroid resistance in COPD? Overlap and differential anti-inflammatory effects in smokers and ex-smokers.
PLoS ONE
PUBLISHED: 01-01-2014
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Inhaled corticosteroids (ICS) reduce exacerbation rates and improve health status but can increase the risk of pneumonia in COPD. The GLUCOLD study, investigating patients with mild-to-moderate COPD, has shown that long-term (2.5-year) ICS therapy induces anti-inflammatory effects. The literature suggests that cigarette smoking causes ICS insensitivity. The aim of this study is to compare anti-inflammatory effects of ICS in persistent smokers and persistent ex-smokers in a post-hoc analysis of the GLUCOLD study.
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Arg16 ADRB2 genotype increases the risk of asthma exacerbation in children with a reported use of long-acting ?2-agonists: results of the pacman cohort.
Pharmacogenomics
PUBLISHED: 11-28-2013
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Background: Current evidence suggests that asthma patients with the ADRB2 Arg16 genotype have a poorer response to long-acting ?2-agonists (LABA), but the results remain inconsistent. Aim: This study assessed the association between Arg16 variants and treatment outcome in children treated with inhaled corticosteroids (ICS) and LABA. Materials & methods: ADRB2 Arg16 was genotyped in 597 children (4-12 years of age) participating in the PACMAN cohort study. A questionnaire was used to assess asthma control, frequency of asthma-related emergency department visits and use of oral corticosteroids in the past year. Results: Arg/Arg carriers with a reported use of ICS and LABA had an increased risk of oral corticosteroid use (odds ratio: 14.9; 95% CI: 1.59-140.1) and emergency department visits in the past year (odds ratio: 11.9; 95% CI: 1.22-115.8) compared to Gly/Gly carriers. This effect was not observed in Arg/Arg genotype carriers reporting ICS use only. Conclusion: Children who are homozygous for ADRB2 Arg16 have an increased risk of exacerbations when treated with combined LABA and ICS. Original submitted 4 September 2013; Revision submitted 27 September 2013.
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Genome-wide protein QTL mapping identifies human plasma kallikrein as a post-translational regulator of serum uPAR levels.
FASEB J.
PUBLISHED: 11-18-2013
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The soluble cleaved urokinase plasminogen activator receptor (scuPAR) is a circulating protein detected in multiple diseases, including various cancers, cardiovascular disease, and kidney disease, where elevated levels of scuPAR have been associated with worsening prognosis and increased disease aggressiveness. We aimed to identify novel genetic and biomolecular mechanisms regulating scuPAR levels. Elevated serum scuPAR levels were identified in asthma (n=514) and chronic obstructive pulmonary disease (COPD; n=219) cohorts when compared to controls (n=96). In these cohorts, a genome-wide association study of serum scuPAR levels identified a human plasma kallikrein gene (KLKB1) promoter polymorphism (rs4253238) associated with serum scuPAR levels in a control/asthma population (P=1.17×10(-7)), which was also observed in a COPD population (combined P=5.04×10(-12)). Using a fluorescent assay, we demonstrated that serum KLKB1 enzymatic activity was driven by rs4253238 and is inverse to scuPAR levels. Biochemical analysis identified that KLKB1 cleaves scuPAR and negates scuPARs effects on primary human bronchial epithelial cells (HBECs) in vitro. Chymotrypsin was used as a proproteolytic control, while basal HBECs were used as a control to define scuPAR-driven effects. In summary, we reveal a novel post-translational regulatory mechanism for scuPAR using a hypothesis-free approach with implications for multiple human diseases.-Portelli, M. A., Siedlinski, M., Stewart, C. E., Postma, D. S., Nieuwenhuis, M. A., Vonk, J. M., Nurnberg, P., Altmuller, J., Moffatt, M. F., Wardlaw, A. J., Parker, S. G., Connolly, M. J., Koppelman, G. H., Sayers, I. Genome-wide protein QTL mapping identifies human plasma kallikrein as a post-translational regulator of serum uPAR levels.
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Differential effects of fluticasone on extracellular matrix production by airway and parenchymal fibroblasts in severe COPD.
Am. J. Physiol. Lung Cell Mol. Physiol.
