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1. Kidney resident macrophages have distinct subsets and multifunctional roles

Author

Chew, Christine, Brand, Oliver J, Yamamura, Tomohiko, Lawless, Craig, Morais, Mychel Raony Paiva Teixeira, Zeef, Leo, Lin, I-Hsuan, Howell, Gareth, Lui, Sylvia, Lausecker, Franziska, Jagger, Christopher, Shaw, Tovah N, Krishnan, Siddharth, McClure, Flora A, Bridgeman, Hayley, Wemyss, Kelly, Konkel, Joanne E, Hussell, Tracy, and Lennon, Rachel

Published
2024
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3. Transforming Growth Factor-β and Interleukin-1β Signaling Pathways Converge on the Chemokine CCL20 Promoter*

Author

Brand, Oliver J, Somanath, Sangeeta, Moermans, Catherine, Yanagisawa, Haruhiko, Hashimoto, Mitsuo, Cambier, Stephanie, Markovics, Jennifer, Bondesson, Andrew J, Hill, Arthur, Jablons, David, Wolters, Paul, Lou, Jianlong, Marks, James D, Baron, Jody L, and Nishimura, Stephen L

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Clinical Research, Lung, Chronic Obstructive Pulmonary Disease, Aetiology, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Underpinning research, Respiratory, Animals, Base Sequence, Cells, Cultured, Chemokine CCL20, Fibroblasts, Gene Expression Regulation, Humans, Interleukin-1beta, Mice, Mice, Inbred C57BL, NF-kappa B, Response Elements, Signal Transduction, Transforming Growth Factor beta, TGF-β, chemokine, inflammation, integrin, transcription, Chemical Sciences, Medical and Health Sciences, Biochemistry & Molecular Biology, Biological sciences, Biomedical and clinical sciences, Chemical sciences
Abstract

CCL20 is the only chemokine ligand for the chemokine receptor CCR6, which is expressed by the critical antigen presenting cells, dendritic cells. Increased expression of CCL20 is likely involved in the increased recruitment of dendritic cells observed in fibroinflammatory diseases such as chronic obstructive pulmonary disease (COPD). CCL20 expression is increased by the proinflammatory cytokine IL-1β. We have determined that IL-1β-dependent CCL20 expression is also dependent on the multifunctional cytokine TGF-β. TGF-β is expressed in a latent form that must be activated to function, and activation is achieved through binding to the integrin αvβ8 (itgb8). Here we confirm correlative increases in αvβ8 and IL-1β with CCL20 protein in lung parenchymal lysates of a large cohort of COPD patients. How IL-1β- and αvβ8-mediated TGF-β activation conspire to increase fibroblast CCL20 expression remains unknown, because these pathways have not been shown to directly interact. We evaluate the 5'-flanking region of CCL20 to determine that IL-1β-driven CCL20 expression is dependent on αvβ8-mediated activation of TGF-β. We identify a TGF-β-responsive element (i.e. SMAD) located on an upstream enhancer of the human CCL20 promoter required for efficient IL-1β-dependent CCL20 expression. By chromatin immunoprecipitation, this upstream enhancer complexes with the p50 subunit of NF-κB on a NF-κB-binding element close to the transcriptional start site of CCL20. These interactions are confirmed by electromobility shift assays in nuclear extracts from human lung fibroblasts. These data define a mechanism by which αvβ8-dependent activation of TGF-β regulates IL-1β-dependent CCL20 expression in COPD.

Published
2015

4. Selective Targeting of TGF-β Activation to Treat Fibroinflammatory Airway Disease

Author

Minagawa, Shunsuke, Lou, Jianlong, Seed, Robert I, Cormier, Anthony, Wu, Shenping, Cheng, Yifan, Murray, Lynne, Tsui, Ping, Connor, Jane, Herbst, Ronald, Govaerts, Cedric, Barker, Tyren, Cambier, Stephanie, Yanagisawa, Haruhiko, Goodsell, Amanda, Hashimoto, Mitsuo, Brand, Oliver J, Cheng, Ran, Ma, Royce, McKnelly, Kate J, Wen, Weihua, Hill, Arthur, Jablons, David, Wolters, Paul, Kitamura, Hideya, Araya, Jun, Barczak, Andrea J, Erle, David J, Reichardt, Louis F, Marks, James D, Baron, Jody L, and Nishimura, Stephen L

Subjects
Medical Biotechnology, Biomedical and Clinical Sciences, Lung, Chronic Obstructive Pulmonary Disease, Aetiology, Development of treatments and therapeutic interventions, 2.1 Biological and endogenous factors, 5.1 Pharmaceuticals, Respiratory, Good Health and Well Being, Animals, Humans, Mice, Mice, Transgenic, Tracheitis, Transforming Growth Factor beta, Biological Sciences, Medical and Health Sciences, Medical biotechnology, Biomedical engineering
Abstract

Airway remodeling, caused by inflammation and fibrosis, is a major component of chronic obstructive pulmonary disease (COPD) and currently has no effective treatment. Transforming growth factor-β (TGF-β) has been widely implicated in the pathogenesis of airway remodeling in COPD. TGF-β is expressed in a latent form that requires activation. The integrin αvβ8 (encoded by the itgb8 gene) is a receptor for latent TGF-β and is essential for its activation. Expression of integrin αvβ8 is increased in airway fibroblasts in COPD and thus is an attractive therapeutic target for the treatment of airway remodeling in COPD. We demonstrate that an engineered optimized antibody to human αvβ8 (B5) inhibited TGF-β activation in transgenic mice expressing only human and not mouse ITGB8. The B5 engineered antibody blocked fibroinflammatory responses induced by tobacco smoke, cytokines, and allergens by inhibiting TGF-β activation. To clarify the mechanism of action of B5, we used hydrodynamic, mutational, and electron microscopic methods to demonstrate that αvβ8 predominantly adopts a constitutively active, extended-closed headpiece conformation. Epitope mapping and functional characterization of B5 revealed an allosteric mechanism of action due to locking-in of a low-affinity αvβ8 conformation. Collectively, these data demonstrate a new model for integrin function and present a strategy to selectively target the TGF-β pathway to treat fibroinflammatory airway diseases.

Published
2014

5. Association of caveolin-1 gene polymorphism with kidney transplant fibrosis and allograft failure

Author

Moore, Jason, McKnight, Amy Jayne, Simmonds, Matthew J., Courtney, Aisling E., Hanvesakul, Rajesh, Brand, Oliver J., Briggs, David, Ball, Simon, Cockwell, Paul, Patterson, Christopher C., Maxwell, Alexander P., Gough, Stephen C.L., and Borrows, Richard

Subjects
Caveolins -- Research, Genetic polymorphisms -- Research, Single nucleotide polymorphisms -- Usage, Graft rejection -- Genetic aspects, Kidneys -- Transplantation, Kidneys -- Genetic aspects
Abstract

The study aims to evaluate the relationship between caveolin-1 (CAV1_ gene polymorphism with kidney transplant fibrosis and allograft failure. The results indicate that CAV1 gene was significantly associated with allograft failure among kidney transplant donors.

Published
2010

11. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls

Author

Craddock, Nick, Hurles, Matthew E., Cardin, Niall, Pearson, Richard D., Plagnol, Vincent, Robson, Samuel, Vukcevic, Damjan, Barnes, Chris, Conrad, Donald F., Giannoulatou, Eleni, Holmes, Chris, Marchini, Jonathan L., Stirrups, Kathy, Tobin, Martin D., Wain, Louise V., Yau, Chris, Aerts, Jan, Ahmad, Tariq, Daniel Andrews, T., Arbury, Hazel, Attwood, Anthony, Auton, Adam, Ball, Stephen G., Balmforth, Anthony J., Barrett, Jeffrey C., Barroso, Inês, Barton, Anne, Bennett, Amanda J., Bhaskar, Sanjeev, Blaszczyk, Katarzyna, Bowes, John, Brand, Oliver J., Braund, Peter S., Bredin, Francesca, Breen, Gerome, Brown, Morris J., Bruce, Ian N., Bull, Jaswinder, Burren, Oliver S., Burton, John, Byrnes, Jake, Caesar, Sian, Clee, Chris M., Coffey, Alison J., Connell, John M. C., Cooper, Jason D., Dominiczak, Anna F., Downes, Kate, Drummond, Hazel E., Dudakia, Darshna, Dunham, Andrew, Ebbs, Bernadette, Eccles, Diana, Edkins, Sarah, Edwards, Cathryn, Elliot, Anna, Emery, Paul, Evans, David M., Evans, Gareth, Eyre, Steve, Farmer, Anne, Nicol Ferrier, I., Feuk, Lars, Fitzgerald, Tomas, Flynn, Edward, Forbes, Alistair, Forty, Liz, Franklyn, Jayne A., Freathy, Rachel M., Gibbs, Polly, Gilbert, Paul, Gokumen, Omer, Gordon-Smith, Katherine, Gray, Emma, Green, Elaine, Groves, Chris J., Grozeva, Detelina, Gwilliam, Rhian, Hall, Anita, Hammond, Naomi, Hardy, Matt, Harrison, Pile, Hassanali, Neelam, Hebaishi, Husam, Hines, Sarah, Hinks, Anne, Hitman, Graham A, Hocking, Lynne, Howard, Eleanor, Howard, Philip, Howson, Joanna M. M., Hughes, Debbie, Hunt, Sarah, Isaacs, John D., Jain, Mahim, Jewell, Derek P., Johnson, Toby, Jolley, Jennifer D., Jones, Ian R., Jones, Lisa A., Kirov, George, Langford, Cordelia F., Lango-Allen, Hana, Mark Lathrop, G., Lee, James, Lee, Kate L., Lees, Charlie, Lewis, Kevin, Lindgren, Cecilia M., Maisuria-Armer, Meeta, Maller, Julian, Mansfield, John, Martin, Paul, Massey, Dunecan C. O., McArdle, Wendy L., McGuffin, Peter, McLay, Kirsten E., Mentzer, Alex, Mimmack, Michael L., Morgan, Ann E., Morris, Andrew P., Mowat, Craig, Myers, Simon, Newman, William, Nimmo, Elaine R., O’Donovan, Michael C., Onipinla, Abiodun, Onyiah, Ifejinelo, Ovington, Nigel R., Owen, Michael J., Palin, Kimmo, Parnell, Kirstie, Pernet, David, Perry, John R. B., Phillips, Anne, Pinto, Dalila, Prescott, Natalie J., Prokopenko, Inga, Quail, Michael A., Rafelt, Suzanne, Rayner, Nigel W., Redon, Richard, Reid, David M., Renwick, Anthony, Ring, Susan M., Robertson, Neil, Russell, Ellie, St Clair, David, Sambrook, Jennifer G., Sanderson, Jeremy D., Schuilenburg, Helen, Scott, Carol E., Scott, Richard, Seal, Sheila, Shaw-Hawkins, Sue, Shields, Beverley M., Simmonds, Matthew J., Smyth, Debbie J., Somaskantharajah, Elilan, Spanova, Katarina, Steer, Sophia, Stephens, Jonathan, Stevens, Helen E., Stone, Millicent A., Su, Zhan, Symmons, Deborah P. M., Thompson, John R., Thomson, Wendy, Travers, Mary E., Turnbull, Clare, Valsesia, Armand, Walker, Mark, Walker, Neil M., Wallace, Chris, Warren-Perry, Margaret, Watkins, Nicholas A., Webster, John, Weedon, Michael N., Wilson, Anthony G., Woodburn, Matthew, Wordsworth, Paul B., Young, Allan H., Zeggini, Eleftheria, Carter, Nigel P., Frayling, Timothy M., Lee, Charles, McVean, Gil, Munroe, Patricia B., Palotie, Aarno, Sawcer, Stephen J., Scherer, Stephen W., Strachan, David P., Tyler-Smith, Chris, Brown, Matthew A., Burton, Paul R., Caulfield, Mark J., Compston, Alastair, Farrall, Martin, Gough, Stephen C. L., Hall, Alistair S., Hattersley, Andrew T., Hill, Adrian V. S., Mathew, Christopher G., Pembrey, Marcus, Satsangi, Jack, Stratton, Michael R., Worthington, Jane, Deloukas, Panos, Duncanson, Audrey, Kwiatkowski, Dominic P., McCarthy, Mark I., Ouwehand, Willem H., Parkes, Miles, Rahman, Nazneen, Todd, John A., Samani, Nilesh J., and Donnelly, Peter

Published
2010
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12. Association of the thyroid stimulating hormone receptor gene (TSHR) with Gravesʼ disease

Author

Brand, Oliver J., Barrett, Jeffrey C., Simmonds, Matthew J., Newby, Paul R., McCabe, Christopher J., Bruce, Christopher K., Kysela, Boris, Carr-Smith, Jackie D., Brix, Thomas, Hunt, Penny J., Wiersinga, Wilmar M., Hegedüs, Laszlo, Connell, John, Wass, John A.H., Franklyn, Jayne A., Weetman, Anthony P., Heward, Joanne M., and Gough, Stephen C.L.

