PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (105)
 

Clipboard (0)
None

Select a Filter Below

Year of Publication
more »
1.  Fractional exhaled nitric oxide in childhood is associated with 17q11.2-q12 and 17q12-q21 variants 
Background
The fractional concentration of nitric oxide in exhaled air (FeNO) is a biomarker of eosinophilic airway inflammation and associated with childhood asthma. Identification of common genetic variants associated with childhood FeNO may help to define biological mechanisms related to specific asthma phenotypes.
Objective
To identify genetic variants associated with childhood FeNO, and their relation with asthma.
Methods
FeNO was measured in children aged 5 to 15 years. In 14 genome-wide association (GWA) studies (N = 8,858), we examined the associations of ~2.5 million single nucleotide polymorphisms (SNPs) with FeNO. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci (eQTLs) in genome-wide expression datasets of lymphoblastoid cell lines (N = 1,830), and were related with asthma in a previously published GWA dataset (cases: n=10,365; controls: n=16,110).
Results
We identified 3 SNPs associated with FeNO: rs3751972 in LYR motif containing 9 (LYRM9) (P = 1.97×10−10) and rs944722 in inducible nitric oxide synthase 2 (NOS2) (P = 1.28×10−9) both located at 17q11.2-q12, and rs8069176 near gasdermin B (GSDMB) (P = 1.88×10−8) at 17q12-q21. We found a cis eQTL for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. Rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. Rs8069176 at 17q12-q21, and not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma.
Conclusion
This study identified 3 variants associated with FeNO, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight in the regulation of FeNO. This study highlights that both shared and distinct genetic factors affect FeNO and childhood asthma.
doi:10.1016/j.jaci.2013.08.053
PMCID: PMC4334587  PMID: 24315451
airway inflammation; asthma phenotypes; biomarker; genetics; genome-wide association study
3.  Change in HbA1c Levels between the Age of 8 Years and the Age of 12 Years in Dutch Children without Diabetes: The PIAMA Birth Cohort Study 
PLoS ONE  2015;10(4):e0119615.
Objective
HbA1c is associated with cardiovascular risk in persons without diabetes and cardiovascular risk accumulates over the life course. Therefore, insight in factors determining HbA1c from childhood onwards is important. We investigated (lifestyle) determinants of HbA1c at age 12 years and the effects of growth on change in HbA1c and the tracking of HbA1c between the age of 8 and 12 years.
Study Design and Methods
Anthropometric measurements were taken and HbA1c levels were assessed in 955 children without diabetes aged around 12 years participating in the PIAMA birth cohort study. In 363 of these children HbA1c was also measured at age 8 years. Data on parents and children were collected prospectively by questionnaires.
Results
We found no significant association between known risk factors for diabetes and HbA1c at age 12 years. Mean(SD) change in HbA1c between ages 8 and 12 years was 0.6(0.7) mmol/mol per year (or 0.1(0.1) %/yr). Anthropometric measures at age 8 and their change between age 8 and 12 years were not associated with the change in HbA1c. 68.9% of the children remained in the same quintile or had an HbA1c one quintile higher or lower at age 8 years compared to age 12 years.
Conclusion
The lack of association between known risk factors for diabetes and HbA1c suggest that HbA1c in children without diabetes is relatively unaffected by factors associated with glycaemia. HbA1c at age 8 years is by far the most important predictor of HbA1c at age 12. Therefore, the ranking of HbA1c levels appear to be fairly stable over time.
doi:10.1371/journal.pone.0119615
PMCID: PMC4395421  PMID: 25875773
4.  Parent-of-origin specific allelic associations among 106 genomic loci for age at menarche 
Perry, John RB | Day, Felix | Elks, Cathy E | Sulem, Patrick | Thompson, Deborah J | Ferreira, Teresa | He, Chunyan | Chasman, Daniel I | Esko, Tõnu | Thorleifsson, Gudmar | Albrecht, Eva | Ang, Wei Q | Corre, Tanguy | Cousminer, Diana L | Feenstra, Bjarke | Franceschini, Nora | Ganna, Andrea | Johnson, Andrew D | Kjellqvist, Sanela | Lunetta, Kathryn L | McMahon, George | Nolte, Ilja M | Paternoster, Lavinia | Porcu, Eleonora | Smith, Albert V | Stolk, Lisette | Teumer, Alexander | Tšernikova, Natalia | Tikkanen, Emmi | Ulivi, Sheila | Wagner, Erin K | Amin, Najaf | Bierut, Laura J | Byrne, Enda M | Hottenga, Jouke-Jan | Koller, Daniel L | Mangino, Massimo | Pers, Tune H | Yerges-Armstrong, Laura M | Zhao, Jing Hua | Andrulis, Irene L | Anton-Culver, Hoda | Atsma, Femke | Bandinelli, Stefania | Beckmann, Matthias W | Benitez, Javier | Blomqvist, Carl | Bojesen, Stig E | Bolla, Manjeet K | Bonanni, Bernardo | Brauch, Hiltrud | Brenner, Hermann | Buring, Julie E | Chang-Claude, Jenny | Chanock, Stephen | Chen, Jinhui | Chenevix-Trench, Georgia | Collée, J. Margriet | Couch, Fergus J | Couper, David | Coveillo, Andrea D | Cox, Angela | Czene, Kamila | D’adamo, Adamo Pio | Smith, George Davey | De Vivo, Immaculata | Demerath, Ellen W | Dennis, Joe | Devilee, Peter | Dieffenbach, Aida K | Dunning, Alison M | Eiriksdottir, Gudny | Eriksson, Johan G | Fasching, Peter A | Ferrucci, Luigi | Flesch-Janys, Dieter | Flyger, Henrik | Foroud, Tatiana | Franke, Lude | Garcia, Melissa E | García-Closas, Montserrat | Geller, Frank | de Geus, Eco EJ | Giles, Graham G | Gudbjartsson, Daniel F | Gudnason, Vilmundur | Guénel, Pascal | Guo, Suiqun | Hall, Per | Hamann, Ute | Haring, Robin | Hartman, Catharina A | Heath, Andrew C | Hofman, Albert | Hooning, Maartje J | Hopper, John L | Hu, Frank B | Hunter, David J | Karasik, David | Kiel, Douglas P | Knight, Julia A | Kosma, Veli-Matti | Kutalik, Zoltan | Lai, Sandra | Lambrechts, Diether | Lindblom, Annika | Mägi, Reedik | Magnusson, Patrik K | Mannermaa, Arto | Martin, Nicholas G | Masson, Gisli | McArdle, Patrick F | McArdle, Wendy L | Melbye, Mads | Michailidou, Kyriaki | Mihailov, Evelin | Milani, Lili | Milne, Roger L | Nevanlinna, Heli | Neven, Patrick | Nohr, Ellen A | Oldehinkel, Albertine J | Oostra, Ben A | Palotie, Aarno | Peacock, Munro | Pedersen, Nancy L | Peterlongo, Paolo | Peto, Julian | Pharoah, Paul DP | Postma, Dirkje S | Pouta, Anneli | Pylkäs, Katri | Radice, Paolo | Ring, Susan | Rivadeneira, Fernando | Robino, Antonietta | Rose, Lynda M | Rudolph, Anja | Salomaa, Veikko | Sanna, Serena | Schlessinger, David | Schmidt, Marjanka K | Southey, Mellissa C | Sovio, Ulla | Stampfer, Meir J | Stöckl, Doris | Storniolo, Anna M | Timpson, Nicholas J | Tyrer, Jonathan | Visser, Jenny A | Vollenweider, Peter | Völzke, Henry | Waeber, Gerard | Waldenberger, Melanie | Wallaschofski, Henri | Wang, Qin | Willemsen, Gonneke | Winqvist, Robert | Wolffenbuttel, Bruce HR | Wright, Margaret J | Boomsma, Dorret I | Econs, Michael J | Khaw, Kay-Tee | Loos, Ruth JF | McCarthy, Mark I | Montgomery, Grant W | Rice, John P | Streeten, Elizabeth A | Thorsteinsdottir, Unnur | van Duijn, Cornelia M | Alizadeh, Behrooz Z | Bergmann, Sven | Boerwinkle, Eric | Boyd, Heather A | Crisponi, Laura | Gasparini, Paolo | Gieger, Christian | Harris, Tamara B | Ingelsson, Erik | Järvelin, Marjo-Riitta | Kraft, Peter | Lawlor, Debbie | Metspalu, Andres | Pennell, Craig E | Ridker, Paul M | Snieder, Harold | Sørensen, Thorkild IA | Spector, Tim D | Strachan, David P | Uitterlinden, André G | Wareham, Nicholas J | Widen, Elisabeth | Zygmunt, Marek | Murray, Anna | Easton, Douglas F | Stefansson, Kari | Murabito, Joanne M | Ong, Ken K
Nature  2014;514(7520):92-97.