PUBLISHED: 08-30-2013
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Chronic obstructive pulmonary disease (COPD) is characterized by abnormal repair in the lung resulting in airway obstruction associated with emphysema and peripheral airway fibrosis. Because the presence and degree of airways disease and emphysema varies between COPD patients, this may explain the heterogeneity in the response to treatment. It is currently unknown whether and to what extent inhaled steroids can affect the abnormal repair process in the airways and lung parenchyma in COPD. We investigated the effects of fluticasone on transforming growth factor (TGF)-?- and cigarette smoke-induced changes in mothers against decapentaplegic homolog (Smad) signaling and extracellular matrix (ECM) production in airway and parenchymal lung fibroblasts from patients with severe COPD. We showed that TGF-?-induced ECM production by pulmonary fibroblasts, but not activation of the Smad pathway, was sensitive to the effects of fluticasone. Fluticasone induced decorin production by airway fibroblasts and partly reversed the negative effects of TGF-? treatment. Fluticasone inhibited biglycan production in both airway and parenchymal fibroblasts and procollagen 1 production only in parenchymal fibroblasts, thereby restoring the basal difference in procollagen 1 production between airway and parenchymal fibroblasts. Our findings suggest that the effects of steroids on the airway compartment may be beneficial for patients with severe COPD, i.e., restoration of decorin loss around the airways, whereas the effects of steroids on the parenchyma may be detrimental, since the tissue repair response, i.e., biglycan and procollagen production, is inhibited. More research is needed to further disentangle these differential effects of steroid treatment on the different lung compartments and its impact on tissue repair and remodeling in COPD.
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Oxidant-induced corticosteroid unresponsiveness in human bronchial epithelial cells.
Thorax
PUBLISHED: 08-26-2013
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We hypothesised that increased oxidative stress, as present in the airways of asthma and chronic obstructive pulmonary disease (COPD) patients, induces epithelial damage and reduces epithelial responsiveness to suppressive effects of corticosteroids on proinflammatory cytokine production and barrier function.
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ITGB5 and AGFG1 variants are associated with severity of airway responsiveness.
BMC Med. Genet.
PUBLISHED: 08-22-2013
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Airway hyperresponsiveness (AHR), a primary characteristic of asthma, involves increased airway smooth muscle contractility in response to certain exposures. We sought to determine whether common genetic variants were associated with AHR severity.
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Airway gene expression in COPD is dynamic with inhaled corticosteroid treatment and reflects biological pathways associated with disease activity.
Thorax
PUBLISHED: 08-07-2013
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A core feature of chronic obstructive pulmonary disease (COPD) is the accelerated decline in forced expiratory volume in one second (FEV1). The recent Groningen and Leiden Universities study of Corticosteroids in Obstructive Lung Disease (GLUCOLD) study suggested that particular phenotypes of COPD benefit from fluticasone±salmeterol by reducing the rate of FEV1 decline, yet the underlying mechanisms are unknown.
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Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization.
Nat. Genet.
PUBLISHED: 06-10-2013
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Allergen-specific immunoglobulin E (present in allergic sensitization) has a central role in the pathogenesis of allergic disease. We performed the first large-scale genome-wide association study (GWAS) of allergic sensitization in 5,789 affected individuals and 10,056 controls and followed up the top SNP at each of 26 loci in 6,114 affected individuals and 9,920 controls. We increased the number of susceptibility loci with genome-wide significant association with allergic sensitization from three to ten, including SNPs in or near TLR6, C11orf30, STAT6, SLC25A46, HLA-DQB1, IL1RL1, LPP, MYC, IL2 and HLA-B. All the top SNPs were associated with allergic symptoms in an independent study. Risk-associated variants at these ten loci were estimated to account for at least 25% of allergic sensitization and allergic rhinitis. Understanding the molecular mechanisms underlying these associations may provide new insights into the etiology of allergic disease.
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Inflammatory phenotypes underlying uncontrolled childhood asthma despite inhaled corticosteroid treatment: rationale and design of the PACMAN2 study.