Published
2009

15. Suberanilohydroxamic acid prevents TGF-?1-induced COX-2 repression in human lung fibroblasts post-transcriptionally by TIA-1 downregulation

Author

Pasini, Alice, Brand, Oliver J., Jenkins, Gisli, Knox, Alan J., and Pang, Linhua

Subjects
Histone deacetylase inhibitor, epigenetics, Post-transcriptional regulation, Transforming growth factor ?1 (TGF-?1), Pulmonary fibrosis, Cyclooxygenase 2 (COX-2)
Abstract

Cyclooxygenase-2 (COX-2), with its main antifibrotic metabolite PGE, is regarded as an antifibrotic gene. Repressed COX-2 expression and deficient PGE have been shown to contribute to the activation of lung fibroblasts and excessive deposition of collagen in pulmonary fibrosis. We have previously demonstrated that COX-2 expression in lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) is epigenetically silenced and can be restored by epigenetic inhibitors. This study aimed to investigate whether COX-2 downregulation induced by the profibrotic cytokine transforming growth factor-?1 (TGF-?1) in normal lung fibroblasts could be prevented by epigenetic inhibitors. We found that COX-2 protein expression and PGE production were markedly reduced by TGF-?1 and this was prevented by the pan-histone deacetylase inhibitor suberanilohydroxamic acid (SAHA) and to a lesser extent by the DNA demethylating agent Decitabine (DAC), but not by the G9a histone methyltransferase (HMT) inhibitor BIX01294 or the EZH2 HMT inhibitor 3-deazaneplanocin A (DZNep). However, chromatin immunoprecipitation assay revealed that the effect of SAHA was unlikely mediated by histone modifications. Instead 3'-untranslated region (3'-UTR) luciferase reporter assay indicated the involvement of post-transcriptional mechanisms. This was supported by the downregulation by SAHA of the 3'-UTR mRNA binding protein TIA-1 (T-cell intracellular antigen-1), a negative regulator of COX-2 translation. Furthermore, TIA-1 knockdown by siRNA mimicked the effect of SAHA on COX-2 expression. These findings suggest SAHA can prevent TGF-?1-induced COX-2 repression in lung fibroblasts post-transcriptionally through a novel TIA-1-dependent mechanism and provide new insights into the mechanisms underlying its potential antifibrotic activity.

Published
2018

16. Defective lung function following influenza virus is due to prolonged, reversible hyaluronan synthesis

Author

Bell, Thomas J., Brand, Oliver J., Morgan, David J., Salek-Ardakani, Samira, Jagger, Christopher, Fujimori, Toshifumi, Cholewa, Lauren, Tilakaratna, Viranga, Östling, Jörgen, Thomas, Matt, Day, Anthony J., Snelgrove, Robert J., and Hussell, Tracy

Subjects
HA, hyaluronan, Article, Mice, Pulmonary Disease, Chronic Obstructive, Influenza A Virus, H1N1 Subtype, Alpha-Globulins, Influenza, Human, Animals, Humans, Hyaluronic Acid, Lung, Inflammation, Matrix, HYAL, hyaluronidase, Macrophages, Endothelial Cells, Epithelial Cells, Fibroblasts, Lung function, Influenza, Respiratory Function Tests, Hyaluronan Receptors, inflammation, 4MU, 4-methylumbelliferone, Female, Has2, HA synthase 2, Cell Adhesion Molecules, Hyaluronan Synthases
Abstract

Little is known about the impact of viral infections on lung matrix despite its important contribution to mechanical stability and structural support. The composition of matrix also indirectly controls inflammation by influencing cell adhesion, migration, survival, proliferation and differentiation. Hyaluronan is a significant component of the lung extracellular matrix and production and degradation must be carefully balanced. We have discovered an imbalance in hyaluronan production following resolution of a severe lung influenza virus infection, driven by hyaluronan synthase 2 from epithelial cells, endothelial cells and fibroblasts. Furthermore hyaluronan is complexed with inter-α-inhibitor heavy chains due to elevated TNF-stimulated gene 6 expression and sequesters CD44-expressing macrophages. We show that intranasal administration of exogenous hyaluronidase is sufficient to release inter-α-inhibitor heavy chains, reduce lung hyaluronan content and restore lung function. Hyaluronidase is already used to facilitate dispersion of co-injected materials in the clinic. It is therefore feasible that fibrotic changes following severe lung infection and inflammation could be overcome by targeting abnormal matrix production., Highlights • Influenza causes prolonged changes in hyaluronan due to increased synthase activity • Influenza induces persistent hyaluronan cross-linking by inter-alpha-inhibitor heavy chains • Pockets of persistent hyaluronan are associated with CD44-expressing macrophages • Digestion of hyaluronan with intranasal hyaluronidase restores lung function but upon cessation of treatment post-viral complications return

Published
2018

17. Sensing of apoptotic cells through Axl causes lung basal cell proliferation in inflammatory diseases

Author

Fujino, Naoya, primary, Brand, Oliver J., additional, Morgan, David J., additional, Fujimori, Toshifumi, additional, Grabiec, Aleksander M., additional, Jagger, Christopher P., additional, Maciewicz, Rose A., additional, Yamada, Mitsuhiro, additional, Itakura, Koji, additional, Sugiura, Hisatoshi, additional, Ichinose, Masakazu, additional, and Hussell, Tracy, additional

Published
2019
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18. Defective lung function following influenza virus is due to prolonged, reversible hyaluronan synthesis

Author

Bell, Thomas J., primary, Brand, Oliver J., additional, Morgan, David J., additional, Salek-Ardakani, Samira, additional, Jagger, Christopher, additional, Fujimori, Toshifumi, additional, Cholewa, Lauren, additional, Tilakaratna, Viranga, additional, Östling, Jörgen, additional, Thomas, Matt, additional, Day, Anthony J., additional, Snelgrove, Robert J., additional, and Hussell, Tracy, additional

Published
2019
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20. Effect of epigenetic inhibitors on lung fibroblast phenotype change in idiopathic pulmonary fibrosis

Author

Pasini, Alice, Brand, Oliver J., Jenkins, Gisli, Knox, Alan J., and Pang, Linhua

Abstract

Introduction and objectives: Idiopathic Pulmonary Fibrosis (IFP) is a fatal interstitial lung disease with unknown aetiology. Lung myofibroblasts (activated fibrobalsts) are the major effector cells in the pathogenesis of IPF. Transforming growth factor-β (TGF-β1) is a potent activator of fibroblasts. Lack of effective treatment options necessitates novel therapeutic approaches. Epigenetic drugs, by inhibiting chromatin modifying enzymes involved in gene expression control, represent promising agents capable of modulating the cellular phenotype. We previously demonstrated that the cyclooxygenase-2 (COX-2) gene is epigenetically silenced in lung fibroblasts from IPF patients (F-IPF)[1] and epigenetic inhibitors and restore COX-2 expression. However, whether epigenetic inhibitors can alter fibroblast phenotype remains unknown. This study aimed to investigate the effect of four different epigenetic enzyme inhibitors on fibroblast phenotype change in IPF. Methods: F-IPF and fibroblasts from non-fibrotic lung (F-NL) treated with TGF-β1 were cultured to test the effects of the epigenetic inhibitors BIX01294 (BIX, G9a histone methyltransferase inhibitor), 3- deazaneplanocin A (DZNep, EZH2 histone methyltransferase inhibitor), SAHA (histone deacetylases inhibitor) and Decitabine (DAC, DNA demethylating agent), in comparison with the COX-2 products prostaglandin E2 (PGE2). The expression of COX-2 and myofibroblast markers collagen 1 (COL1) and α- smooth muscle actin (α-SMA) was assessed. The COX-2 DNA promoter methylation level was analysed by bisulfite sequencing. Results: TGF-β1 induced a myofibroblast phenotype in F-NL characterised by COL1 and α-SMA upregulation and COX-2 downregulation, similar to F-IPF. PGE2 and SAHA were able to maintain/restore COX-2 expression in TGF-β1-induced myofibroblasts and F-IPF. DAC demonstrated similar effect in TGF-β1 treated F-NL only. SAHA also reduced COL1 and α-SMA expression. But DZNep and BIX showed no effect. No differences in the COX-2 promoter methylation was detected between F-NL and F-IPF. Conclusions: Among the epigenetic inhibitors tested, SAHA shows a promising antifibrotic effect by inhibiting fibroblast activation and the underlying molecular mechanisms are currently under investigation.

Published
2016

23. Suberanilohydroxamic acid (SAHA) inhibits collagen deposition in a transforming growth factor β1-driven precision cut lung slice (PCLS) model of pulmonary fibrosis

Author

Brand, Oliver J., Pasini, Alice, Habgood, Antony, Knox, Alan J., Jenkins, Gisli, and Pang, Linhua

Abstract

Introduction and Objectives: Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive interstitial lung disease that is refractory to current treatment options. Transforming growth factor (TGF)-β1 is a key pro-fibrotic cytokine that plays a crucial role in IPF pathogenesis. Our group previously demonstrated distinct epigenetic modifications involved in repression of the antifibrotic gene cyclooxygenase-2 (COX-2) in fibroblasts from IPF (F-IPF) lungs compared with fibroblasts from non-fibrotic lungs (F-NL). Epigenetic drugs capable of inhibiting DNA and histone modifications may, therefore, represent a putative novel therapy. The aim of this study was to investigate the ability of 4 epigenetic inhibitors to regulate TGF-β-driven fibrosis in ex vivo mouse lung. Methods: A precision-cut lung slice (PCLS) model of fibrosis was established using the previously described [1] CC10-tTS-rtTA-TGFβ1 transgenic (tgTGF-β1) mouse. The model was first assessed by investigating PCLS overexpression of TGF-β1 in response to stimulation of the transgene by doxycycline treatment. Gene expression of COX-2 and fibrotic markers including collagen were assessed after 4 days of treatment. The anti-fibrotic potential of 4 epigenetic inhibitors; BIX01294 (BIX, inhibitor of G9a histone methyltransferase), 3-deazaneplanocin A (DZNep, inhibitor of EZH2 histone methyltransferase), SAHA (inhibitor of histone deacetylases, HDACs) and Decitabine (DAC, DNA demethylating agent) was investigated. Viability of PCLS was assessed by MTT and Prestoblue® viability assay. Results: Treatment of PCLS from tgTGF-β1 mice with doxycycline induced a concentration-dependent increase in global TGF-β1, pro-fibrotic markers including collagen and pro-inflammatory COX-2, which was comparable to recombinant TGF-β1 treatment. Treatment with three of the epigenetic inhibitors BIX01294, DZNep and DAC did not reduce the pro-fibrotic response following doxycycline treatment. However SAHA demonstrated a significant suppressive effect on COX-2 and collagen expression, while not directly affecting TGF-β1 transgene expression. Conclusions: The data suggests that SAHA has the potential to reduce fibrosis in a TGF-β1 driven model of pulmonary fibrosis. Further work is currently underway to assess the anti-fibrotic potential of this drug in tgTGF-β1 animals.