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 mortality1. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation2,3, 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<5×10−8) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1/WDR25, MKRN3/MAGEL2 and KCNK9) demonstrating parent-of-origin specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signaling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.
doi:10.1038/nature13545
PMCID: PMC4185210  PMID: 25231870
5.  Genetic studies of body mass index yield new insights for obesity biology 
Locke, Adam E. | Kahali, Bratati | Berndt, Sonja I. | Justice, Anne E. | Pers, Tune H. | Day, Felix R. | Powell, Corey | Vedantam, Sailaja | Buchkovich, Martin L. | Yang, Jian | Croteau-Chonka, Damien C. | Esko, Tonu | Fall, Tove | Ferreira, Teresa | Gustafsson, Stefan | Kutalik, Zoltán | Luan, Jian’an | Mägi, Reedik | Randall, Joshua C. | Winkler, Thomas W. | Wood, Andrew R. | Workalemahu, Tsegaselassie | Faul, Jessica D. | Smith, Jennifer A. | Zhao, Jing Hua | Zhao, Wei | Chen, Jin | Fehrmann, Rudolf | Hedman, Åsa K. | Karjalainen, Juha | Schmidt, Ellen M. | Absher, Devin | Amin, Najaf | Anderson, Denise | Beekman, Marian | Bolton, Jennifer L. | Bragg-Gresham, Jennifer L. | Buyske, Steven | Demirkan, Ayse | Deng, Guohong | Ehret, Georg B. | Feenstra, Bjarke | Feitosa, Mary F. | Fischer, Krista | Goel, Anuj | Gong, Jian | Jackson, Anne U. | Kanoni, Stavroula | Kleber, Marcus E. | Kristiansson, Kati | Lim, Unhee | Lotay, Vaneet | Mangino, Massimo | Leach, Irene Mateo | Medina-Gomez, Carolina | Medland, Sarah E. | Nalls, Michael A. | Palmer, Cameron D. | Pasko, Dorota | Pechlivanis, Sonali | Peters, Marjolein J. | Prokopenko, Inga | Shungin, Dmitry | Stančáková, Alena | Strawbridge, Rona J. | Sung, Yun Ju | Tanaka, Toshiko | Teumer, Alexander | Trompet, Stella | van der Laan, Sander W. | van Setten, Jessica | Van Vliet-Ostaptchouk, Jana V. | Wang, Zhaoming | Yengo, Loïc | Zhang, Weihua | Isaacs, Aaron | Albrecht, Eva | Ärnlöv, Johan | Arscott, Gillian M. | Attwood, Antony P. | Bandinelli, Stefania | Barrett, Amy | Bas, Isabelita N. | Bellis, Claire | Bennett, Amanda J. | Berne, Christian | Blagieva, Roza | Blüher, Matthias | Böhringer, Stefan | Bonnycastle, Lori L. | Böttcher, Yvonne | Boyd, Heather A. | Bruinenberg, Marcel | Caspersen, Ida H. | Chen, Yii-Der Ida | Clarke, Robert | Daw, E. Warwick | de Craen, Anton J. M. | Delgado, Graciela | Dimitriou, Maria | Doney, Alex S. F. | Eklund, Niina | Estrada, Karol | Eury, Elodie | Folkersen, Lasse | Fraser, Ross M. | Garcia, Melissa E. | Geller, Frank | Giedraitis, Vilmantas | Gigante, Bruna | Go, Alan S. | Golay, Alain | Goodall, Alison H. | Gordon, Scott D. | Gorski, Mathias | Grabe, Hans-Jörgen | Grallert, Harald | Grammer, Tanja B. | Gräßler, Jürgen | Grönberg, Henrik | Groves, Christopher J. | Gusto, Gaëlle | Haessler, Jeffrey | Hall, Per | Haller, Toomas | Hallmans, Goran | Hartman, Catharina A. | Hassinen, Maija | Hayward, Caroline | Heard-Costa, Nancy L. | Helmer, Quinta | Hengstenberg, Christian | Holmen, Oddgeir | Hottenga, Jouke-Jan | James, Alan L. | Jeff, Janina M. | Johansson, Åsa | Jolley, Jennifer | Juliusdottir, Thorhildur | Kinnunen, Leena | Koenig, Wolfgang | Koskenvuo, Markku | Kratzer, Wolfgang | Laitinen, Jaana | Lamina, Claudia | Leander, Karin | Lee, Nanette R. | Lichtner, Peter | Lind, Lars | Lindström, Jaana | Lo, Ken Sin | Lobbens, Stéphane | Lorbeer, Roberto | Lu, Yingchang | Mach, François | Magnusson, Patrik K. E. | Mahajan, Anubha | McArdle, Wendy L. | McLachlan, Stela | Menni, Cristina | Merger, Sigrun | Mihailov, Evelin | Milani, Lili | Moayyeri, Alireza | Monda, Keri L. | Morken, Mario A. | Mulas, Antonella | Müller, Gabriele | Müller-Nurasyid, Martina | Musk, Arthur W. | Nagaraja, Ramaiah | Nöthen, Markus M. | Nolte, Ilja M. | Pilz, Stefan | Rayner, Nigel W. | Renstrom, Frida | Rettig, Rainer | Ried, Janina S. | Ripke, Stephan | Robertson, Neil R. | Rose, Lynda M. | Sanna, Serena | Scharnagl, Hubert | Scholtens, Salome | Schumacher, Fredrick R. | Scott, William R. | Seufferlein, Thomas | Shi, Jianxin | Smith, Albert Vernon | Smolonska, Joanna | Stanton, Alice V. | Steinthorsdottir, Valgerdur | Stirrups, Kathleen | Stringham, Heather M. | Sundström, Johan | Swertz, Morris A. | Swift, Amy J. | Syvänen, Ann-Christine | Tan, Sian-Tsung | Tayo, Bamidele O. | Thorand, Barbara | Thorleifsson, Gudmar | Tyrer, Jonathan P. | Uh, Hae-Won | Vandenput, Liesbeth | Verhulst, Frank C. | Vermeulen, Sita H. | Verweij, Niek | Vonk, Judith M. | Waite, Lindsay L. | Warren, Helen R. | Waterworth, Dawn | Weedon, Michael N. | Wilkens, Lynne R. | Willenborg, Christina | Wilsgaard, Tom | Wojczynski, Mary K. | Wong, Andrew | Wright, Alan F. | Zhang, Qunyuan | Brennan, Eoin P. | Choi, Murim | Dastani, Zari | Drong, Alexander W. | Eriksson, Per | Franco-Cereceda, Anders | Gådin, Jesper R. | Gharavi, Ali G. | Goddard, Michael