BMC Pediatr
PUBLISHED: 06-10-2013
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BACKGROUND: The diagnosis of childhood asthma covers a broad spectrum of pathological mechanisms that can lead to similarly presenting clinical symptoms, but may nonetheless require different treatment approaches. Distinct underlying inflammatory patterns are thought to influence responsiveness to standard asthma medication.Methods/design: The purpose of the PACMAN2 study is to identify inflammatory phenotypes that can discriminate uncontrolled childhood asthma from controlled childhood asthma by measures in peripheral blood and exhaled air. PACMAN2 is a nested, case--control follow-up study to the ongoing pharmacy-based "Pharmacogenetics of Asthma medication in Children: Medication with Anti-inflammatory effects" (PACMAN) study. The original PACMAN cohort consists of children aged 4--12 years with reported use of asthma medication. The PACMAN2 study will be conducted within the larger PACMAN cohort, and will focus on detailed phenotyping of a subset of the PACMAN children. The selected participants will be invited to a follow-up visit in a clinical setting at least six months after their baseline visit based on their adherence to usage of inhaled corticosteroids, their asthma symptoms in the past year, and their age (>= 8 years). During the follow-up visit, current and long-term asthma symptoms, medication use, environmental factors, medication adherence and levels of exhaled nitric oxide will be reassessed. The following measures will also be examined: pulmonary function, exhaled volatile organic compounds, as well as inflammatory markers in peripheral blood and blood plasma. Comparative analysis and cluster-analyses will be used to identify markers that differentiate children with uncontrolled asthma despite their use of inhaled corticosteroids (ICS) (cases) from children whose asthma is controlled by the use of ICS (controls). DISCUSSION: Asthmatic children with distinct inflammatory phenotypes may respond differently to anti-inflammatory therapy. Therefore, by identifying inflammatory phenotypes in children with the PACMAN2 study, we may greatly impact future personalised treatment strategies, uncover new leads for therapeutic targets and improve the design of future clinical studies in the assessment of the efficacy of novel therapeutics.
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Caveolin-1 controls airway epithelial barrier function. Implications for asthma.
Am. J. Respir. Cell Mol. Biol.
PUBLISHED: 06-08-2013
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The molecular basis for airway epithelial fragility in asthma has remained unclear. We investigated whether the loss of caveolin-1, the major component of caveolae and a known stabilizer of adherens junctions, contributes to epithelial barrier dysfunction in asthma. We studied the expression of caveolin-1 and adhesion molecules E-cadherin and ?-catenin in airway sections, and we cultured bronchial epithelial cells from patients with asthma and from healthy control subjects. To determine the functional role of caveolin-1, we investigated the effects of caveolin-1 up-regulation and down-regulation on E-cadherin expression, barrier function, and proallergic activity in the human bronchial epithelial cell lines 16HBE and BEAS-2B. The membrane expression of caveolin-1 was significantly lower in airway epithelia from patients with asthma than from subjects without asthma, and this lower expression was maintained in vitro upon air-liquid interface and submerged culturing. Importantly, reduced caveolin-1 expression was accompanied by a loss of junctional E-cadherin and ?-catenin expression, disrupted epithelial barrier function, and increased levels of the proallergic cytokine thymic stromal lymphopoietin (TSLP). Furthermore, E-cadherin redistribution upon exposure to epidermal growth factor or house dust mite was paralleled by the internalization of caveolin-1 in 16HBE cells. These effects appear to be causally related, because the short, interfering RNA down-regulation of caveolin-1 resulted in the delocalization of E-cadherin and barrier dysfunction in 16HBE cells. Moreover, caveolin-1 overexpression improved barrier function and reduced TSLP expression in BEAS-2B cells. Together, our data demonstrate a crucial role for caveolin-1 in epithelial cell-cell adhesion, with important consequences for epithelial barrier function and the promotion of Th2 responses in asthma.
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Expression of vascular remodelling markers in relation to bradykinin receptors in asthma and COPD.
Thorax
PUBLISHED: 06-05-2013
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Vascular remodelling plays a central role in asthma and chronic obstructive pulmonary disease (COPD). Bradykinin (BK) is a vasoactive proinflammatory peptide mediating acute responses in asthma. We investigated the role of angiogenic factors in relation to BK receptors in asthma and COPD.
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Early life microbial exposure and fractional exhaled nitric oxide in school-age children: a prospective birth cohort study.
Environ Health
PUBLISHED: 05-13-2013
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Inflammation is a key factor in the pathogenesis of respiratory diseases. Early life exposure to microbial agents may have an effect on the development of the immune system and on respiratory health later in life.In the present work we aimed to evaluate the associations between early life microbial exposures, and fractional exhaled nitric oxide (FeNO) at school age.