Published
2016

24. A Method to Exploit the Structure of Genetic Ancestry Space to Enhance Case-Control Studies

Author

Bodea, Corneliu A., primary, Neale, Benjamin M., additional, Ripke, Stephan, additional, Daly, Mark J., additional, Devlin, Bernie, additional, Roeder, Kathryn, additional, Barclay, Murray, additional, Peyrin-Biroulet, Laurent, additional, Chamaillard, Mathias, additional, Colombel, Jean-Frederick, additional, Cottone, Mario, additional, Croft, Anthony, additional, D’Incà, Renata, additional, Halfvarson, Jonas, additional, Hanigan, Katherine, additional, Henderson, Paul, additional, Hugot, Jean-Pierre, additional, Karban, Amir, additional, Kennedy, Nicholas A., additional, Khan, Mohammed Azam, additional, Lémann, Marc, additional, Levine, Arie, additional, Massey, Dunecan, additional, Milla, Monica, additional, Montgomery, Grant W., additional, Ng, Sok Meng Evelyn, additional, Oikonomou, Ioannis, additional, Peeters, Harald, additional, Proctor, Deborah D., additional, Rahier, Jean-Francois, additional, Roberts, Rebecca, additional, Rutgeerts, Paul, additional, Seibold, Frank, additional, Stronati, Laura, additional, Taylor, Kirstin M., additional, Törkvist, Leif, additional, Ublick, Kullak, additional, Van Limbergen, Johan, additional, Van Gossum, Andre, additional, Vatn, Morten H., additional, Zhang, Hu, additional, Zhang, Wei, additional, Andrews, Jane M., additional, Bampton, Peter A., additional, Florin, Timothy H., additional, Gearry, Richard, additional, Krishnaprasad, Krupa, additional, Lawrance, Ian C., additional, Mahy, Gillian, additional, Radford-Smith, Graham, additional, Roberts, Rebecca L., additional, Simms, Lisa A., additional, Amininijad, Leila, additional, Cleynen, Isabelle, additional, Dewit, Olivier, additional, Franchimont, Denis, additional, Georges, Michel, additional, Laukens, Debby, additional, Theatre, Emilie, additional, Van Gossum, André, additional, Vermeire, Severine, additional, Aumais, Guy, additional, Baidoo, Leonard, additional, Barrie, Arthur M., additional, Beck, Karen, additional, Bernard, Edmond-Jean, additional, Binion, David G., additional, Bitton, Alain, additional, Brant, Steve R., additional, Cho, Judy H., additional, Cohen, Albert, additional, Croitoru, Kenneth, additional, Datta, Lisa W., additional, Deslandres, Colette, additional, Duerr, Richard H., additional, Dutridge, Debra, additional, Ferguson, John, additional, Fultz, Joann, additional, Goyette, Philippe, additional, Greenberg, Gordon R., additional, Haritunians, Talin, additional, Jobin, Gilles, additional, Katz, Seymour, additional, Lahaie, Raymond G., additional, McGovern, Dermot P., additional, Nelson, Linda, additional, Ng, Sok Meng, additional, Ning, Kaida, additional, Paré, Pierre, additional, Regueiro, Miguel D., additional, Rioux, John D., additional, Ruggiero, Elizabeth, additional, Schumm, L. Philip, additional, Schwartz, Marc, additional, Scott, Regan, additional, Sharma, Yashoda, additional, Silverberg, Mark S., additional, Spears, Denise, additional, Steinhart, A. Hillary, additional, Stempak, Joanne M., additional, Swoger, Jason M., additional, Tsagarelis, Constantina, additional, Zhang, Clarence, additional, Zhao, Hongyu, additional, Aerts, Jan, additional, Ahmad, Tariq, additional, Arbury, Hazel, additional, Attwood, Anthony, additional, Auton, Adam, additional, Ball, Stephen G., additional, Balmforth, Anthony J., additional, Barnes, Chris, additional, Barrett, Jeffrey C., additional, Barroso, Inês, additional, Barton, Anne, additional, Bennett, Amanda J., additional, Bhaskar, Sanjeev, additional, Blaszczyk, Katarzyna, additional, Bowes, John, additional, Brand, Oliver J., additional, Braund, Peter S., additional, Bredin, Francesca, additional, Breen, Gerome, additional, Brown, Morris J., additional, Bruce, Ian N., additional, Bull, Jaswinder, additional, Burren, Oliver S., additional, Burton, John, additional, Byrnes, Jake, additional, Caesar, Sian, additional, Cardin, Niall, additional, Clee, Chris M., additional, Coffey, Alison J., additional, Connell, John M.C., additional, Conrad, Donald F., additional, Cooper, Jason D., additional, Dominiczak, Anna F., additional, Downes, Kate, additional, Drummond, Hazel E., additional, Dudakia, Darshna, additional, Dunham, Andrew, additional, Ebbs, Bernadette, additional, Eccles, Diana, additional, Edkins, Sarah, additional, Edwards, Cathryn, additional, Elliot, Anna, additional, Emery, Paul, additional, Evans, David M., additional, Evans, Gareth, additional, Eyre, Steve, additional, Farmer, Anne, additional, Ferrier, Nicol, additional, Flynn, Edward, additional, Forbes, Alistair, additional, Forty, Liz, additional, Franklyn, Jayne A., additional, Frayling, Timothy M., additional, Freathy, Rachel M., additional, Giannoulatou, Eleni, additional, Gibbs, Polly, additional, Gilbert, Paul, additional, Gordon-Smith, Katherine, additional, Gray, Emma, additional, Green, Elaine, additional, Groves, Chris J., additional, Grozeva, Detelina, additional, Gwilliam, Rhian, additional, Hall, Anita, additional, Hammond, Naomi, additional, Hardy, Matt, additional, Harrison, Pile, additional, Hassanali, Neelam, additional, Hebaishi, Husam, additional, Hines, Sarah, additional, Hinks, Anne, additional, Hitman, Graham A., additional, Hocking, Lynne, additional, Holmes, Chris, additional, Howard, Eleanor, additional, Howard, Philip, additional, Howson, Joanna M.M., additional, Hughes, Debbie, additional, Hunt, Sarah, additional, Isaacs, John D., additional, Jain, Mahim, additional, Jewell, Derek P., additional, Johnson, Toby, additional, Jolley, Jennifer D., additional, Jones, Ian R., additional, Jones, Lisa A., additional, Kirov, George, additional, Langford, Cordelia F., additional, Lango-Allen, Hana, additional, Lathrop, G. Mark, additional, Lee, James, additional, Lee, Kate L., additional, Lees, Charlie, additional, Lewis, Kevin, additional, Lindgren, Cecilia M., additional, Maisuria-Armer, Meeta, additional, Maller, Julian, additional, Mansfield, John, additional, Marchini, Jonathan L., additional, Martin, Paul, additional, Massey, Dunecan C.O., additional, McArdle, Wendy L., additional, McGuffin, Peter, additional, McLay, Kirsten E., additional, McVean, Gil, additional, Mentzer, Alex, additional, Mimmack, Michael L., additional, Morgan, Ann E., additional, Morris, Andrew P., additional, Mowat, Craig, additional, Munroe, Patricia B., additional, Myers, Simon, additional, Newman, William, additional, Nimmo, Elaine R., additional, O’Donovan, Michael C., additional, Onipinla, Abiodun, additional, Ovington, Nigel R., additional, Owen, Michael J., additional, Palin, Kimmo, additional, Palotie, Aarno, additional, Parnell, Kirstie, additional, Pearson, Richard, additional, Pernet, David, additional, Perry, John R.B., additional, Phillips, Anne, additional, Plagnol, Vincent, additional, Prescott, Natalie J., additional, Prokopenko, Inga, additional, Quail, Michael A., additional, Rafelt, Suzanne, additional, Rayner, Nigel W., additional, Reid, David M., additional, Renwick, Anthony, additional, Ring, Susan M., additional, Robertson, Neil, additional, Robson, Samuel, additional, Russell, Ellie, additional, St Clair, David, additional, Sambrook, Jennifer G., additional, Sanderson, Jeremy D., additional, Sawcer, Stephen J., additional, Schuilenburg, Helen, additional, Scott, Carol E., additional, Scott, Richard, additional, Seal, Sheila, additional, Shaw-Hawkins, Sue, additional, Shields, Beverley M., additional, Simmonds, Matthew J., additional, Smyth, Debbie J., additional, Somaskantharajah, Elilan, additional, Spanova, Katarina, additional, Steer, Sophia, additional, Stephens, Jonathan, additional, Stevens, Helen E., additional, Stirrups, Kathy, additional, Stone, Millicent A., additional, Strachan, David P., additional, Su, Zhan, additional, Symmons, Deborah P.M., additional, Thompson, John R., additional, Thomson, Wendy, additional, Tobin, Martin D., additional, Travers, Mary E., additional, Turnbull, Clare, additional, Vukcevic, Damjan, additional, Wain, Louise V., additional, Walker, Mark, additional, Walker, Neil M., additional, Wallace, Chris, additional, Warren-Perry, Margaret, additional, Watkins, Nicholas A., additional, Webster, John, additional, Weedon, Michael N., additional, Wilson, Anthony G., additional, Woodburn, Matthew, additional, Wordsworth, B. Paul, additional, Yau, Chris, additional, Young, Allan H., additional, Zeggini, Eleftheria, additional, Brown, Matthew A., additional, Burton, Paul R., additional, Caulfield, Mark J., additional, Compston, Alastair, additional, Farrall, Martin, additional, Gough, Stephen C.L., additional, Hall, Alistair S., additional, Hattersley, Andrew T., additional, Hill, Adrian V.S., additional, Mathew, Christopher G., additional, Pembrey, Marcus, additional, Satsangi, Jack, additional, Stratton, Michael R., additional, Worthington, Jane, additional, Hurles, Matthew E., additional, Duncanson, Audrey, additional, Ouwehand, Willem H., additional, Parkes, Miles, additional, Rahman, Nazneen, additional, Todd, John A., additional, Samani, Nilesh J., additional, Kwiatkowski, Dominic P., additional, McCarthy, Mark I., additional, Craddock, Nick, additional, Deloukas, Panos, additional, Donnelly, Peter, additional, Blackwell, Jenefer M., additional, Bramon, Elvira, additional, Casas, Juan P., additional, Corvin, Aiden, additional, Jankowski, Janusz, additional, Markus, Hugh S., additional, Palmer, Colin N.A., additional, Plomin, Robert, additional, Rautanen, Anna, additional, Trembath, Richard C., additional, Viswanathan, Ananth C., additional, Wood, Nicholas W., additional, Spencer, Chris C.A., additional, Band, Gavin, additional, Bellenguez, Céline, additional, Freeman, Colin, additional, Hellenthal, Garrett, additional, Pirinen, Matti, additional, Strange, Amy, additional, Blackburn, Hannah, additional, Bumpstead, Suzannah J., additional, Dronov, Serge, additional, Gillman, Matthew, additional, Jayakumar, Alagurevathi, additional, McCann, Owen T., additional, Liddle, Jennifer, additional, Potter, Simon C., additional, Ravindrarajah, Radhi, additional, Ricketts, Michelle, additional, Waller, Matthew, additional, Weston, Paul, additional, Widaa, Sara, additional, and Whittaker, Pamela, additional