E. | Handsaker, Robert E. | Huang, Jinyan | Karpe, Fredrik | Kathiresan, Sekar | Keildson, Sarah | Kiryluk, Krzysztof | Kubo, Michiaki | Lee, Jong-Young | Liang, Liming | Lifton, Richard P. | Ma, Baoshan | McCarroll, Steven A. | McKnight, Amy J. | Min, Josine L. | Moffatt, Miriam F. | Montgomery, Grant W. | Murabito, Joanne M. | Nicholson, George | Nyholt, Dale R. | Okada, Yukinori | Perry, John R. B. | Dorajoo, Rajkumar | Reinmaa, Eva | Salem, Rany M. | Sandholm, Niina | Scott, Robert A. | Stolk, Lisette | Takahashi, Atsushi | Tanaka, Toshihiro | van ’t Hooft, Ferdinand M. | Vinkhuyzen, Anna A. E. | Westra, Harm-Jan | Zheng, Wei | Zondervan, Krina T. | Heath, Andrew C. | Arveiler, Dominique | Bakker, Stephan J. L. | Beilby, John | Bergman, Richard N. | Blangero, John | Bovet, Pascal | Campbell, Harry | Caulfield, Mark J. | Cesana, Giancarlo | Chakravarti, Aravinda | Chasman, Daniel I. | Chines, Peter S. | Collins, Francis S. | Crawford, Dana C. | Cupples, L. Adrienne | Cusi, Daniele | Danesh, John | de Faire, Ulf | den Ruijter, Hester M. | Dominiczak, Anna F. | Erbel, Raimund | Erdmann, Jeanette | Eriksson, Johan G. | Farrall, Martin | Felix, Stephan B. | Ferrannini, Ele | Ferrières, Jean | Ford, Ian | Forouhi, Nita G. | Forrester, Terrence | Franco, Oscar H. | Gansevoort, Ron T. | Gejman, Pablo V. | Gieger, Christian | Gottesman, Omri | Gudnason, Vilmundur | Gyllensten, Ulf | Hall, Alistair S. | Harris, Tamara B. | Hattersley, Andrew T. | Hicks, Andrew A. | Hindorff, Lucia A. | Hingorani, Aroon D. | Hofman, Albert | Homuth, Georg | Hovingh, G. Kees | Humphries, Steve E. | Hunt, Steven C. | Hyppönen, Elina | Illig, Thomas | Jacobs, Kevin B. | Jarvelin, Marjo-Riitta | Jöckel, Karl-Heinz | Johansen, Berit | Jousilahti, Pekka | Jukema, J. Wouter | Jula, Antti M. | Kaprio, Jaakko | Kastelein, John J. P. | Keinanen-Kiukaanniemi, Sirkka M. | Kiemeney, Lambertus A. | Knekt, Paul | Kooner, Jaspal S. | Kooperberg, Charles | Kovacs, Peter | Kraja, Aldi T. | Kumari, Meena | Kuusisto, Johanna | Lakka, Timo A. | Langenberg, Claudia | Marchand, Loic Le | Lehtimäki, Terho | Lyssenko, Valeriya | Männistö, Satu | Marette, André | Matise, Tara C. | McKenzie, Colin A. | McKnight, Barbara | Moll, Frans L. | Morris, Andrew D. | Morris, Andrew P. | Murray, Jeffrey C. | Nelis, Mari | Ohlsson, Claes | Oldehinkel, Albertine J. | Ong, Ken K. | Madden, Pamela A. F. | Pasterkamp, Gerard | Peden, John F. | Peters, Annette | Postma, Dirkje S. | Pramstaller, Peter P. | Price, Jackie F. | Qi, Lu | Raitakari, Olli T. | Rankinen, Tuomo | Rao, D. C. | Rice, Treva K. | Ridker, Paul M. | Rioux, John D. | Ritchie, Marylyn D. | Rudan, Igor | Salomaa, Veikko | Samani, Nilesh J. | Saramies, Jouko | Sarzynski, Mark A. | Schunkert, Heribert | Schwarz, Peter E. H. | Sever, Peter | Shuldiner, Alan R. | Sinisalo, Juha | Stolk, Ronald P. | Strauch, Konstantin | Tönjes, Anke | Trégouët, David-Alexandre | Tremblay, Angelo | Tremoli, Elena | Virtamo, Jarmo | Vohl, Marie-Claude | Völker, Uwe | Waeber, Gérard | Willemsen, Gonneke | Witteman, Jacqueline C. | Zillikens, M. Carola | Adair, Linda S. | Amouyel, Philippe | Asselbergs, Folkert W. | Assimes, Themistocles L. | Bochud, Murielle | Boehm, Bernhard O. | Boerwinkle, Eric | Bornstein, Stefan R. | Bottinger, Erwin P. | Bouchard, Claude | Cauchi, Stéphane | Chambers, John C. | Chanock, Stephen J. | Cooper, Richard S. | de Bakker, Paul I. W. | Dedoussis, George | Ferrucci, Luigi | Franks, Paul W. | Froguel, Philippe | Groop, Leif C. | Haiman, Christopher A. | Hamsten, Anders | Hui, Jennie | Hunter, David J. | Hveem, Kristian | Kaplan, Robert C. | Kivimaki, Mika | Kuh, Diana | Laakso, Markku | Liu, Yongmei | Martin, Nicholas G. | März, Winfried | Melbye, Mads | Metspalu, Andres | Moebus, Susanne | Munroe, Patricia B. | Njølstad, Inger | Oostra, Ben A. | Palmer, Colin N. A. | Pedersen, Nancy L. | Perola, Markus | Pérusse, Louis | Peters, Ulrike | Power, Chris | Quertermous, Thomas | Rauramaa, Rainer | Rivadeneira, Fernando | Saaristo, Timo E. | Saleheen, Danish | Sattar, Naveed | Schadt, Eric E. | Schlessinger, David | Slagboom, P. Eline | Snieder, Harold | Spector, Tim D. | Thorsteinsdottir, Unnur | Stumvoll, Michael | Tuomilehto, Jaakko | Uitterlinden, André G. | Uusitupa, Matti | van der Harst, Pim | Walker, Mark | Wallaschofski, Henri | Wareham, Nicholas J. | Watkins, Hugh | Weir, David R. | Wichmann, H-Erich | Wilson, James F. | Zanen, Pieter | Borecki, Ingrid B. | Deloukas, Panos | Fox, Caroline S. | Heid, Iris M. | O’Connell, Jeffrey R. | Strachan, David P. | Stefansson, Kari | van Duijn, Cornelia M. | Abecasis, Gonçalo R. | Franke, Lude | Frayling, Timothy M. | McCarthy, Mark I. | Visscher, Peter M. | Scherag, André | Willer, Cristen J. | Boehnke, Michael | Mohlke, Karen L. | Lindgren, Cecilia M. | Beckmann, Jacques S. | Barroso, Inês | North, Kari E. | Ingelsson, Erik | Hirschhorn, Joel N. | Loos, Ruth J. F. | Speliotes, Elizabeth K.