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Transient early wheeze and lung function in early childhood associated with chronic obstructive pulmonary disease genes.
J. Allergy Clin. Immunol.
PUBLISHED: 05-01-2013
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It has been hypothesized that a disturbed early lung development underlies the susceptibility to chronic obstructive pulmonary disease (COPD). Little is known about whether subjects genetically predisposed to COPD show their first symptoms or reduced lung function in childhood.
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Factor analysis in predominantly severe COPD: Identification of disease heterogeneity by easily measurable characteristics.
Respir Med
PUBLISHED: 04-18-2013
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The clinical and demographic variables defining the heterogeneity of chronic obstructive pulmonary disease (COPD) are unclear. A post-hoc analysis of five randomised studies in patients with a history of previous exacerbations examined the clinical and demographic characteristics describing moderate-to-very-severe COPD.
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Inflammation and corticosteroid responsiveness in ex-, current- and never-smoking asthmatics.
BMC Pulm Med
PUBLISHED: 04-09-2013
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It has been suggested that smoking asthmatics benefit less from corticosteroid treatment than never-smoking asthmatics. We investigated differences in blood and sputum inflammatory profiles between ex-, current-, and never-smokers and assessed their ICS treatment response after 2-week and 1-year treatment.
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GST-omega genes interact with environmental tobacco smoke on adult level of lung function.
Respir. Res.
PUBLISHED: 04-02-2013
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Lung growth in utero and lung function loss during adulthood can be affected by exposure to environmental tobacco smoke (ETS). The underlying mechanisms have not been fully elucidated. Both ETS exposure and single nucleotide polymorphisms (SNPs) in Glutathione S-Transferase (GST) Omega genes have been associated with the level of lung function. This study aimed to assess if GSTO SNPs interact with ETS exposure in utero and during adulthood on the level of lung function during adulthood.
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Genome-wide association study of coronary and aortic calcification implicates risk loci for coronary artery disease and myocardial infarction.
Atherosclerosis
PUBLISHED: 02-26-2013
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Arterial calcification is a well-known risk factor for coronary artery disease (CAD) and myocardial infarction (MI). We performed a genome-wide association study on coronary artery calcification and aortic calcification as intermediate traits for CAD/MI. We tested ?2.5 million SNPs for association with coronary artery calcification and aortic calcification in 2620 male individuals of the NELSON trial, who underwent chest CT scans. All participants were current or former heavy smokers. No SNPs were associated with aortic calcification on a genome-wide scale. The 9p21 locus was significantly associated with coronary artery calcification (rs1537370, P = 2.3 × 10(-11)). Since this locus corresponds to the strongest SNP association for CAD/MI, we tested 24 published and validated CAD/MI risk SNPs for association with arterial calcification. Besides the CAD/MI SNP at 9p21 (rs4977574, P = 3.1 × 10(-10)), two additional loci at ADAMTS7 (rs3825807, P = 6.5 × 10(-6)) and at PHACTR1 (rs12526453, P = 1.0 × 10(-3)) show a nominally significant association with coronary artery calcification with MI/CAD risk alleles increasing the degree of arterial calcification. The 9p21 locus was also nominally associated with aortic calcification (P = 3.2 × 10(-4)). These findings indicate that these CAD and MI risk loci are likely involved in arterial calcification.
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Rate of progression of CT-quantified emphysema in male current and ex-smokers: a follow-up study.
Respir. Res.
PUBLISHED: 02-20-2013
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Little is known about the factors associated with CT-quantified emphysema progression in heavy smokers. The objective of this study was to investigate the effect of length of smoking cessation and clinical / demographical factors on the rate of emphysema progression and FEV1-decline in male heavy smokers.
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Genetics of onset of asthma.
Curr Opin Allergy Clin Immunol
PUBLISHED: 02-15-2013
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Most asthma starts early in life. Defining phenotypes of asthma at this age is difficult as many preschool children have asthma-like respiratory symptoms. This review discusses progress in defining early wheezing phenotypes and describes genetic factors associated with the age of onset of asthma.
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Small-airways dysfunction associates with respiratory symptoms and clinical features of asthma: a systematic review.