Published
2016
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25. Skewing of Female X-Chromosome Inactivation

Author

Simmonds, Matthew J., primary, Benavente, David, additional, Brand, Oliver J., additional, Moore, Jason, additional, Ball, Simon, additional, Ferro, Charles J., additional, Briggs, David, additional, Gough, Stephen C.L., additional, and Borrows, Richard J., additional

Published
2013
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26. Donor ABCB1 Variant Associates with Increased Risk for Kidney Allograft Failure

Author

Moore, Jason, primary, McKnight, Amy Jayne, additional, Döhler, Bernd, additional, Simmonds, Matthew J., additional, Courtney, Aisling E., additional, Brand, Oliver J., additional, Briggs, David, additional, Ball, Simon, additional, Cockwell, Paul, additional, Patterson, Christopher C., additional, Maxwell, Alexander P., additional, Gough, Stephen C.L., additional, Opelz, Gerhard, additional, and Borrows, Richard, additional

Published
2012
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28. Thyroid Stimulating Hormone Receptor (TSHR) Intron 1 Variants Are Major Risk Factors for Graves' Disease in Three European Caucasian Cohorts

Author

Płoski, Rafał, primary, Brand, Oliver J., additional, Jurecka-Lubieniecka, Beata, additional, Franaszczyk, Maria, additional, Kula, Dorota, additional, Krajewski, Paweł, additional, Karamat, Muhammad A., additional, Simmonds, Matthew J., additional, Franklyn, Jayne A., additional, Gough, Stephen C. L., additional, Jarząb, Barbara, additional, and Bednarczuk, Tomasz, additional

Published
2010
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29. Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behçet's disease

Author

Remmers, Elaine F, primary, Cosan, Fulya, additional, Kirino, Yohei, additional, Ombrello, Michael J, additional, Abaci, Neslihan, additional, Satorius, Colleen, additional, Le, Julie M, additional, Yang, Barbara, additional, Korman, Benjamin D, additional, Cakiris, Aris, additional, Aglar, Oznur, additional, Emrence, Zeliha, additional, Azakli, Hulya, additional, Ustek, Duran, additional, Tugal-Tutkun, Ilknur, additional, Akman-Demir, Gulsen, additional, Chen, Wei, additional, Amos, Christopher I, additional, Dizon, Michael B, additional, Kose, Afet Akdag, additional, Azizlerli, Gulsevim, additional, Erer, Burak, additional, Brand, Oliver J, additional, Kaklamani, Virginia G, additional, Kaklamanis, Phaedon, additional, Ben-Chetrit, Eldad, additional, Stanford, Miles, additional, Fortune, Farida, additional, Ghabra, Marwen, additional, Ollier, William E R, additional, Cho, Young-Hun, additional, Bang, Dongsik, additional, O'Shea, John, additional, Wallace, Graham R, additional, Gadina, Massimo, additional, Kastner, Daniel L, additional, and Gül, Ahmet, additional

Published
2010
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35. Follow-up of potential novel Graves' disease susceptibility loci, identified in the UK WTCCC genome-wide nonsynonymous SNP study.

Author

Newby, Paul R., Pickles, Oliver J., Mazumdar, Samaresh, Brand, Oliver J., Carr-Smith, Jaqueline D., Pearce, Simon H. S., Franklyn, Jayne A., Evans, David M., Simmonds, Matthew J., and Gough, Stephen C. L.

Subjects
GRAVES' disease, GENOMES, NUCLEOTIDES, GENETIC polymorphisms
Abstract

A recent association scan using a genome-wide set of nonsynonymous coding single-nucleotide polymorphisms (nsSNPs) conducted in four diseases including Graves' disease (GD), identified nine novel possible regions of association with GD. We used a case–control approach in an attempt to replicate association of these nine regions in an independent collection of 1578 British GD patients and 1946 matched Caucasian controls. Although none of these loci showed evidence of association with GD in the independent data set, when combined with the original Wellcome Trust Case–Control Consortium study group, minor differences in allele frequencies (P10−3) remained in the combined collection of 5924 subjects for four of the nsSNPs, present within HDLBP, TEKT1, JSRP1 and UTX. An additional 29 Tag SNPs were screened within these four gene regions to determine if further associations could be detected. Similarly, minor differences only (P=0.042–0.002) were detected in two HDLBP and two TEKT1 Tag SNPs in the combined UK GD collection. In conclusion, it is unlikely that the SNPs selected in this replication study have a significant effect on the risk of GD in the United Kingdom. Our study confirms the need for large data sets and stringent analysis criteria when searching for susceptibility loci in common diseases. [ABSTRACT FROM AUTHOR]

Published
2010
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36. Association of the interleukin-2 receptor alpha ( IL-2Rα)/ CD25 gene region with Graves’ disease using a multilocus test and tag SNPs.

Author

Brand, Oliver J., Lowe, Christopher E., Heward, Joanne M., Franklyn, Jayne A., Cooper, Jason D., Todd, John A., and Gough, Stephen C. L.

Subjects
*INTERLEUKIN-2, *GRAVES' disease, *AUTOIMMUNE diseases, *GENETIC polymorphisms, *T cells, *LYMPHOCYTES
Abstract

Objective A small number of immune response genes have been consistently associated with the common autoimmune conditions. Recently, a linkage disequilibrium (LD) mapping approach, using tag single nucleotide polymorphisms (SNPs), identified genetic association between type 1 diabetes (T1D) and the interleukin-2 receptor alpha ( IL-2Rα)/ CD25 gene region on chromosome 10p15. Because certain autoimmune diseases, such as autoimmune thyroid disease (AITD) and T1D cluster together in certain families, we sought to determine if the TID-associated CD25 region was also associated with Graves’ disease (GD). Design We performed a case-control association study of 20 tag SNPs. Patients 1896 GD patients were collected from seven major centres in the UK and 1822 geographically matched controls from the 1958 British Birth Cohort. Measurements The 20 tag SNPs were analysed using a multilocus test to identify an association between GD and the CD25 region. Odds ratios (ORs) were calculated for the tag SNPs, allowing a comparison with previous results for T1D. Results The multilocus test provided statistical evidence of an association between GD and the CD25 region ( P = 4·5 × 10−4), with the pattern of association of the 20 tag SNPs similar to that found in T1D. Conclusions Association with GD, as well as that previously reported with T1D, suggests that the CD25 region is acting as a general susceptibility locus for autoimmune disease, and is consistent with a major role for the IL-2-receptor pathway in the development and function of T cells in the control of autoimmunity. [ABSTRACT FROM AUTHOR]

Published
2007
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37. Rare and functional SIAE variants are not associated with autoimmune disease risk in up to 66,924 individuals of European ancestry.

Author

Hunt, Karen A, Smyth, Deborah J, Balschun, Tobias, Ban, Maria, Mistry, Vanisha, Ahmad, Tariq, Anand, Vidya, Barrett, Jeffrey C, Bhaw-Rosun, Leena, Bockett, Nicholas A, Brand, Oliver J, Brouwer, Elisabeth, Concannon, Patrick, Cooper, Jason D, Dias, Kerith-Rae M, van Diemen, Cleo C, Dubois, Patrick C, Edkins, Sarah, Fölster-Holst, Regina, and Fransen, Karin

Subjects
LETTERS to the editor, SIALIC acids, ACETYLESTERASE
Abstract

A letter to the editor is presented in response to the article which discusses the study conducted by I. Surolia and colleagues, on the disassociation of sialic acid acetylesterase (SIAE) with immunie disease in European ancestry.

Published
2012
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38. Comparative performances of machine learning methods for classifying Crohn Disease patients using genome-wide genotyping data