Nature  2015;518(7538):197-206.
Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10−8), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ~2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
doi:10.1038/nature14177
PMCID: PMC4382211  PMID: 25673413
6.  Difference in the Breast Milk Proteome between Allergic and Non-Allergic Mothers 
PLoS ONE  2015;10(3):e0122234.
Background
Breastfeeding has been linked to a reduction in the prevalence of allergy and asthma. However, studies on this relationship vary in outcome, which may partly be related to differences in breast milk composition. In particular breast milk composition may differ between allergic and non-allergic mothers. Important components that may be involved are breast milk proteins, as these are known to regulate immune development in the newborn. The objective of this study was therefore to explore differences in the proteins of breast milk from 20 allergic and non-allergic mothers. The results from this comparison may then be used to generate hypotheses on proteins associated with allergy in their offspring.
Methods
Milk samples from allergic and non-allergic mothers were obtained from the PIAMA project, a prospective birth cohort study on incidence, risk factors, and prevention of asthma and inhalant allergy. Non-targeted proteomics technology, based on liquid chromatography and mass spectrometry, was used to compare breast milk from allergic and non-allergic mothers.
Results
Nineteen proteins, out of a total of 364 proteins identified in both groups, differed significantly in concentration between the breast milk of allergic and non-allergic mothers. Protease inhibitors and apolipoproteins were present in much higher concentrations in breast milk of allergic than non-allergic mothers. These proteins have been suggested to be linked to allergy and asthma.
Conclusions
The non-targeted milk proteomic analysis employed has provided new targets for future studies on the relation between breast milk composition and allergy.
doi:10.1371/journal.pone.0122234
PMCID: PMC4370490  PMID: 25798592
7.  Genome-Wide Study of Percent Emphysema on Computed Tomography in the General Population. The Multi-Ethnic Study of Atherosclerosis Lung/SNP Health Association Resource Study 
Rationale: Pulmonary emphysema overlaps partially with spirometrically defined chronic obstructive pulmonary disease and is heritable, with moderately high familial clustering.
Objectives: To complete a genome-wide association study (GWAS) for the percentage of emphysema-like lung on computed tomography in the Multi-Ethnic Study of Atherosclerosis (MESA) Lung/SNP Health Association Resource (SHARe) Study, a large, population-based cohort in the United States.
Methods: We determined percent emphysema and upper-lower lobe ratio in emphysema defined by lung regions less than −950 HU on cardiac scans. Genetic analyses were reported combined across four race/ethnic groups: non-Hispanic white (n = 2,587), African American (n = 2,510), Hispanic (n = 2,113), and Chinese (n = 704) and stratified by race and ethnicity.
Measurements and Main Results: Among 7,914 participants, we identified regions at genome-wide significance for percent emphysema in or near SNRPF (rs7957346; P = 2.2 × 10−8) and PPT2 (rs10947233; P = 3.2 × 10−8), both of which replicated in an additional 6,023 individuals of European ancestry. Both single-nucleotide polymorphisms were previously implicated as genes influencing lung function, and analyses including lung function revealed independent associations for percent emphysema. Among Hispanics, we identified a genetic locus for upper-lower lobe ratio near the α-mannosidase–related gene MAN2B1 (rs10411619; P = 1.1 × 10−9; minor allele frequency [MAF], 4.4%). Among Chinese, we identified single-nucleotide polymorphisms associated with upper-lower lobe ratio near DHX15 (rs7698250; P = 1.8 × 10−10; MAF, 2.7%) and MGAT5B (rs7221059; P = 2.7 × 10−8; MAF, 2.6%), which acts on α-linked mannose. Among African Americans, a locus near a third α-mannosidase–related gene, MAN1C1 (rs12130495; P = 9.9 × 10−6; MAF, 13.3%) was associated with percent emphysema.
Conclusions: Our results suggest that some genes previously identified as influencing lung function are independently associated with emphysema rather than lung function, and that genes related to α-mannosidase may influence risk of emphysema.
doi:10.1164/rccm.201306-1061OC
PMCID: PMC3977717  PMID: 24383474
emphysema; computed tomography; multiethnic; cohort study; genetic association
8.  A score to predict short-term risk of COPD exacerbations (SCOPEX) 
Background
There is no clinically useful score to predict chronic obstructive pulmonary disease (COPD) exacerbations. We aimed to derive this by analyzing data from three existing COPD clinical trials of budesonide/formoterol, formoterol, or placebo in patients with moderate-to-very-severe COPD and a history of exacerbations in the previous year.
Methods
Predictive variables were selected using Cox regression for time to first severe COPD exacerbation. We determined absolute risk estimates for an exacerbation by identifying variables in a binomial model, adjusting for observation time, study, and treatment. The model was further reduced to clinically useful variables and the final regression coefficients scaled to obtain risk scores of 0–100 to predict an exacerbation within 6 months. Receiver operating characteristic (ROC) curves and the corresponding C-index were used to investigate the discriminatory properties of predictive variables.
Results
The best predictors of an exacerbation in the next 6 months were more COPD maintenance medications prior to the trial, higher mean daily reliever use, more exacerbations during the previous year, lower forced expiratory volume in 1 second/forced vital capacity ratio, and female sex. Using these risk variables, we developed a score to predict short-term (6-month) risk of COPD exacerbations (SCOPEX). Budesonide/formoterol reduced future exacerbation risk more than formoterol or as-needed short-acting β2-agonist (salbutamol).