J. Allergy Clin. Immunol.
PUBLISHED: 02-04-2013
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Traditionally, asthma has been considered a disease that predominantly involves the large airways. Today, this concept is being challenged, and increasing evidence has become available showing that abnormalities in the small airways also contribute to the clinical expression of asthma. The small airways can be affected by inflammation, remodeling, and changes in the surrounding tissue, all contributing to small-airways dysfunction. In this article we have performed a systematic review of the literature on the association between small-airways dysfunction and clinical signs and symptoms of asthma. This review shows that small-airways dysfunction associates with worse control of asthma, higher numbers of exacerbations, the presence of nocturnal asthma, more severe bronchial hyperresponsiveness, exercise-induced asthma, and the late-phase allergic response. Importantly, small-airways dysfunction can already be present in patients with mild asthma. Our review provides suggestive evidence that a better response of the small airways to inhaled steroids or montelukast associates with better asthma control. For this reason, an early recognition of small-airways dysfunction is important because it enables the physician to start timely treatment to target the small airways. It is important to develop simpler and more reliable tools (eg, questionnaires or bronchial provocation tests with small-particle stimuli) to assess the presence and extent of small-airways dysfunction in daily clinical practice.
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Role of aberrant WNT signalling in the airway epithelial response to cigarette smoke in chronic obstructive pulmonary disease.
Thorax
PUBLISHED: 01-31-2013
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WNT signalling is activated during lung tissue damage and inflammation. We investigated whether lung epithelial expression of WNT ligands, receptors (frizzled; FZD) or target genes is dysregulated on cigarette smoking and/or in chronic obstructive pulmonary disease (COPD).
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Fluticasone uptake across Calu-3 cells is mediated by salmeterol when deposited as a combination powder inhaler.
Respirology
PUBLISHED: 01-26-2013
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We assessed whether co-deposition of a long-acting ?2 -agonist and a corticosteroid affects their respective transport rates across epithelial cells.
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Variants in the 15q24/25 locus associate with lung function decline in active smokers.
PLoS ONE
PUBLISHED: 01-18-2013
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Genetic variation in nicotinic acetylcholine receptor subunit genes (nAChRs) is associated with lung function level and chronic obstructive pulmonary disease (COPD). It is unknown whether these variants also predispose to an accelerated lung function decline. We investigated the association of nAChR susceptibility variants with lung function decline and COPD severity. The rs1051730 and rs8034191 variants were genotyped in a population-based cohort of 1,226 heavy smokers (COPACETIC) and in an independent cohort of 883 heavy smokers, of which 653 with COPD of varying severity (LEUVEN). Participants underwent pulmonary function tests at baseline. Lung function decline was assessed over a median follow-up of 3 years in COPACETIC. Current smokers homozygous for the rs1051730 A-allele or rs8034191 G-allele had significantly greater FEV(1)/FVC decline than homozygous carriers of wild-type alleles (3.3% and 4.3%, p?=?0.026 and p?=?0.009, respectively). In the LEUVEN cohort, rs1051730 AA-carriers and rs8034191 GG-carriers had a two-fold increased risk to suffer from COPD GOLD IV (OR 2.29, 95% confidence interval [CI]?=?1.11-4.75; p?=?0.025 and OR?=?2.42, 95% [CI]?=?1.18-4.95; p?=?0.016, respectively). The same risk alleles conferred, respectively, a five- and four-fold increased risk to be referred for lung transplantation because of end-stage COPD (OR?=?5.0, 95% [CI]?=?1.68-14.89; p?=?0.004 and OR?=?4.06, 95% [CI]?=?1.39-11.88; p?=?0.010). In Europeans, variants in nAChRs associate with an accelerated lung function decline in current smokers and with clinically relevant COPD.
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Low-dose CT measurements of airway dimensions and emphysema associated with airflow limitation in heavy smokers: a cross sectional study.
Respir. Res.
PUBLISHED: 01-17-2013
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Increased airway wall thickness (AWT) and parenchymal lung destruction both contribute to airflow limitation. Advances in computed tomography (CT) post-processing imaging allow to quantify these features. The aim of this Dutch population study is to assess the relationships between AWT, lung function, emphysema and respiratory symptoms.
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Proteomic analysis of human epithelial lining fluid by microfluidics-based nanoLC-MS/MS: a feasibility study.