Author

Romagnoni, Alberto, Jégou, Simon, Van Steen, Kristel, Wainrib, Gilles, Hugot, Jean-Pierre, Peyrin-Biroulet, Laurent, Chamaillard, Mathias, Colombel, Jean-Frederick, Cottone, Mario, D’Amato, Mauro, D’Incà, Renata, Halfvarson, Jonas, Henderson, Paul, Karban, Amir, Kennedy, Nicholas A., Khan, Mohammed Azam, Lémann, Marc, Levine, Arie, Massey, Dunecan, Milla, Monica, Ng, Sok Meng Evelyn, Oikonomou, Ioannis, Peeters, Harald, Proctor, Deborah D., Rahier, Jean-Francois, Rutgeerts, Paul, Seibold, Frank, Stronati, Laura, Taylor, Kirstin M., Törkvist, Leif, Ublick, Kullak, Van Limbergen, Johan, Van Gossum, Andre, Vatn, Morten H., Zhang, Hu, Zhang, Wei, Andrews, Jane M., Bampton, Peter A., Barclay, Murray, Florin, Timothy H., Gearry, Richard, Krishnaprasad, Krupa, Lawrance, Ian C., Mahy, Gillian, Montgomery, Grant W., Radford-Smith, Graham, Roberts, Rebecca L., Simms, Lisa A., Hanigan, Katherine, Croft, Anthony, Amininijad, Leila, Cleynen, Isabelle, Dewit, Olivier, Franchimont, Denis, Georges, Michel, Laukens, Debby, Theatre, Emilie, Van Gossum, André, Vermeire, Severine, Aumais, Guy, Baidoo, Leonard, Barrie, Arthur M., Beck, Karen, Bernard, Edmond-Jean, Binion, David G., Bitton, Alain, Brant, Steve R., Cho, Judy H., Cohen, Albert, Croitoru, Kenneth, Daly, Mark J., Datta, Lisa W., Deslandres, Colette, Duerr, Richard H., Dutridge, Debra, Ferguson, John, Fultz, Joann, Goyette, Philippe, Greenberg, Gordon R., Haritunians, Talin, Jobin, Gilles, Katz, Seymour, Lahaie, Raymond G., McGovern, Dermot P., Nelson, Linda, Ng, Sok Meng, Ning, Kaida, Paré, Pierre, Regueiro, Miguel D., Rioux, John D., Ruggiero, Elizabeth, Schumm, L. Philip, Schwartz, Marc, Scott, Regan, Sharma, Yashoda, Silverberg, Mark S., Spears, Denise, Steinhart, A. Hillary, Stempak, Joanne M., Swoger, Jason M., Tsagarelis, Constantina, Zhang, Clarence, Zhao, Hongyu, Aerts, Jan, Ahmad, Tariq, Arbury, Hazel, Attwood, Anthony, Auton, Adam, Ball, Stephen G., Balmforth, Anthony J., Barnes, Chris, Barrett, Jeffrey C., Barroso, Inês, Barton, Anne, Bennett, Amanda J., Bhaskar, Sanjeev, Blaszczyk, Katarzyna, Bowes, John, Brand, Oliver J., Braund, Peter S., Bredin, Francesca, Breen, Gerome, Brown, Morris J., Bruce, Ian N., Bull, Jaswinder, Burren, Oliver S., Burton, John, Byrnes, Jake, Caesar, Sian, Cardin, Niall, Clee, Chris M., Coffey, Alison J., MC Connell, John, Conrad, Donald F., Cooper, Jason D., Dominiczak, Anna F., Downes, Kate, Drummond, Hazel E., Dudakia, Darshna, Dunham, Andrew, Ebbs, Bernadette, Eccles, Diana, Edkins, Sarah, Edwards, Cathryn, Elliot, Anna, Emery, Paul, Evans, David M., Evans, Gareth, Eyre, Steve, Farmer, Anne, Ferrier, I. Nicol, Flynn, Edward, Forbes, Alistair, Forty, Liz, Franklyn, Jayne A., Frayling, Timothy M., Freathy, Rachel M., Giannoulatou, Eleni, Gibbs, Polly, Gilbert, Paul, Gordon-Smith, Katherine, Gray, Emma, Green, Elaine, Groves, Chris J., Grozeva, Detelina, Gwilliam, Rhian, Hall, Anita, Hammond, Naomi, Hardy, Matt, Harrison, Pile, Hassanali, Neelam, Hebaishi, Husam, Hines, Sarah, Hinks, Anne, Hitman, Graham A., Hocking, Lynne, Holmes, Chris, Howard, Eleanor, Howard, Philip, Howson, Joanna M. M., Hughes, Debbie, Hunt, Sarah, Isaacs, John D., Jain, Mahim, Jewell, Derek P., Johnson, Toby, Jolley, Jennifer D., Jones, Ian R., Jones, Lisa A., Kirov, George, Langford, Cordelia F., Lango-Allen, Hana, Lathrop, G. Mark, Lee, James, Lee, Kate L., Lees, Charlie, Lewis, Kevin, Lindgren, Cecilia M., Maisuria-Armer, Meeta, Maller, Julian, Mansfield, John, Marchini, Jonathan L., Martin, Paul, Massey, Dunecan CO, McArdle, Wendy L., McGuffin, Peter, McLay, Kirsten E., McVean, Gil, Mentzer, Alex, Mimmack, Michael L., Morgan, Ann E., Morris, Andrew P., Mowat, Craig, Munroe, Patricia B., Myers, Simon, Newman, William, Nimmo, Elaine R., O’Donovan, Michael C., Onipinla, Abiodun, Ovington, Nigel R., Owen, Michael J., Palin, Kimmo, Palotie, Aarno, Parnell, Kirstie, Pearson, Richard, Pernet, David, Perry, John RB, Phillips, Anne, Plagnol, Vincent, Prescott, Natalie J., Prokopenko, Inga, Quail, Michael A., Rafelt, Suzanne, Rayner, Nigel W., Reid, David M., Renwick, Anthony, Ring, Susan M., Robertson, Neil, Robson, Samuel, Russell, Ellie, Clair, David St, Sambrook, Jennifer G., Sanderson, Jeremy D., Sawcer, Stephen J., Schuilenburg, Helen, Scott, Carol E., Scott, Richard, Seal, Sheila, Shaw-Hawkins, Sue, Shields, Beverley M., Simmonds, Matthew J., Smyth, Debbie J., Somaskantharajah, Elilan, Spanova, Katarina, Steer, Sophia, Stephens, Jonathan, Stevens, Helen E., Stirrups, Kathy, Stone, Millicent A., Strachan, David P., Su, Zhan, Symmons, Deborah P. M., Thompson, John R., Thomson, Wendy, Tobin, Martin D., Travers, Mary E., Turnbull, Clare, Vukcevic, Damjan, Wain, Louise V., Walker, Mark, Walker, Neil M., Wallace, Chris, Warren-Perry, Margaret, Watkins, Nicholas A., Webster, John, Weedon, Michael N., Wilson, Anthony G., Woodburn, Matthew, Wordsworth, B. Paul, Yau, Chris, Young, Allan H., Zeggini, Eleftheria, Brown, Matthew A., Burton, Paul R., Caulfield, Mark J., Compston, Alastair, Farrall, Martin, Gough, Stephen C. L., Hall, Alistair S., Hattersley, Andrew T., Hill, Adrian V. S., Mathew, Christopher G., Pembrey, Marcus, Satsangi, Jack, Stratton, Michael R., Worthington, Jane, Hurles, Matthew E., Duncanson, Audrey, Ouwehand, Willem H., Parkes, Miles, Rahman, Nazneen, Todd, John A., Samani, Nilesh J., Kwiatkowski, Dominic P., McCarthy, Mark I., Craddock, Nick, Deloukas, Panos, Donnelly, Peter, Blackwell, Jenefer M., Bramon, Elvira, Casas, Juan P., Corvin, Aiden, Jankowski, Janusz, Markus, Hugh S., Palmer, Colin NA, Plomin, Robert, Rautanen, Anna, Trembath, Richard C., Viswanathan, Ananth C., Wood, Nicholas W., Spencer, Chris C. A., Band, Gavin, Bellenguez, Céline, Freeman, Colin, Hellenthal, Garrett, Pirinen, Matti, Strange, Amy, Blackburn, Hannah, Bumpstead, Suzannah J., Dronov, Serge, Gillman, Matthew, Jayakumar, Alagurevathi, McCann, Owen T., Liddle, Jennifer, Potter, Simon C., Ravindrarajah, Radhi, Ricketts, Michelle, Waller, Matthew, Weston, Paul, Widaa, Sara, and Whittaker, Pamela

Subjects
692/4020/1503/257/1402, 45, 692/308/2056, 45/43, article, 129, 3. Good health
Abstract

Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers.

39. Suberanilohydroxamic acid (SAHA) inhibits collagen deposition in a transforming growth factor β1-driven precision cut lung slice (PCLS) model of pulmonary fibrosis

Author

Brand, Oliver J., Pasini, Alice, Habgood, Antony, Knox, Alan J., Jenkins, Gisli, Pang, Linhua, Brand, Oliver J., Pasini, Alice, Habgood, Antony, Knox, Alan J., Jenkins, Gisli, and Pang, Linhua

Abstract

Introduction and Objectives: Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive interstitial lung disease that is refractory to current treatment options. Transforming growth factor (TGF)-β1 is a key pro-fibrotic cytokine that plays a crucial role in IPF pathogenesis. Our group previously demonstrated distinct epigenetic modifications involved in repression of the antifibrotic gene cyclooxygenase-2 (COX-2) in fibroblasts from IPF (F-IPF) lungs compared with fibroblasts from non-fibrotic lungs (F-NL). Epigenetic drugs capable of inhibiting DNA and histone modifications may, therefore, represent a putative novel therapy. The aim of this study was to investigate the ability of 4 epigenetic inhibitors to regulate TGF-β-driven fibrosis in ex vivo mouse lung. Methods: A precision-cut lung slice (PCLS) model of fibrosis was established using the previously described [1] CC10-tTS-rtTA-TGFβ1 transgenic (tgTGF-β1) mouse. The model was first assessed by investigating PCLS overexpression of TGF-β1 in response to stimulation of the transgene by doxycycline treatment. Gene expression of COX-2 and fibrotic markers including collagen were assessed after 4 days of treatment. The anti-fibrotic potential of 4 epigenetic inhibitors; BIX01294 (BIX, inhibitor of G9a histone methyltransferase), 3-deazaneplanocin A (DZNep, inhibitor of EZH2 histone methyltransferase), SAHA (inhibitor of histone deacetylases, HDACs) and Decitabine (DAC, DNA demethylating agent) was investigated. Viability of PCLS was assessed by MTT and Prestoblue® viability assay. Results: Treatment of PCLS from tgTGF-β1 mice with doxycycline induced a concentration-dependent increase in global TGF-β1, pro-fibrotic markers including collagen and pro-inflammatory COX-2, which was comparable to recombinant TGF-β1 treatment. Treatment with three of the epigenetic inhibitors BIX01294, DZNep and DAC did not reduce the pro-fibrotic response following doxycycline treatment. However SAHA demonstrated a significant suppr

40. Effect of epigenetic inhibitors on lung fibroblast phenotype change in idiopathic pulmonary fibrosis

Author

Pasini, Alice, Brand, Oliver J., Jenkins, Gisli, Knox, Alan J., Pang, Linhua, Pasini, Alice, Brand, Oliver J., Jenkins, Gisli, Knox, Alan J., and Pang, Linhua

Abstract

Introduction and objectives: Idiopathic Pulmonary Fibrosis (IFP) is a fatal interstitial lung disease with unknown aetiology. Lung myofibroblasts (activated fibrobalsts) are the major effector cells in the pathogenesis of IPF. Transforming growth factor-β (TGF-β1) is a potent activator of fibroblasts. Lack of effective treatment options necessitates novel therapeutic approaches. Epigenetic drugs, by inhibiting chromatin modifying enzymes involved in gene expression control, represent promising agents capable of modulating the cellular phenotype. We previously demonstrated that the cyclooxygenase-2 (COX-2) gene is epigenetically silenced in lung fibroblasts from IPF patients (F-IPF)[1] and epigenetic inhibitors and restore COX-2 expression. However, whether epigenetic inhibitors can alter fibroblast phenotype remains unknown. This study aimed to investigate the effect of four different epigenetic enzyme inhibitors on fibroblast phenotype change in IPF. Methods: F-IPF and fibroblasts from non-fibrotic lung (F-NL) treated with TGF-β1 were cultured to test the effects of the epigenetic inhibitors BIX01294 (BIX, G9a histone methyltransferase inhibitor), 3- deazaneplanocin A (DZNep, EZH2 histone methyltransferase inhibitor), SAHA (histone deacetylases inhibitor) and Decitabine (DAC, DNA demethylating agent), in comparison with the COX-2 products prostaglandin E2 (PGE2). The expression of COX-2 and myofibroblast markers collagen 1 (COL1) and α- smooth muscle actin (α-SMA) was assessed. The COX-2 DNA promoter methylation level was analysed by bisulfite sequencing. Results: TGF-β1 induced a myofibroblast phenotype in F-NL characterised by COL1 and α-SMA upregulation and COX-2 downregulation, similar to F-IPF. PGE2 and SAHA were able to maintain/restore COX-2 expression in TGF-β1-induced myofibroblasts and F-IPF. DAC demonstrated similar effect in TGF-β1 treated F-NL only. SAHA also reduced COL1 and α-SMA expression. But DZNep and BIX showed no effect. No differences in the C

41. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants

Author

Burton, Paul R, Clayton, David G, Cardon, Lon R, Craddock, Nick, Deloukas, Panos, Duncanson, Audrey, Kwiatkowski, Dominic P, McCarthy, Mark I, Ouwehand, Willem H, Samani, Nilesh J, Todd, John A, Donnelly (Chair), Peter, Barrett, Jeffrey C, Davison, Dan, Donnelly, Peter, Easton, Doug, Evans, David M, Leung, Hin-Tak, Marchini, Jonathan L, Morris, Andrew P, Spencer, Chris CA, Tobin, Martin D, Attwood, Antony P, Boorman, James P, Cant, Barbara, Everson, Ursula, Hussey, Judith M, Jolley, Jennifer D, Knight, Alexandra S, Koch, Kerstin, Meech, Elizabeth, Nutland, Sarah, Prowse, Christopher V, Stevens, Helen E, Taylor, Niall C, Walters, Graham R, Walker, Neil M, Watkins, Nicholas A, Winzer, Thilo, Jones, Richard W, McArdle, Wendy L, Ring, Susan M, Strachan, David P, Pembrey, Marcus, Breen, Gerome, Clair, David St, Caesar, Sian, Gordon-Smith, Katharine, Jones, Lisa, Fraser, Christine, Green, Elaine K, Grozeva, Detelina, Hamshere, Marian L, Holmans, Peter A, Jones, Ian R, Kirov, George, Moskivina, Valentina, Nikolov, Ivan, O'Donovan, Michael C, Owen, Michael J, Collier, David A, Elkin, Amanda, Farmer, Anne, Williamson, Richard, McGuffin, Peter, Young, Allan H, Ferrier, I Nicol, Ball, Stephen G, Balmforth, Anthony J, Barrett, Jennifer H, Bishop, Timothy D, Iles, Mark M, Maqbool, Azhar, Yuldasheva, Nadira, Hall, Alistair S, Braund, Peter S, Dixon, Richard J, Mangino, Massimo, Stevens, Suzanne, Thompson, John R, Bredin, Francesca, Tremelling, Mark, Parkes, Miles, Drummond, Hazel, Lees, Charles W, Nimmo, Elaine R, Satsangi, Jack, Fisher, Sheila A, Forbes, Alastair, Lewis, Cathryn M, Onnie, Clive M, Prescott, Natalie J, Sanderson, Jeremy, Matthew, Christopher G, Barbour, Jamie, Mohiuddin, M Khalid, Todhunter, Catherine E, Mansfield, John C, Ahmad, Tariq, Cummings, Fraser R, Jewell, Derek P, Webster, John, Brown, Morris J, Lathrop, Mark G, Connell, John, Dominiczak, Anna, Marcano, Carolina A Braga, Burke, Beverley, Dobson, Richard, Gungadoo, Johannie, Lee, Kate L, Munroe, Patricia B, Newhouse, Stephen J, Onipinla, Abiodun, Wallace, Chris, Xue, Mingzhan, Caulfield, Mark, Farrall, Martin, Barton, Anne, Bruce, Ian N, Donovan, Hannah, Eyre, Steve, Gilbert, Paul D, Hilder, Samantha L, Hinks, Anne M, John, Sally L, Potter, Catherine, Silman, Alan J, Symmons, Deborah PM, Thomson, Wendy, Worthington, Jane, Dunger, David B, Widmer, Barry, Frayling, Timothy M, Freathy, Rachel M, Lango, Hana, Perry, John R B, Shields, Beverley M, Weedon, Michael N, Hattersley, Andrew T, Hitman, Graham A, Walker, Mark, Elliott, Kate S, Groves, Christopher J, Lindgren, Cecilia M, Rayner, Nigel W, Timpson, Nicolas J, Zeggini, Eleftheria, Newport, Melanie, Sirugo, Giorgio, Lyons, Emily, Vannberg, Fredrik, Hill, Adrian V S, Bradbury, Linda A, Farrar, Claire, Pointon, Jennifer J, Wordsworth, Paul, Brown, Matthew A, Franklyn, Jayne A, Heward, Joanne M, Simmonds, Matthew J, Gough, Stephen CL, Seal, Sheila, Stratton, Michael R, Rahman, Nazneen, Ban, Maria, Goris, An, Sawcer, Stephen J, Compston, Alastair, Conway, David, Jallow, Muminatou, Rockett, Kirk A, Bumpstead, Suzannah J, Chaney, Amy, Downes, Kate, Ghori, Mohammed JR, Gwilliam, Rhian, Hunt, Sarah E, Inouye, Michael, Keniry, Andrew, King, Emma, McGinnis, Ralph, Potter, Simon, Ravindrarajah, Rathi, Whittaker, Pamela, Widden, Claire, Withers, David, Cardin, Niall J, Ferreira, Teresa, Pereira-Gale, Joanne, Hallgrimsdóttir, Ingeleif B, Howie, Bryan N, Su, Zhan, Teo, Yik Ying, Vukcevic, Damjan, Bentley, David, Mitchell, Sarah L, Newby, Paul R, Brand, Oliver J, Carr-Smith, Jackie, Pearce, Simon H S, Gough, Stephen C L, McGinnis, R, Keniry, A, Deloukas, P, Reveille, John D, Zhou, Xiaodong, Sims, Anne-Marie, Dowling, Alison, Taylor, Jacqueline, Doan, Tracy, Davis, John C, Savage, Laurie, Ward, Michael M, Learch, Thomas L, Weisman, Michael H, Burton, Paul R, Clayton, David G, Cardon, Lon R, Craddock, Nick, Deloukas, Panos, Duncanson, Audrey, Kwiatkowski, Dominic P, McCarthy, Mark I, Ouwehand, Willem H, Samani, Nilesh J, Todd, John A, Donnelly (Chair), Peter, Barrett, Jeffrey C, Davison, Dan, Donnelly, Peter, Easton, Doug, Evans, David M, Leung, Hin-Tak, Marchini, Jonathan L, Morris, Andrew P, Spencer, Chris CA, Tobin, Martin D, Attwood, Antony P, Boorman, James P, Cant, Barbara, Everson, Ursula, Hussey, Judith M, Jolley, Jennifer D, Knight, Alexandra S, Koch, Kerstin, Meech, Elizabeth, Nutland, Sarah, Prowse, Christopher V, Stevens, Helen E, Taylor, Niall C, Walters, Graham R, Walker, Neil M, Watkins, Nicholas A, Winzer, Thilo, Jones, Richard W, McArdle, Wendy L, Ring, Susan M, Strachan, David P, Pembrey, Marcus, Breen, Gerome, Clair, David St, Caesar, Sian, Gordon-Smith, Katharine, Jones, Lisa, Fraser, Christine, Green, Elaine K, Grozeva, Detelina, Hamshere, Marian L, Holmans, Peter A, Jones, Ian R, Kirov, George, Moskivina, Valentina, Nikolov, Ivan, O'Donovan, Michael C, Owen, Michael J, Collier, David A, Elkin, Amanda, Farmer, Anne, Williamson, Richard, McGuffin, Peter, Young, Allan H, Ferrier, I Nicol, Ball, Stephen G, Balmforth, Anthony J, Barrett, Jennifer H, Bishop, Timothy D, Iles, Mark M, Maqbool, Azhar, Yuldasheva, Nadira, Hall, Alistair S, Braund, Peter S, Dixon, Richard J, Mangino, Massimo, Stevens, Suzanne, Thompson, John R, Bredin, Francesca, Tremelling, Mark, Parkes, Miles, Drummond, Hazel, Lees, Charles W, Nimmo, Elaine R, Satsangi, Jack, Fisher, Sheila A, Forbes, Alastair, Lewis, Cathryn M, Onnie, Clive M, Prescott, Natalie J, Sanderson, Jeremy, Matthew, Christopher G, Barbour, Jamie, Mohiuddin, M Khalid, Todhunter, Catherine E, Mansfield, John C, Ahmad, Tariq, Cummings, Fraser R, Jewell, Derek P, Webster, John, Brown, Morris J, Lathrop, Mark G, Connell, John, Dominiczak, Anna, Marcano, Carolina A Braga, Burke, Beverley, Dobson, Richard, Gungadoo, Johannie, Lee, Kate L, Munroe, Patricia B, Newhouse, Stephen J, Onipinla, Abiodun, Wallace, Chris, Xue, Mingzhan, Caulfield, Mark, Farrall, Martin, Barton, Anne, Bruce, Ian N, Donovan, Hannah, Eyre, Steve, Gilbert, Paul D, Hilder, Samantha L, Hinks, Anne M, John, Sally L, Potter, Catherine, Silman, Alan J, Symmons, Deborah PM, Thomson, Wendy, Worthington, Jane, Dunger, David B, Widmer, Barry, Frayling, Timothy M, Freathy, Rachel M, Lango, Hana, Perry, John R B, Shields, Beverley M, Weedon, Michael N, Hattersley, Andrew T, Hitman, Graham A, Walker, Mark, Elliott, Kate S, Groves, Christopher J, Lindgren, Cecilia M, Rayner, Nigel W, Timpson, Nicolas J, Zeggini, Eleftheria, Newport, Melanie, Sirugo, Giorgio, Lyons, Emily, Vannberg, Fredrik, Hill, Adrian V S, Bradbury, Linda A, Farrar, Claire, Pointon, Jennifer J, Wordsworth, Paul, Brown, Matthew A, Franklyn, Jayne A, Heward, Joanne M, Simmonds, Matthew J, Gough, Stephen CL, Seal, Sheila, Stratton, Michael R, Rahman, Nazneen, Ban, Maria, Goris, An, Sawcer, Stephen J, Compston, Alastair, Conway, David, Jallow, Muminatou, Rockett, Kirk A, Bumpstead, Suzannah J, Chaney, Amy, Downes, Kate, Ghori, Mohammed JR, Gwilliam, Rhian, Hunt, Sarah E, Inouye, Michael, Keniry, Andrew, King, Emma, McGinnis, Ralph, Potter, Simon, Ravindrarajah, Rathi, Whittaker, Pamela, Widden, Claire, Withers, David, Cardin, Niall J, Ferreira, Teresa, Pereira-Gale, Joanne, Hallgrimsdóttir, Ingeleif B, Howie, Bryan N, Su, Zhan, Teo, Yik Ying, Vukcevic, Damjan, Bentley, David, Mitchell, Sarah L, Newby, Paul R, Brand, Oliver J, Carr-Smith, Jackie, Pearce, Simon H S, Gough, Stephen C L, McGinnis, R, Keniry, A, Deloukas, P, Reveille, John D, Zhou, Xiaodong, Sims, Anne-Marie, Dowling, Alison, Taylor, Jacqueline, Doan, Tracy, Davis, John C, Savage, Laurie, Ward, Michael M, Learch, Thomas L, and Weisman, Michael H

Abstract

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.

42. Follow-up of potential novel Graves' disease susceptibility loci, identified in the UK WTCCC genome-wide nonsynonymous SNP study

Author

Newby, Paul R., Pickles, Oliver J., Mazumdar, Samaresh, Brand, Oliver J., Carr-Smith, Jacqueline D., Pearce, Simon H. S., Franklyn, Jayne A., Evans, David M., Simmonds, Matthew J., Gough, Stephen C. L., Welcome Trust Case-Control Consortium (WTCCC), ., Newby, Paul R., Pickles, Oliver J., Mazumdar, Samaresh, Brand, Oliver J., Carr-Smith, Jacqueline D., Pearce, Simon H. S., Franklyn, Jayne A., Evans, David M., Simmonds, Matthew J., Gough, Stephen C. L., and Welcome Trust Case-Control Consortium (WTCCC), .

Abstract

A recent association scan using a genome-wide set of nonsynonymous coding single-nucleotide polymorphisms (nsSNPs) conducted in four diseases including Graves' disease (GD), identified nine novel possible regions of association with GD. We used a case-control approach in an attempt to replicate association of these nine regions in an independent collection of 1578 British GD patients and 1946 matched Caucasian controls. Although none of these loci showed evidence of association with GD in the independent data set, when combined with the original Wellcome Trust Case-Control Consortium study group, minor differences in allele frequencies (P smaller than or equal to 10-3) remained in the combined collection of 5924 subjects for four of the nsSNPs, present within HDLBP, TEKT1, JSRP1 and UTX. An additional 29 Tag SNPs were screened within these four gene regions to determine if further associations could be detected. Similarly, minor differences only (P=0.042-0.002) were detected in two HDLBP and two TEKT1 Tag SNPs in the combined UK GD collection. In conclusion, it is unlikely that the SNPs selected in this replication study have a significant effect on the risk of GD in the United Kingdom. Our study confirms the need for large data sets and stringent analysis criteria when searching for susceptibility loci in common diseases. © 2010 Macmillan Publishers Limited All rights reserved.