Conclusion
SCOPEX incorporates easily identifiable patient characteristics and can be readily applied in clinical practice to target therapy to reduce COPD exacerbations in patients at the highest risk.
doi:10.2147/COPD.S69589
PMCID: PMC4315304  PMID: 25670896
chronic obstructive pulmonary disease; exacerbation; model; predictor; inhaled corticosteroids; bronchodilators
9.  Genome-wide association analysis identifies six new loci associated with forced vital capacity 
Loth, Daan W. | Artigas, María Soler | Gharib, Sina A. | Wain, Louise V. | Franceschini, Nora | Koch, Beate | Pottinger, Tess | Smith, Albert Vernon | Duan, Qing | Oldmeadow, Chris | Lee, Mi Kyeong | Strachan, David P. | James, Alan L. | Huffman, Jennifer E. | Vitart, Veronique | Ramasamy, Adaikalavan | Wareham, Nicholas J. | Kaprio, Jaakko | Wang, Xin-Qun | Trochet, Holly | Kähönen, Mika | Flexeder, Claudia | Albrecht, Eva | Lopez, Lorna M. | de Jong, Kim | Thyagarajan, Bharat | Alves, Alexessander Couto | Enroth, Stefan | Omenaas, Ernst | Joshi, Peter K. | Fall, Tove | Viňuela, Ana | Launer, Lenore J. | Loehr, Laura R. | Fornage, Myriam | Li, Guo | Wilk, Jemma B. | Tang, Wenbo | Manichaikul, Ani | Lahousse, Lies | Harris, Tamara B. | North, Kari E. | Rudnicka, Alicja R. | Hui, Jennie | Gu, Xiangjun | Lumley, Thomas | Wright, Alan F. | Hastie, Nicholas D. | Campbell, Susan | Kumar, Rajesh | Pin, Isabelle | Scott, Robert A. | Pietiläinen, Kirsi H. | Surakka, Ida | Liu, Yongmei | Holliday, Elizabeth G. | Schulz, Holger | Heinrich, Joachim | Davies, Gail | Vonk, Judith M. | Wojczynski, Mary | Pouta, Anneli | Johansson, Åsa | Wild, Sarah H. | Ingelsson, Erik | Rivadeneira, Fernando | Völzke, Henry | Hysi, Pirro G. | Eiriksdottir, Gudny | Morrison, Alanna C. | Rotter, Jerome I. | Gao, Wei | Postma, Dirkje S. | White, Wendy B. | Rich, Stephen S. | Hofman, Albert | Aspelund, Thor | Couper, David | Smith, Lewis J. | Psaty, Bruce M. | Lohman, Kurt | Burchard, Esteban G. | Uitterlinden, André G. | Garcia, Melissa | Joubert, Bonnie R. | McArdle, Wendy L. | Musk, A. Bill | Hansel, Nadia | Heckbert, Susan R. | Zgaga, Lina | van Meurs, Joyce B.J. | Navarro, Pau | Rudan, Igor | Oh, Yeon-Mok | Redline, Susan | Jarvis, Deborah | Zhao, Jing Hua | Rantanen, Taina | O’Connor, George T. | Ripatti, Samuli | Scott, Rodney J. | Karrasch, Stefan | Grallert, Harald | Gaddis, Nathan C. | Starr, John M. | Wijmenga, Cisca | Minster, Ryan L. | Lederer, David J. | Pekkanen, Juha | Gyllensten, Ulf | Campbell, Harry | Morris, Andrew P. | Gläser, Sven | Hammond, Christopher J. | Burkart, Kristin M. | Beilby, John | Kritchevsky, Stephen B. | Gudnason, Vilmundur | Hancock, Dana B. | Williams, O. Dale | Polasek, Ozren | Zemunik, Tatijana | Kolcic, Ivana | Petrini, Marcy F. | Wjst, Matthias | Kim, Woo Jin | Porteous, David J. | Scotland, Generation | Smith, Blair H. | Viljanen, Anne | Heliövaara, Markku | Attia, John R. | Sayers, Ian | Hampel, Regina | Gieger, Christian | Deary, Ian J. | Boezen, H. Marike | Newman, Anne | Jarvelin, Marjo-Riitta | Wilson, James F. | Lind, Lars | Stricker, Bruno H. | Teumer, Alexander | Spector, Timothy D. | Melén, Erik | Peters, Marjolein J. | Lange, Leslie A. | Barr, R. Graham | Bracke, Ken R. | Verhamme, Fien M. | Sung, Joohon | Hiemstra, Pieter S. | Cassano, Patricia A. | Sood, Akshay | Hayward, Caroline | Dupuis, Josée | Hall, Ian P. | Brusselle, Guy G. | Tobin, Martin D. | London, Stephanie J.
Nature genetics  2014;46(7):669-677.
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, MIR-129-2/HSD17B12, PRDM11, WWOX, and KCNJ2. Two (GSTCD and PTCH1) loci previously associated with spirometric measures were related to FVC. Newly implicated regions were followed-up in samples of 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 pathogenesis of restrictive lung disease.
doi:10.1038/ng.3011
PMCID: PMC4140093  PMID: 24929828
10.  Development of a tool to recognize small airways dysfunction in asthma (SADT) 
Background
Small airways dysfunction (SAD) contributes to the clinical expression of asthma. The identification of patients who suffer from SAD is important from a clinical perspective, as targeted therapy may improve patients’ well-being and treatment efficacy.
Aims
We aimed to realize the first step in the development of a simple small airways dysfunction tool (SADT) that may help to identify asthma patients having SAD.
Methods
Asthma patients with and without SAD were interviewed. Patients were selected to participate in this study based on FEF50% and R5-R20 values from spirometry and impulse oscillometry respectively.
Results
Ten in depth interviews and two focus groups revealed that patients with and without SAD perceived differences in symptoms and signs, habits and health related issues. For example, patients with SAD reported to wheeze easily, were unable to breathe in deeply, mentioned more symptoms related to bronchial hyperresponsiveness, experienced more pronounced exercise-induced symptoms and more frequently had allergic respiratory symptoms after exposure to cats and birds. Based on these differences, 63 items were retained to be further explored for the SADT.
Conclusions
The first step of the development of the SADT tool shows that there are relevant differences in signs and respiratory symptoms between asthma patients with and without SAD. The next step is to test and validate all items in order to retain the most relevant items to create a short and simple tool, which should be useful to identify asthma patients with SAD in clinical practice.
Electronic supplementary material
The online version of this article (doi:10.1186/s12955-014-0155-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12955-014-0155-7
PMCID: PMC4253607  PMID: 25416552
Small airways dysfunction; Asthma; Questionnaire
11.  Objective allergy markers and risk of cancer mortality and hospitalization in a large population-based cohort 
Cancer Causes & Control  2014;26:99-109.
Purpose
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.
Methods
Associations between three allergy markers (number of peripheral blood eosinophil counts, skin test positivity, and serum total IgE) with mortality and hospitalization from any type and four common types of cancer (lung, colorectal, prostate, and breast cancer) were assessed in the Vlagtwedde–Vlaardingen cohort (1965–1990), with follow-up of mortality until 31 December 2008. Hospitalization data were available since 1 January 1995.
Results
There were no significant associations between objective allergy markers and cancer mortality or hospitalization. We found several associations in specific subgroups. A higher number of eosinophils was associated with a decreased risk of colorectal cancer mortality in ever smokers HR (95 % CI) = 0.61 (0.45–0.83) and in males 0.59 (0.42–0.83); however, no overall association was observed 0.84 (0.64–1.09). Skin test positivity was associated with a decreased risk of any cancer mortality only among females 0.59 (0.38–0.91) and showed no overall association 0.83 (0.67–1.04). Serum total IgE levels were associated with an increased risk of lung cancer mortality among females 4.64 (1.04–20.70), but with a decreased risk of cancer hospitalization in ever smokers 0.77 (0.61–0.97) and males 0.72 (0.55–0.93); however, no overall associations were observed [mortality 0.99 (0.79–1.25), and hospitalization 0.86 (0.71–1.04)].