Electrophoresis
PUBLISHED: 01-16-2013
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Microfluidics-based nanoLC-MS/MS (chipLC-MS/MS) was used to identify and quantify proteins in epithelial lining fluid (ELF), collected during bronchoscopy from the main bronchi of chronic obstructive pulmonary disease (COPD) patients and healthy controls using microprobes. ELF is a biofluid that is well suited to study pathophysiological processes in the lung, because it contains high concentrations of biologically active molecules. 1D-PAGE followed by in-gel tryptic digestion and chipLC-MS/MS resulted in identification of approximately 300 proteins. A comparative study of ELF from COPD patients and non-COPD controls using chemical stable isotope labeling (iTRAQ®-8Plex) showed that the levels of lactotransferrin, high-mobility group protein B1 (HMGB 1), alpha 1-antichymotrypsin and cofilin-1 differed significantly in ELF from COPD patients and non-COPD controls (p-values < 0.05). These results were reproduced in another, independent set of ELF samples from COPD patients and non-COPD controls and further validated by immunohistochemistry. This study shows the feasibility of performing chipLC-MS/MS and quantitative proteomics in human ELF.
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Atopy is a risk factor for respiratory symptoms in COPD patients: results from the EUROSCOP study.
Respir. Res.
PUBLISHED: 01-11-2013
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The pathogenesis of COPD is complex and remains poorly understood. The European Respiratory Society Study on Chronic Obstructive Pulmonary Disease (EUROSCOP) investigated long-term effects of budesonide; 18% of the COPD participants were atopic. So far effects of atopy on the long-term course of COPD have not been elucidated.
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Glycogen synthase kinase-3 (GSK-3) regulates TGF-??-induced differentiation of pulmonary fibroblasts.
Br. J. Pharmacol.
PUBLISHED: 01-10-2013
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Chronic lung diseases such as asthma, COPD and pulmonary fibrosis are characterized by abnormal extracellular matrix (ECM) turnover. TGF-? is a key mediator stimulating ECM production by recruiting and activating lung fibroblasts and initiating their differentiation process into more active myofibroblasts. Glycogen synthase kinase-3 (GSK-3) regulates various intracellular signalling pathways; its role in TGF-??-induced myofibroblast differentiation is currently largely unknown.
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Integration of mouse and human genome-wide association data identifies KCNIP4 as an asthma gene.
PLoS ONE
PUBLISHED: 01-07-2013
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Asthma is a common chronic respiratory disease characterized by airway hyperresponsiveness (AHR). The genetics of asthma have been widely studied in mouse and human, and homologous genomic regions have been associated with mouse AHR and human asthma-related phenotypes. Our goal was to identify asthma-related genes by integrating AHR associations in mouse with human genome-wide association study (GWAS) data. We used Efficient Mixed Model Association (EMMA) analysis to conduct a GWAS of baseline AHR measures from males and females of 31 mouse strains. Genes near or containing SNPs with EMMA p-values <0.001 were selected for further study in human GWAS. The results of the previously reported EVE consortium asthma GWAS meta-analysis consisting of 12,958 diverse North American subjects from 9 study centers were used to select a subset of homologous genes with evidence of association with asthma in humans. Following validation attempts in three human asthma GWAS (i.e., Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG) and two human AHR GWAS (i.e., SHARP, DAG), the Kv channel interacting protein 4 (KCNIP4) gene was identified as nominally associated with both asthma and AHR at a gene- and SNP-level. In EVE, the smallest KCNIP4 association was at rs6833065 (P-value 2.9e-04), while the strongest associations for Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG were 1.5e-03, 1.0e-03, 3.1e-03 at rs7664617, rs4697177, rs4696975, respectively. At a SNP level, the strongest association across all asthma GWAS was at rs4697177 (P-value 1.1e-04). The smallest P-values for association with AHR were 2.3e-03 at rs11947661 in SHARP and 2.1e-03 at rs402802 in DAG. Functional studies are required to validate the potential involvement of KCNIP4 in modulating asthma susceptibility and/or AHR. Our results suggest that a useful approach to identify genes associated with human asthma is to leverage mouse AHR association data.
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GSTCD and INTS12 regulation and expression in the human lung.