43. Donor ABCB1 variant associates with increased risk for kidney allograft failure

Author

Moore, Jason, McKnight, Amy Jayne, Döhler, Bernd, Simmonds, Matthew J., Courtney, Aisling E., Brand, Oliver J., Briggs, David, Ball, Simon, Cockwell, Paul, Patterson, Christopher C., Maxwell, Alexander P., Gough, Stephen C. L., Opelz, Gerhard, Borrows, Richard, Moore, Jason, McKnight, Amy Jayne, Döhler, Bernd, Simmonds, Matthew J., Courtney, Aisling E., Brand, Oliver J., Briggs, David, Ball, Simon, Cockwell, Paul, Patterson, Christopher C., Maxwell, Alexander P., Gough, Stephen C. L., Opelz, Gerhard, and Borrows, Richard

Abstract

The impact of variation within genes responsible for the disposition and metabolism of calcineurin inhibitors (CNIs) on clinical outcomes in kidney transplantation is not well understood. Furthermore, the potential in fluence of donor, rather than recipient, genotypes on clinical endpoints is unknown. Here, we investigated the associations between donor and recipient gene variants with outcome among 4471 white, CNI-treated kidney transplant recipients. We tested for 52 single-nucleotide polymorphisms (SNPs) across five genes: CYP3A4, CYP3A5, ABCB1 ( MDR1; encoding P-glycoprotein), NR1I2 (encoding the pregnane X receptor), and PPIA (encoding cyclophilin). In a discovery cohort of 811 patients from Birmingham, United Kingdom, kidney donor CC genotype at C3435T (rs1045642) within ABCB1, a variant known to alter protein expression, was associated with an increased risk for long-term graft failure compared with non-CC genotype (hazard ratio HR, 1.69; 95% confidence interval CI, 1.20 -2.40; P=0.003). No other donor or recipient SNPs were associated with graft survival or mortality. We validated this association in 675 donors from Belfast, United Kingdom (HR, 1.68; 95% CI, 1.21-2.32; P=0.002), and in 2985 donors from the Collaborative Transplant Study (HR, 1.84; 95% CI, 1.08- 3.13; P=0.006). In conclusion, these data suggest that an ABCB1 variant known to alter protein expression represents an attractive candidate for future study and risk stratification in kidney transplantation. Copyright © 2012 by the American Society of Nephrology.

45. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls

Author

Craddock, Nick, Hurles, Matthew E., Cardin, Niall, Pearson, Richard D., Plagnol, Vincent, Robson, Samuel, Vukcevic, Damjan, Barnes, Chris, Conrad, Donald F., Giannoulatou, Eleni, Holmes, Chris, Marchini, Jonathan L., Stirrups, Kathy, Tobin, Martin D., Wain, Louise V., Yau, Chris, Aerts, Jan, Ahmad, Tariq, Daniel Andrews, T., Arbury, Hazel, Attwood, Anthony, Auton, Adam, Ball, Stephen G., Balmforth, Anthony J., Barrett, Jeffrey C., Barroso, Inês, Barton, Anne, Bennett, Amanda J., Bhaskar, Sanjeev, Blaszczyk, Katarzyna, Bowes, John, Brand, Oliver J., Braund, Peter S., Bredin, Francesca, Breen, Gerome, Brown, Morris J., Bruce, Ian N., Bull, Jaswinder, Burren, Oliver S., Burton, John, Byrnes, Jake, Caesar, Sian, Clee, Chris M., Coffey, Alison J., Connell, John M. C., Cooper, Jason D., Dominiczak, Anna F., Downes, Kate, Drummond, Hazel E., Dudakia, Darshna, Dunham, Andrew, Ebbs, Bernadette, Eccles, Diana, Edkins, Sarah, Edwards, Cathryn, Elliot, Anna, Emery, Paul, Evans, David M., Evans, Gareth, Eyre, Steve, Farmer, Anne, Nicol Ferrier, I., Feuk, Lars, Fitzgerald, Tomas, Flynn, Edward, Forbes, Alistair, Forty, Liz, Franklyn, Jayne A., Freathy, Rachel M., Gibbs, Polly, Gilbert, Paul, Gokumen, Omer, Gordon-Smith, Katherine, Gray, Emma, Green, Elaine, Groves, Chris J., Grozeva, Detelina, Gwilliam, Rhian, Hall, Anita, Hammond, Naomi, Hardy, Matt, Harrison, Pile, Hassanali, Neelam, Hebaishi, Husam, Hines, Sarah, Hinks, Anne, Hitman, Graham A, Hocking, Lynne, Howard, Eleanor, Howard, Philip, Howson, Joanna M. M., Hughes, Debbie, Hunt, Sarah, Isaacs, John D., Jain, Mahim, Jewell, Derek P., Johnson, Toby, Jolley, Jennifer D., Jones, Ian R., Jones, Lisa A., Kirov, George, Langford, Cordelia F., Lango-Allen, Hana, Mark Lathrop, G., Lee, James, Lee, Kate L., Lees, Charlie, Lewis, Kevin, Lindgren, Cecilia M., Maisuria-Armer, Meeta, Maller, Julian, Mansfield, John, Martin, Paul, Massey, Dunecan C. O., McArdle, Wendy L., McGuffin, Peter, McLay, Kirsten E., Mentzer, Alex, Mimmack, Michael L., Morgan, Ann E., Morris, Andrew P., Mowat, Craig, Myers, Simon, Newman, William, Nimmo, Elaine R., O’Donovan, Michael C., Onipinla, Abiodun, Onyiah, Ifejinelo, Ovington, Nigel R., Owen, Michael J., Palin, Kimmo, Parnell, Kirstie, Pernet, David, Perry, John R. B., Phillips, Anne, Pinto, Dalila, Prescott, Natalie J., Prokopenko, Inga, Quail, Michael A., Rafelt, Suzanne, Rayner, Nigel W., Redon, Richard, Reid, David M., Renwick, Anthony, Ring, Susan M., Robertson, Neil, Russell, Ellie, St Clair, David, Sambrook, Jennifer G., Sanderson, Jeremy D., Schuilenburg, Helen, Scott, Carol E., Scott, Richard, Seal, Sheila, Shaw-Hawkins, Sue, Shields, Beverley M., Simmonds, Matthew J., Smyth, Debbie J., Somaskantharajah, Elilan, Spanova, Katarina, Steer, Sophia, Stephens, Jonathan, Stevens, Helen E., Stone, Millicent A., Su, Zhan, Symmons, Deborah P. M., Thompson, John R., Thomson, Wendy, Travers, Mary E., Turnbull, Clare, Valsesia, Armand, Walker, Mark, Walker, Neil M., Wallace, Chris, Warren-Perry, Margaret, Watkins, Nicholas A., Webster, John, Weedon, Michael N., Wilson, Anthony G., Woodburn, Matthew, Wordsworth, B. Paul, Young, Allan H., Zeggini, Eleftheria, Carter, Nigel P., Frayling, Timothy M., Lee, Charles, McVean, Gil, Munroe, Patricia B., Palotie, Aarno, Sawcer, Stephen J., Scherer, Stephen W., Strachan, David P., Tyler-Smith, Chris, Brown, Matthew A., Burton, Paul R., Caulfield, Mark J., Compston, Alastair, Farrall, Martin, Gough, Stephen C. L., Hall, Alistair S., Hattersley, Andrew T., Hill, Adrian V. S., Mathew, Christopher G., Pembrey, Marcus, Satsangi, Jack, Stratton, Michael R., Worthington, Jane, Deloukas, Panos, Duncanson, Audrey, Kwiatkowski, Dominic P., McCarthy, Mark I., Ouwehand, Willem H., Parkes, Miles, Rahman, Nazneen, Todd, John A., Samani, Nilesh J., Donnelly, Peter, Craddock, Nick, Hurles, Matthew E., Cardin, Niall, Pearson, Richard D., Plagnol, Vincent, Robson, Samuel, Vukcevic, Damjan, Barnes, Chris, Conrad, Donald F., Giannoulatou, Eleni, Holmes, Chris, Marchini, Jonathan L., Stirrups, Kathy, Tobin, Martin D., Wain, Louise V., Yau, Chris, Aerts, Jan, Ahmad, Tariq, Daniel Andrews, T., Arbury, Hazel, Attwood, Anthony, Auton, Adam, Ball, Stephen G., Balmforth, Anthony J., Barrett, Jeffrey C., Barroso, Inês, Barton, Anne, Bennett, Amanda J., Bhaskar, Sanjeev, Blaszczyk, Katarzyna, Bowes, John, Brand, Oliver J., Braund, Peter S., Bredin, Francesca, Breen, Gerome, Brown, Morris J., Bruce, Ian N., Bull, Jaswinder, Burren, Oliver S., Burton, John, Byrnes, Jake, Caesar, Sian, Clee, Chris M., Coffey, Alison J., Connell, John M. C., Cooper, Jason D., Dominiczak, Anna F., Downes, Kate, Drummond, Hazel E., Dudakia, Darshna, Dunham, Andrew, Ebbs, Bernadette, Eccles, Diana, Edkins, Sarah, Edwards, Cathryn, Elliot, Anna, Emery, Paul, Evans, David M., Evans, Gareth, Eyre, Steve, Farmer, Anne, Nicol Ferrier, I., Feuk, Lars, Fitzgerald, Tomas, Flynn, Edward, Forbes, Alistair, Forty, Liz, Franklyn, Jayne A., Freathy, Rachel M., Gibbs, Polly, Gilbert, Paul, Gokumen, Omer, Gordon-Smith, Katherine, Gray, Emma, Green, Elaine, Groves, Chris J., Grozeva, Detelina, Gwilliam, Rhian, Hall, Anita, Hammond, Naomi, Hardy, Matt, Harrison, Pile, Hassanali, Neelam, Hebaishi, Husam, Hines, Sarah, Hinks, Anne, Hitman, Graham A, Hocking, Lynne, Howard, Eleanor, Howard, Philip, Howson, Joanna M. M., Hughes, Debbie, Hunt, Sarah, Isaacs, John D., Jain, Mahim, Jewell, Derek P., Johnson, Toby, Jolley, Jennifer D., Jones, Ian R., Jones, Lisa A., Kirov, George, Langford, Cordelia F., Lango-Allen, Hana, Mark Lathrop, G., Lee, James, Lee, Kate L., Lees, Charlie, Lewis, Kevin, Lindgren, Cecilia M., Maisuria-Armer, Meeta, Maller, Julian, Mansfield, John, Martin, Paul, Massey, Dunecan C. O., McArdle, Wendy L., McGuffin, Peter, McLay, Kirsten E., Mentzer, Alex, Mimmack, Michael L., Morgan, Ann E., Morris, Andrew P., Mowat, Craig, Myers, Simon, Newman, William, Nimmo, Elaine R., O’Donovan, Michael C., Onipinla, Abiodun, Onyiah, Ifejinelo, Ovington, Nigel R., Owen, Michael J., Palin, Kimmo, Parnell, Kirstie, Pernet, David, Perry, John R. B., Phillips, Anne, Pinto, Dalila, Prescott, Natalie J., Prokopenko, Inga, Quail, Michael A., Rafelt, Suzanne, Rayner, Nigel W., Redon, Richard, Reid, David M., Renwick, Anthony, Ring, Susan M., Robertson, Neil, Russell, Ellie, St Clair, David, Sambrook, Jennifer G., Sanderson, Jeremy D., Schuilenburg, Helen, Scott, Carol E., Scott, Richard, Seal, Sheila, Shaw-Hawkins, Sue, Shields, Beverley M., Simmonds, Matthew J., Smyth, Debbie J., Somaskantharajah, Elilan, Spanova, Katarina, Steer, Sophia, Stephens, Jonathan, Stevens, Helen E., Stone, Millicent A., Su, Zhan, Symmons, Deborah P. M., Thompson, John R., Thomson, Wendy, Travers, Mary E., Turnbull, Clare, Valsesia, Armand, Walker, Mark, Walker, Neil M., Wallace, Chris, Warren-Perry, Margaret, Watkins, Nicholas A., Webster, John, Weedon, Michael N., Wilson, Anthony G., Woodburn, Matthew, Wordsworth, B. Paul, Young, Allan H., Zeggini, Eleftheria, Carter, Nigel P., Frayling, Timothy M., Lee, Charles, McVean, Gil, Munroe, Patricia B., Palotie, Aarno, Sawcer, Stephen J., Scherer, Stephen W., Strachan, David P., Tyler-Smith, Chris, Brown, Matthew A., Burton, Paul R., Caulfield, Mark J., Compston, Alastair, Farrall, Martin, Gough, Stephen C. L., Hall, Alistair S., Hattersley, Andrew T., Hill, Adrian V. S., Mathew, Christopher G., Pembrey, Marcus, Satsangi, Jack, Stratton, Michael R., Worthington, Jane, Deloukas, Panos, Duncanson, Audrey, Kwiatkowski, Dominic P., McCarthy, Mark I., Ouwehand, Willem H., Parkes, Miles, Rahman, Nazneen, Todd, John A., Samani, Nilesh J., and Donnelly, Peter

Abstract

Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with diseaseIRGM for Crohns disease, HLA for Crohns disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetesalthough in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases. © 2010 Macmillan Publishers Limited. All rights reserved.