Conclusions
We found no associations between objective allergy markers and cancer in the total population. However, skin test positivity and a high number of eosinophils were associated with a reduced risk to die of cancer in specific subgroups. Hence, it seems important to study specific subgroups defined by gender and smoking habits in order to identify allergy markers of predictive value for cancer mortality.
Electronic supplementary material
The online version of this article (doi:10.1007/s10552-014-0489-9) contains supplementary material, which is available to authorized users.
doi:10.1007/s10552-014-0489-9
PMCID: PMC4282688  PMID: 25388801
Cancer mortality; Cancer hospitalization; Eosinophils; IgE; Skin test positivity
12.  Common genes underlying asthma and COPD? Genome-wide analysis on the Dutch hypothesis 
The European respiratory journal  2014;44(4):860-872.
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 NFκβ pathway) and GNG5P5, respectively. SNP rs9534578 in GNG5P5 reached genome-wide significance after first stage replication (p=9.96·*10−9). The second stage replication in seven independent cohorts provided no significant replication. eQTL analysis in blood and lung on the top 20 associated SNPs identified two SNPs in COMMD10 influencing gene expression.
Inflammatory processes differ in asthma and COPD and are mediated by NFκβ, 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 of two COMMD10 SNPs, since they influence gene expression in both blood cells and lung tissue. Our findings either suggest that there is no common genetic component in asthma and COPD or, alternatively, different environmental factors, like lifestyle and occupation in different countries and continents may have obscured the genetic common contribution.
doi:10.1183/09031936.00001914
PMCID: PMC4217133  PMID: 24993907
13.  Comparing the effectiveness of small-particle versus large-particle inhaled corticosteroid in COPD 
Purpose
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.
Patients and methods
Smokers and ex-smokers with COPD ≥40 years old initiating or stepping-up their dose of extrafine beclomethasone or fluticasone were matched 1:1 for demographic characteristics, index prescription year, concomitant therapies, and disease severity during 1 baseline year. During 2 subsequent years, we evaluated treatment change and COPD exacerbations, defined as emergency care/hospitalization for COPD, acute oral corticosteroids, or antibiotics for lower respiratory tract infection.
Results
Mean patient age was 67 years, 57%–60% being male. For both initiation (n=334:334) and step-up (n=189:189) patients, exacerbation rates were comparable between extrafine beclomethasone and fluticasone cohorts during the 2 year outcome period. Odds of treatment stability (no exacerbation or treatment change) were significantly greater for patients initiating extrafine beclomethasone compared with fluticasone (adjusted odds ratio 2.50; 95% confidence interval, 1.32–4.73). Median ICS dose exposure during 2 outcome years was significantly lower (P<0.001) for extrafine beclomethasone than fluticasone cohorts (315 μg/day versus 436 μg/day for initiation, 438 μg/day versus 534 μg/day for step-up patients).
Conclusion
We observed that small-particle ICS at significantly lower doses had comparable effects on exacerbation rates as larger-particle ICS at higher doses, whereas initiation of small-particle ICS was associated with better odds of treatment stability during 2-years’ follow-up.
doi:10.2147/COPD.S68289
PMCID: PMC4207569  PMID: 25378918
COPD exacerbation; extrafine particle; matched cohort analysis; real life; small airways
14.  Increased activation of blood neutrophils after cigarette smoking in young individuals susceptible to COPD 
Respiratory Research  2014;15(1):121.
Background
Cigarette 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.
Methods
All 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.
Results
Young susceptible individuals showed significantly higher increases in the expression of FcγRII (CD32) in its active forms (A17 and A27) 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.
Conclusions
We 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 registration
Clinicaltrials.gov: NCT00807469
Electronic supplementary material
The online version of this article (doi:10.1186/s12931-014-0121-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s12931-014-0121-2
PMCID: PMC4203909  PMID: 25301367
Acute smoking; COPD; Susceptibility; Biomarkers; Inflammation
15.  A novel common variant in DCST2 is associated with length in early life and height in adulthood 
van der Valk, Ralf J.P. | Kreiner-Møller, Eskil | Kooijman, Marjolein N. | Guxens, Mònica | Stergiakouli, Evangelia | Sääf, Annika | Bradfield, Jonathan P. | Geller, Frank | Hayes, M. Geoffrey | Cousminer, Diana L. | Körner, Antje | Thiering, Elisabeth | Curtin, John A. | Myhre, Ronny | Huikari, Ville | Joro, Raimo | Kerkhof, Marjan | Warrington, Nicole M. | Pitkänen, Niina | Ntalla, Ioanna | Horikoshi, Momoko | Veijola, Riitta | Freathy, Rachel M. | Teo, Yik-Ying | Barton, Sheila J. | Evans, David M. | Kemp, John P. | St Pourcain, Beate | Ring, Susan M. | Davey Smith, George | Bergström, Anna | Kull, Inger | Hakonarson, Hakon | Mentch, Frank D. | Bisgaard, Hans | Chawes, Bo | Stokholm, Jakob | Waage, Johannes | Eriksen, Patrick | Sevelsted, Astrid | Melbye, Mads | van Duijn, Cornelia M. | Medina-Gomez, Carolina | Hofman, Albert | de Jongste, Johan C. | Taal, H. Rob | Uitterlinden, André G. | Armstrong, Loren L. | Eriksson, Johan | Palotie, Aarno | Bustamante, Mariona | Estivill, Xavier | Gonzalez, Juan R. | Llop, Sabrina | Kiess, Wieland | Mahajan, Anubha | Flexeder, Claudia | Tiesler, Carla M.T. | Murray, Clare S. | Simpson, Angela | Magnus, Per | Sengpiel, Verena | Hartikainen, Anna-Liisa | Keinanen-Kiukaanniemi, Sirkka | Lewin, Alexandra | Da Silva Couto Alves, Alexessander | Blakemore, Alexandra I. | Buxton, Jessica L. | Kaakinen, Marika | Rodriguez, Alina | Sebert, Sylvain | Vaarasmaki, Marja | Lakka, Timo | Lindi, Virpi | Gehring, Ulrike | Postma, Dirkje S. | Ang, Wei | Newnham, John P. | Lyytikäinen, Leo-Pekka | Pahkala, Katja | Raitakari, Olli T. | Panoutsopoulou, Kalliope | Zeggini, Eleftheria | Boomsma, Dorret I. | Groen-Blokhuis, Maria | Ilonen, Jorma | Franke, Lude | Hirschhorn, Joel N. | Pers, Tune H. | Liang, Liming | Huang, Jinyan | Hocher, Berthold | Knip, Mikael | Saw, Seang-Mei | Holloway, John W. | Melén, Erik | Grant, Struan F.A. | Feenstra, Bjarke | Lowe, William L. | Widén, Elisabeth | Sergeyev, Elena | Grallert, Harald | Custovic, Adnan | Jacobsson, Bo | Jarvelin, Marjo-Riitta | Atalay, Mustafa | Koppelman, Gerard H. | Pennell, Craig E. | Niinikoski, Harri | Dedoussis, George V. | Mccarthy, Mark I. | Frayling, Timothy M. | Sunyer, Jordi | Timpson, Nicholas J. | Rivadeneira, Fernando | Bønnelykke, Klaus | Jaddoe, Vincent W.V.