PLoS ONE
PUBLISHED: 01-01-2013
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Genome-Wide Association Study (GWAS) meta-analyses have identified a strong association signal for lung function, which maps to a region on 4q24 containing two oppositely transcribed genes: glutathione S-transferase, C-terminal domain containing (GSTCD) and integrator complex subunit 12 (INTS12). Both genes were found to be expressed in a range of human airway cell types. The promoter regions and transcription start sites were determined in mRNA from human lung and a novel splice variant was identified for each gene. We obtained the following evidence for GSTCD and INTS12 co-regulation and expression: (i) correlated mRNA expression was observed both via Q-PCR and in a lung expression quantitative trait loci (eQTL) study, (ii) induction of both GSTCD and INTS12 mRNA expression in human airway smooth muscle cells was seen in response to TGF?1, (iii) a lung eQTL study revealed that both GSTCD and INTS12 mRNA levels positively correlate with percent predicted FEV1, and (iv) FEV1 GWAS associated SNPs in 4q24 were found to act as an eQTL for INTS12 in a number of tissues. In fixed sections of human lung tissue, GSTCD protein expression was ubiquitous, whereas INTS12 expression was predominantly in epithelial cells and pneumocytes. During human fetal lung development, GSTCD protein expression was observed to be highest at the earlier pseudoglandular stage (10-12 weeks) compared with the later canalicular stage (17-19 weeks), whereas INTS12 expression levels did not alter throughout these stages. Knowledge of the transcriptional and translational regulation and expression of GSTCD and INTS12 provides important insights into the potential role of these genes in determining lung function. Future work is warranted to fully define the functions of INTS12 and GSTCD.
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Refining susceptibility loci of chronic obstructive pulmonary disease with lung eqtls.
PLoS ONE
PUBLISHED: 01-01-2013
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Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of mortality worldwide. Recent genome-wide association studies (GWAS) have identified robust susceptibility loci associated with COPD. However, the mechanisms mediating the risk conferred by these loci remain to be found. The goal of this study was to identify causal genes/variants within susceptibility loci associated with COPD. In the discovery cohort, genome-wide gene expression profiles of 500 non-tumor lung specimens were obtained from patients undergoing lung surgery. Blood-DNA from the same patients were genotyped for 1,2 million SNPs. Following genotyping and gene expression quality control filters, 409 samples were analyzed. Lung expression quantitative trait loci (eQTLs) were identified and overlaid onto three COPD susceptibility loci derived from GWAS; 4q31 (HHIP), 4q22 (FAM13A), and 19q13 (RAB4B, EGLN2, MIA, CYP2A6). Significant eQTLs were replicated in two independent datasets (n?=?363 and 339). SNPs previously associated with COPD and lung function on 4q31 (rs1828591, rs13118928) were associated with the mRNA expression of HHIP. An association between mRNA expression level of FAM13A and SNP rs2045517 was detected at 4q22, but did not reach statistical significance. At 19q13, significant eQTLs were detected with EGLN2. In summary, this study supports HHIP, FAM13A, and EGLN2 as the most likely causal COPD genes on 4q31, 4q22, and 19q13, respectively. Strong lung eQTL SNPs identified in this study will need to be tested for association with COPD in case-control studies. Further functional studies will also be needed to understand the role of genes regulated by disease-related variants in COPD.
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ADAM33 gene polymorphisms and mortality. A prospective cohort study.
PLoS ONE
PUBLISHED: 01-01-2013
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The ADAM33 gene is associated with the pathophysiology of Chronic Obstructive Pulmonary Disease (COPD) and atherosclerosis. In this study we investigated all-cause, COPD and cardiovascular mortality, in relation to single nucleotide polymorphisms (SNPs) in ADAM33 (Q_1, S_1, S_2, T_1 and T_2) that were genotyped in 1,390 subjects from the Vlagtwedde/Vlaardingen cohort. Participants were examined at entry in 1989/1990 and followed up till evaluation of the vital status on December 31(st), 2008. Using Cox proportional hazards regression we estimated the risk of the SNPs in relation to mortality, adjusting for gender, age, FEV1, height, place of residence and packyears of smoking. Additionally, we performed stratified analyses according to gender and smoking habits. After 18 years, 284 (20.4%) subjects had died (107 due to cardiovascular disease and 20 due to COPD). Individuals homozygous for the minor allele of SNP T_2 had an increased risk of all-cause and cardiovascular mortality compared to wild types: hazard ratio 3.6 (95% confidence interval 2.0 to 6.7) and 3.4 (1.2 to 9.5) respectively. Individuals homozygous for the minor allele of S_1, S_2, T_2 or Q_1 had a significantly increased risk of COPD mortality. In stratified analyses the risk of all-cause mortality associated with SNP T_2 did not change: females 3.5 (1.5 to 8.3), males 3.1 (1.2 to 7.6), never smokers 3.8 (0.9 to 16.3), ever smokers 3.6 (1.8 to 7.2). This study shows for the first time that ADAM33 is a pleiotropic gene that is associated with all-cause, COPD and cardiovascular mortality, independent of potential confounders.