46. Interplay between EZH2 and G9a Regulates CXCL10 Gene Repression in Idiopathic Pulmonary Fibrosis

Author

Alan J. Knox, William R. Coward, Linhua Pang, Oliver Brand, Gisli Jenkins, Alice Pasini, Coward, William R., Brand, Oliver J., Pasini, Alice, Jenkins, Gisli, Knox, Alan J., and Pang, Linhua

Subjects
0301 basic medicine, Pulmonary and Respiratory Medicine, Clinical Biochemistry, Down-Regulation, macromolecular substances, Epigenetic Repression, Lung fibroblast, Histone methylation, Transforming Growth Factor beta1, 03 medical and health sciences, Histone H3, Histocompatibility Antigens, Histone H2A, Humans, Enhancer of Zeste Homolog 2 Protein, Epigenetics, Promoter Regions, Genetic, Lung, Molecular Biology, Cells, Cultured, biology, Chemistry, CXCL10, EZH2, Histone-Lysine N-Methyltransferase, Cell Biology, DNA Methylation, Fibroblasts, respiratory system, Idiopathic Pulmonary Fibrosis, respiratory tract diseases, Chemokine CXCL10, 030104 developmental biology, Histone, Case-Control Studies, Cancer research, biology.protein, Gene expression, Pulmonary fibrosi, Chromatin immunoprecipitation, Signal Transduction
Abstract

Selective repression of the antifibrotic gene CXCL10 contributes to tissue remodeling in idiopathic pulmonary fibrosis (IPF). We have previously reported that histone deacetylation and histone H3 lysine 9 (H3K9) methylation are involved in CXCL10 repression. In this study, we explored the role of H3K27 methylation and the interplay between the two histone lysine methyltransferases enhancer of zest homolog 2 (EZH2) and G9a in CXCL10 repression in IPF. By applying chromatin immunoprecipitation, Re-ChIP, and proximity ligation assays, we demonstrated that, like G9a-mediated H3K9 methylation, EZH2-mediated histone H3 lysine 27 trimethylation (H3K27me3) was significantly enriched at the CXCL10 promoter in fibroblasts from IPF lungs (F-IPF) compared with fibroblasts from nonfibrotic lungs, and we also found that EZH2 and G9a physically interacted with each other. EZH2 knockdown reduced not only EZH2 and H3K27me3 but also G9a and H3K9me3, and G9a knockdown reduced not only G9 and H3K9me3 but also EZH2 and H3K27me3. Depletion and inhibition of EZH2 and G9a also reversed histone deacetylation and restored CXCL10 expression in F-IPF. Furthermore, treatment of fibroblasts from nonfibrotic lungs with the profibrotic cytokine transforming growth factor-β1 increased EZH2, G9a, H3K27me3, H3K9me3, and histone deacetylation at the CXCL10 promoter, similar to that observed in F-IPF, which was correlated with CXCL10 repression and was prevented by EZH2 and G9a knockdown. These findings suggest that a novel and functionally interdependent interplay between EZH2 and G9a regulates histone methylation-mediated epigenetic repression of the antifibrotic CXCL10 gene in IPF. This interdependent interplay may prove to be a target for epigenetic intervention to restore the expression of CXCL10 and other antifibrotic genes in IPF.

Published
2018

47. Rare and functional SIAE variants are not associated with autoimmune disease risk in up to 66,924 individuals of European ancestry.

Author

Hunt KA, Smyth DJ, Balschun T, Ban M, Mistry V, Ahmad T, Anand V, Barrett JC, Bhaw-Rosun L, Bockett NA, Brand OJ, Brouwer E, Concannon P, Cooper JD, Dias KR, van Diemen CC, Dubois PC, Edkins S, Fölster-Holst R, Fransen K, Glass DN, Heap GA, Hofmann S, Huizinga TW, Hunt S, Langford C, Lee J, Mansfield J, Marrosu MG, Mathew CG, Mein CA, Müller-Quernheim J, Nutland S, Onengut-Gumuscu S, Ouwehand W, Pearce K, Prescott NJ, Posthumus MD, Potter S, Rosati G, Sambrook J, Satsangi J, Schreiber S, Shtir C, Simmonds MJ, Sudman M, Thompson SD, Toes R, Trynka G, Vyse TJ, Walker NM, Weidinger S, Zhernakova A, Zoledziewska M, Weersma RK, Gough SC, Sawcer S, Wijmenga C, Parkes M, Cucca F, Franke A, Deloukas P, Rich SS, Todd JA, and van Heel DA

Subjects
Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Risk Factors, White People, Acetylesterase genetics, Autoimmune Diseases genetics, Genetic Variation
Published
2011
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48. Immunogenetic mechanisms leading to thyroid autoimmunity: recent advances in identifying susceptibility genes and regions.

Author

Brand OJ and Gough SC

Abstract

The autoimmune thyroid diseases (AITD) include Graves' disease (GD) and Hashimoto's thyroiditis (HT), which are characterised by a breakdown in immune tolerance to thyroid antigens. Unravelling the genetic architecture of AITD is vital to better understanding of AITD pathogenesis, required to advance therapeutic options in both disease management and prevention. The early whole-genome linkage and candidate gene association studies provided the first evidence that the HLA region and CTLA-4 represented AITD risk loci. Recent improvements in; high throughput genotyping technologies, collection of larger disease cohorts and cataloguing of genome-scale variation have facilitated genome-wide association studies and more thorough screening of candidate gene regions. This has allowed identification of many novel AITD risk genes and more detailed association mapping. The growing number of confirmed AITD susceptibility loci, implicates a number of putative disease mechanisms most of which are tightly linked with aspects of immune system function. The unprecedented advances in genetic study will allow future studies to identify further novel disease risk genes and to identify aetiological variants within specific gene regions, which will undoubtedly lead to a better understanding of AITD patho-physiology.

Published
2011
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49. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants.

Author

Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A, Kwiatkowski DP, McCarthy MI, Ouwehand WH, Samani NJ, Todd JA, Donnelly P, Barrett JC, Davison D, Easton D, Evans DM, Leung HT, Marchini JL, Morris AP, Spencer CC, Tobin MD, Attwood AP, Boorman JP, Cant B, Everson U, Hussey JM, Jolley JD, Knight AS, Koch K, Meech E, Nutland S, Prowse CV, Stevens HE, Taylor NC, Walters GR, Walker NM, Watkins NA, Winzer T, Jones RW, McArdle WL, Ring SM, Strachan DP, Pembrey M, Breen G, St Clair D, Caesar S, Gordon-Smith K, Jones L, Fraser C, Green EK, Grozeva D, Hamshere ML, Holmans PA, Jones IR, Kirov G, Moskivina V, Nikolov I, O'Donovan MC, Owen MJ, Collier DA, Elkin A, Farmer A, Williamson R, McGuffin P, Young AH, Ferrier IN, Ball SG, Balmforth AJ, Barrett JH, Bishop TD, Iles MM, Maqbool A, Yuldasheva N, Hall AS, Braund PS, Dixon RJ, Mangino M, Stevens S, Thompson JR, Bredin F, Tremelling M, Parkes M, Drummond H, Lees CW, Nimmo ER, Satsangi J, Fisher SA, Forbes A, Lewis CM, Onnie CM, Prescott NJ, Sanderson J, Matthew CG, Barbour J, Mohiuddin MK, Todhunter CE, Mansfield JC, Ahmad T, Cummings FR, Jewell DP, Webster J, Brown MJ, Lathrop MG, Connell J, Dominiczak A, Marcano CA, Burke B, Dobson R, Gungadoo J, Lee KL, Munroe PB, Newhouse SJ, Onipinla A, Wallace C, Xue M, Caulfield M, Farrall M, Barton A, Bruce IN, Donovan H, Eyre S, Gilbert PD, Hilder SL, Hinks AM, John SL, Potter C, Silman AJ, Symmons DP, Thomson W, Worthington J, Dunger DB, Widmer B, Frayling TM, Freathy RM, Lango H, Perry JR, Shields BM, Weedon MN, Hattersley AT, Hitman GA, Walker M, Elliott KS, Groves CJ, Lindgren CM, Rayner NW, Timpson NJ, Zeggini E, Newport M, Sirugo G, Lyons E, Vannberg F, Hill AV, Bradbury LA, Farrar C, Pointon JJ, Wordsworth P, Brown MA, Franklyn JA, Heward JM, Simmonds MJ, Gough SC, Seal S, Stratton MR, Rahman N, Ban M, Goris A, Sawcer SJ, Compston A, Conway D, Jallow M, Newport M, Sirugo G, Rockett KA, Bumpstead SJ, Chaney A, Downes K, Ghori MJ, Gwilliam R, Hunt SE, Inouye M, Keniry A, King E, McGinnis R, Potter S, Ravindrarajah R, Whittaker P, Widden C, Withers D, Cardin NJ, Davison D, Ferreira T, Pereira-Gale J, Hallgrimsdo'ttir IB, Howie BN, Su Z, Teo YY, Vukcevic D, Bentley D, Brown MA, Compston A, Farrall M, Hall AS, Hattersley AT, Hill AV, Parkes M, Pembrey M, Stratton MR, Mitchell SL, Newby PR, Brand OJ, Carr-Smith J, Pearce SH, McGinnis R, Keniry A, Deloukas P, Reveille JD, Zhou X, Sims AM, Dowling A, Taylor J, Doan T, Davis JC, Savage L, Ward MM, Learch TL, Weisman MH, and Brown M

Subjects
Aminopeptidases genetics, Breast Neoplasms epidemiology, Case-Control Studies, Chromosome Mapping, Genetics, Population, Genotype, Haplotypes genetics, Humans, Linkage Disequilibrium, Minor Histocompatibility Antigens, Multiple Sclerosis epidemiology, North America epidemiology, Polymerase Chain Reaction, Receptors, Immunologic genetics, Receptors, Interleukin genetics, Spondylitis, Ankylosing epidemiology, Thyroiditis, Autoimmune epidemiology, Autoimmunity genetics, Breast Neoplasms genetics, Multiple Sclerosis genetics, Polymorphism, Single Nucleotide genetics, Spondylitis, Ankylosing genetics, Thyroiditis, Autoimmune genetics
Abstract

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.

Published
2007
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