Human Molecular Genetics  2014;24(4):1155-1168.
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; β = 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.
doi:10.1093/hmg/ddu510
PMCID: PMC4447786  PMID: 25281659
16.  Susceptibility to COPD: Differential Proteomic Profiling after Acute Smoking 
PLoS ONE  2014;9(7):e102037.
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.
doi:10.1371/journal.pone.0102037
PMCID: PMC4103835  PMID: 25036363
17.  Co-morbidities are the key nominators of the health related quality of life in mild and moderate COPD 
BMC Pulmonary Medicine  2014;14:102.
Background
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.
Methods
Using both generic (15D) and respiratory-specific (AQ20) instruments, HRQoL was assessed in a hospital based COPD population (N = 739, 64% males, mean age 64 years, SD 7 years) in this observational study with inferential analysis. The prevalence of their co-morbidities was compared with those of 5000 population controls. The patients represented all severity stages of COPD and the patterns of common concomitant disorders differed between patients.
Results
Co-morbidities such as psychiatric conditions, alcohol abuse, cardiovascular diseases, and diabetes were more common among COPD patients than in age and gender matched controls. Psychiatric conditions and alcohol abuse were the strongest determinants of HRQoL in COPD and could be detected by both 15D (Odds Ratio 4.7 and 2.3 respectively) and AQ20 (OR 2.0 and 3.0) instruments. Compared to respiratory specific AQ20, generic 15D was more sensitive to the effects of comorbidities while AQ20 was slightly more sensitive for the low FEV1. FEV1 was a strong determinant of HRQoL only at more severe stages of disease (FEV1 < 40% of predicted). Poor HRQoL also predicted death during the next five years.
Conclusions
The results suggest that co-morbidities may impair HRQoL at an early stage of the disease, while bronchial obstruction becomes a significant determinant of HRQoL only in severe COPD.
doi:10.1186/1471-2466-14-102
PMCID: PMC4229911  PMID: 24946786
Generic HRQoL; Respiratory specific HRQoL; HRQoL; COPD; 15D; AQ20; Co-morbidities; Mortality
18.  Glycogen synthase kinase-3 (GSK-3) regulates TGF-β1-induced differentiation of pulmonary fibroblasts 
British Journal of Pharmacology  2013;169(3):590-603.
Background
Chronic lung diseases such as asthma, COPD and pulmonary fibrosis are characterized by abnormal extracellular matrix (ECM) turnover. TGF-β 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-β1-induced myofibroblast differentiation is currently largely unknown.
Purpose
To determine the contribution of GSK-3 signalling in TGF-β1-induced myofibroblast differentiation.
Experimental Approach
We used MRC5 human lung fibroblasts and primary pulmonary fibroblasts of individuals with and without COPD. Protein and mRNA expression were determined by immunoblotting and RT-PCR analysis respectively.
Results
Stimulation of MRC5 and primary human lung fibroblasts with TGF-β1 resulted in time- and dose-dependent increases of α-sm-actin and fibronectin expression, indicative of myofibroblast differentiation. Pharmacological inhibition of GSK-3 by SB216763 dose-dependently attenuated TGF-β1-induced expression of these myofibroblasts markers. Moreover, silencing of GSK-3 by siRNA or pharmacological inhibition by CT/CHIR99021 fully inhibited the TGF-β1-induced expression of α-sm-actin and fibronectin. The effect of GSK-3 inhibition on α-sm-actin expression was similar in fibroblasts from individuals with and without COPD. Neither smad, NF-κB nor ERK1/2 were involved in the inhibitory actions of GSK-3 inhibition by SB126763 on myofibroblast differentiation. Rather, SB216763 increased the phosphorylation of CREB, which in its phosphorylated form acts as a functional antagonist of TGF-β/smad signalling.
Conclusion and Implication
We demonstrate that GSK-3 signalling regulates TGF-β1-induced myofibroblast differentiation by regulating CREB phosphorylation. GSK-3 may constitute a useful target for treatment of chronic lung diseases.
doi:10.1111/bph.12098
PMCID: PMC3682707  PMID: 23297769
cAMP response element-binding protein (CREB); fibronectin; α-sm-actin; COPD; SB216763
19.  A Dynamic Bronchial Airway Gene Expression Signature of Chronic Obstructive Pulmonary Disease and Lung Function Impairment 
Rationale: Molecular phenotyping of chronic obstructive pulmonary disease (COPD) has been impeded in part by the difficulty in obtaining lung tissue samples from individuals with impaired lung function.
Objectives: We sought to determine whether COPD-associated processes are reflected in gene expression profiles of bronchial airway epithelial cells obtained by bronchoscopy.
Methods: Gene expression profiling of bronchial brushings obtained from 238 current and former smokers with and without COPD was performed using Affymetrix Human Gene 1.0 ST Arrays.
Measurements and Main Results: We identified 98 genes whose expression levels were associated with COPD status, FEV1% predicted, and FEV1/FVC. In silico analysis identified activating transcription factor 4 (ATF4) as a potential transcriptional regulator of genes with COPD-associated airway expression, and ATF4 overexpression in airway epithelial cells in vitro recapitulates COPD-associated gene expression changes. Genes with COPD-associated expression in the bronchial airway epithelium had similarly altered expression profiles in prior studies performed on small-airway epithelium and lung parenchyma, suggesting that transcriptomic alterations in the bronchial airway epithelium reflect molecular events found at more distal sites of disease activity. Many of the airway COPD-associated gene expression changes revert toward baseline after therapy with the inhaled corticosteroid fluticasone in independent cohorts.
Conclusions: Our findings demonstrate a molecular field of injury throughout the bronchial airway of active and former smokers with COPD that may be driven in part by ATF4 and is modifiable with therapy. Bronchial airway epithelium may ultimately serve as a relatively accessible tissue in which to measure biomarkers of disease activity for guiding clinical management of COPD.
doi:10.1164/rccm.201208-1449OC
PMCID: PMC3707363  PMID: 23471465
chronic obstructive pulmonary disease; gene expression profiling; biologic markers
20.  Susceptibility to Chronic Mucus Hypersecretion, a Genome Wide Association Study 
PLoS ONE  2014;9(4):e91621.
Background
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.
Methods
GWA analysis was performed in the NELSON-study using the Illumina 610 array, followed by replication and meta-analysis in 11 additional cohorts. In total 2,704 subjects with, and 7,624 subjects without CMH were included, all current or former heavy smokers (≥20 pack-years). Additional studies were performed to test the functional relevance of the most significant single nucleotide polymorphism (SNP).
Results
A strong association with CMH, consistent across all cohorts, was observed with rs6577641 (p = 4.25×10−6, OR = 1.17), located in intron 9 of the special AT-rich sequence-binding protein 1 locus (SATB1) on chromosome 3. The risk allele (G) was associated with higher mRNA expression of SATB1 (4.3×10−9) in lung tissue. Presence of CMH was associated with increased SATB1 mRNA expression in bronchial biopsies from COPD patients. SATB1 expression was induced during differentiation of primary human bronchial epithelial cells in culture.