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Inhaled steroids modulate extracellular matrix composition in bronchial biopsies of COPD patients: a randomized, controlled trial.
PLoS ONE
PUBLISHED: 01-01-2013
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Smoking and inflammation contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD), which involves changes in extracellular matrix. This is thought to contribute to airway remodeling and airflow obstruction. We have previously observed that long-term treatment with inhaled corticosteroids can not only reduce bronchial inflammation, but can also attenuate lung function decline in moderate-severe COPD. We hypothesized that inhaled corticosteroids and current smoking modulate bronchial extracellular matrix components in COPD.
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Genetic variation in FADS genes and plasma cholesterol levels in 2-year-old infants: KOALA Birth Cohort Study.
PLoS ONE
PUBLISHED: 01-01-2013
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Single nucleotide polymorphisms (SNPs) in genes involved in fatty acid metabolism (FADS1 FADS2 gene cluster) are associated with plasma lipid levels. We aimed to investigate whether these associations are already present early in life and compare the relative contribution of FADS SNPs vs traditional (non-genetic) factors as determinants of plasma lipid levels.
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Acute and chronic inflammatory responses induced by smoking in individuals susceptible and non-susceptible to development of COPD: from specific disease phenotyping towards novel therapy. Protocol of a cross-sectional study.
BMJ Open
PUBLISHED: 01-01-2013
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Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with pulmonary and extra-pulmonary manifestations. Although COPD is a complex disease, diagnosis and staging are still based on simple spirometry measurements. Different COPD phenotypes exist based on clinical, physiological, immunological and radiological observations. Cigarette smoking is the most important risk factor for COPD, but only 15-20% of smokers develop the disease, suggesting a genetic predisposition. Unfortunately, little is known about the pathogenesis of COPD, and even less on the very first steps that are associated with an aberrant response to smoke exposure. This study aims to investigate the underlying local and systemic inflammation of different clinical COPD phenotypes, and acute effects of cigarette smoke exposure in individuals susceptible and non-susceptible for the development of COPD. Furthermore, we will investigate mechanisms associated with corticosteroid insensitivity. Our study will provide valuable information regarding the pathogenetic mechanisms underlying the natural course of COPD.
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Characterization of protocadherin-1 expression in primary bronchial epithelial cells: association with epithelial cell differentiation.
FASEB J.
PUBLISHED: 10-07-2011
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Protocadherin-1 (PCDH1) is a novel susceptibility gene for asthma that is expressed in airway epithelium. We aimed to characterize PCDH1 mRNA transcripts and protein expression in primary bronchial epithelial cells and to determine regulation of PCDH1 during mucociliary differentiation. Total RNA and protein were isolated from human primary bronchial epithelial cells. PCDH1 transcripts were characterized by rapid amplification of cDNA ends in bronchial epithelial cells of 4 subjects. PCDH1 expression was quantified by quantitative RT-PCR and Western blotting in bronchial epithelial cells directly ex vivo and after air liquid interface (ALI) or submerged culture. We identified 5 novel exons on the 5 end and 1 exon on the 3 end of PCDH1. Novel transcripts showed major variation in expression of intracellular conserved motifs. Expression levels of PCDH1 transcripts encoding exon 1-2 were 4-fold higher, and transcripts encoding exon 3-4 were 15-fold higher in freshly isolated bronchial epithelial cells than in submerged cultures. PCDH1 mRNA (3- to 8-fold) and protein levels (2- to 3-fold) were strongly up-regulated during mucociliary differentiation of primary bronchial epithelial cells in ALI cultures. In summary, PCDH1 transcripts display remarkable variability in expression of conserved intracellular signaling domains. Enhanced PCDH1 expression levels strongly correlate with differentiation of bronchial epithelial cells.
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