Conclusions
Our findings, that SNP rs6577641 is associated with CMH in multiple cohorts and is a cis-eQTL for SATB1, together with our additional observation that SATB1 expression increases during epithelial differentiation provide suggestive evidence that SATB1 is a gene that affects CMH.
doi:10.1371/journal.pone.0091621
PMCID: PMC3979657  PMID: 24714607
21.  GSTP1 and TNF Gene Variants and Associations between Air Pollution and Incident Childhood Asthma: The Traffic, Asthma and Genetics (TAG) Study 
Environmental Health Perspectives  2014;122(4):418-424.
Background: Genetics may partially explain observed heterogeneity in associations between traffic-related air pollution and incident asthma.
Objective: Our aim was to investigate the impact of gene variants associated with oxidative stress and inflammation on associations between air pollution and incident childhood asthma.
Methods: Traffic-related air pollution, asthma, wheeze, gene variant, and potential confounder data were pooled across six birth cohorts. Parents reported physician-diagnosed asthma and wheeze from birth to 7–8 years of age (confirmed by pediatric allergist in two cohorts). Individual estimates of annual average air pollution [nitrogen dioxide (NO2), particulate matter ≤ 2.5 μm (PM2.5), PM2.5 absorbance, ozone] were assigned to each child’s birth address using land use regression, atmospheric modeling, and ambient monitoring data. Effect modification by variants in GSTP1 (rs1138272/Ala114Val and rs1695/IIe105Val) and TNF (rs1800629/G-308A) was investigated.
Results: Data on asthma, wheeze, potential confounders, at least one SNP of interest, and NO2 were available for 5,115 children. GSTP1 rs1138272 and TNF rs1800629 SNPs were associated with asthma and wheeze, respectively. In relation to air pollution exposure, children with one or more GSTP1 rs1138272 minor allele were at increased risk of current asthma [odds ratio (OR) = 2.59; 95% CI: 1.43, 4.68 per 10 μg/m3 NO2] and ever asthma (OR = 1.64; 95% CI: 1.06, 2.53) compared with homozygous major allele carriers (OR = 0.95; 95% CI: 0.68, 1.32 for current and OR = 1.20; 95% CI: 0.98, 1.48 for ever asthma; Bonferroni-corrected interaction p = 0.04 and 0.01, respectively). Similarly, for GSTP1 rs1695, associations between NO2 and current and ever asthma had ORs of 1.43 (95% CI: 1.03, 1.98) and 1.36 (95% CI: 1.08, 1.70), respectively, for minor allele carriers compared with ORs of 0.82 (95% CI: 0.52, 1.32) and 1.12 (95% CI: 0.84, 1.49) for homozygous major allele carriers (Bonferroni-corrected interaction p-values 0.48 and 0.09). There were no clear differences by TNF genotype.
Conclusions: Children carrying GSTP1 rs1138272 or rs1695 minor alleles may constitute a susceptible population at increased risk of asthma associated with air pollution.
Citation: MacIntyre EA, Brauer M, Melén E, Bauer CP, Bauer M, Berdel D, Bergström A, Brunekreef B, Chan-Yeung M, Klümper C, Fuertes E, Gehring U, Gref A, Heinrich J, Herbarth O, Kerkhof M, Koppelman GH, Kozyrskyj AL, Pershagen G, Postma DS, Thiering E, Tiesler CM, Carlsten C, TAG Study Group. 2014. GSTP1 and TNF gene variants and associations between air pollution and incident childhood asthma: the traffic, asthma and genetics (TAG) Study. Environ Health Perspect 122:418–424; http://dx.doi.org/10.1289/ehp.1307459
doi:10.1289/ehp.1307459
PMCID: PMC3984232  PMID: 24465030
22.  Lower Corticosteroid Skin Blanching Response Is Associated with Severe COPD 
PLoS ONE  2014;9(3):e91788.
Background
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.
Methods
COPD patients GOLD stage I–IV (n = 27, 24, 22, and 16 respectively) and healthy never-smokers and smokers (n = 28 and 56 respectively) were included. Corticosteroid sensitivity was assessed by the corticosteroid skin blanching test. Budesonide was applied in 8 logarithmically increasing concentrations (0–100 μg/ml) on subject's forearm. Assessment of blanching was performed after 7 hours using a 7-point scale (normal skin to intense blanching). All subjects performed spirometry and body plethysmography.
Results
Both GOLD III and GOLD IV COPD patients showed significantly lower skin blanching responses than healthy never-smokers and smokers, GOLD I, and GOLD II patients. Their area under the dose-response curve values of the skin blanching response were 586 and 243 vs. 1560, 1154, 1380, and 1309 respectively, p<0.05. Lower FEV1 levels and higher RV/TLC ratios were significantly associated with lower skin blanching responses (p = 0.001 and p = 0.004 respectively). GOLD stage I, II, III and IV patients had similar age and packyears.
Conclusions
In this study, severe and very severe COPD patients had lower skin corticosteroid sensitivity than mild and moderate COPD patients and non-COPD controls with comparable age and packyears. Our findings together suggest that the reduced skin blanching response fits with a subgroup of COPD patients that has an early-onset COPD phenotype.
doi:10.1371/journal.pone.0091788
PMCID: PMC3951419  PMID: 24622644
24.  Steroid Resistance in COPD? Overlap and Differential Anti-Inflammatory Effects in Smokers and Ex-Smokers 
PLoS ONE  2014;9(2):e87443.
Background
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.
Methods
Persistent smokers (n = 41) and persistent ex-smokers (n = 31) from the GLUCOLD cohort were investigated. Effects of ICS treatment compared with placebo were estimated by analysing changes in lung function, hyperresponsiveness, and inflammatory cells in sputum and bronchial biopsies during short-term (0–6 months) and long-term (6–30 months) treatment using multiple regression analyses.
Results
Bronchial mast cells were reduced by short-term and long-term ICS treatment in both smokers and ex-smokers. In contrast, CD3+, CD4+, and CD8+ cells were reduced by short-term ICS treatment in smokers only. In addition, sputum neutrophils and lymphocytes, and bronchial CD8+ cells were reduced after long-term treatment in ex-smokers only. No significant interactions existed between smoking and ICS treatment.
Conclusion
Even in the presence of smoking, long-term ICS treatment may lead to anti-inflammatory effects in the lung. Some anti-inflammatory ICS effects are comparable in smokers and ex-smokers with COPD, other effects are cell-specific. The clinical relevance of these findings, however, are uncertain.
doi:10.1371/journal.pone.0087443
PMCID: PMC3914834  PMID: 24505290
25.  Genome-wide protein QTL mapping identifies human plasma kallikrein as a post-translational regulator of serum uPAR levels 
The FASEB Journal  2014;28(2):923-934.
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 scuPAR's 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.
doi:10.1096/fj.13-240879
PMCID: PMC3898658  PMID: 24249636
GWAS; proteolysis; respiratory disease; HBECs; cellular proliferation and wound repair

Results 1-25 (105)