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1.  Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus 
Mahajan, Anubha | Sim, Xueling | Ng, Hui Jin | Manning, Alisa | Rivas, Manuel A. | Highland, Heather M. | Locke, Adam E. | Grarup, Niels | Im, Hae Kyung | Cingolani, Pablo | Flannick, Jason | Fontanillas, Pierre | Fuchsberger, Christian | Gaulton, Kyle J. | Teslovich, Tanya M. | Rayner, N. William | Robertson, Neil R. | Beer, Nicola L. | Rundle, Jana K. | Bork-Jensen, Jette | Ladenvall, Claes | Blancher, Christine | Buck, David | Buck, Gemma | Burtt, Noël P. | Gabriel, Stacey | Gjesing, Anette P. | Groves, Christopher J. | Hollensted, Mette | Huyghe, Jeroen R. | Jackson, Anne U. | Jun, Goo | Justesen, Johanne Marie | Mangino, Massimo | Murphy, Jacquelyn | Neville, Matt | Onofrio, Robert | Small, Kerrin S. | Stringham, Heather M. | Syvänen, Ann-Christine | Trakalo, Joseph | Abecasis, Goncalo | Bell, Graeme I. | Blangero, John | Cox, Nancy J. | Duggirala, Ravindranath | Hanis, Craig L. | Seielstad, Mark | Wilson, James G. | Christensen, Cramer | Brandslund, Ivan | Rauramaa, Rainer | Surdulescu, Gabriela L. | Doney, Alex S. F. | Lannfelt, Lars | Linneberg, Allan | Isomaa, Bo | Tuomi, Tiinamaija | Jørgensen, Marit E. | Jørgensen, Torben | Kuusisto, Johanna | Uusitupa, Matti | Salomaa, Veikko | Spector, Timothy D. | Morris, Andrew D. | Palmer, Colin N. A. | Collins, Francis S. | Mohlke, Karen L. | Bergman, Richard N. | Ingelsson, Erik | Lind, Lars | Tuomilehto, Jaakko | Hansen, Torben | Watanabe, Richard M. | Prokopenko, Inga | Dupuis, Josee | Karpe, Fredrik | Groop, Leif | Laakso, Markku | Pedersen, Oluf | Florez, Jose C. | Morris, Andrew P. | Altshuler, David | Meigs, James B. | Boehnke, Michael | McCarthy, Mark I. | Lindgren, Cecilia M. | Gloyn, Anna L.
PLoS Genetics  2015;11(1):e1004876.
Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights.
Author Summary
Understanding how FI and FG levels are regulated is important because their derangement is a feature of T2D. Despite recent success from GWAS in identifying regions of the genome influencing glycemic traits, collectively these loci explain only a small proportion of trait variance. Unlocking the biological mechanisms driving these associations has been challenging because the vast majority of variants map to non-coding sequence, and the genes through which they exert their impact are largely unknown. In the current study, we sought to increase our understanding of the physiological pathways influencing both traits using exome-array genotyping in up to 33,231 non-diabetic individuals to identify coding variants and consequently genes associated with either FG or FI levels. We identified novel association signals for both traits including the receptor for GLP-1 agonists which are a widely used therapy for T2D. Furthermore, we identified coding variants at several GWAS loci which point to the genes underlying these association signals. Importantly, we found that multiple coding variants in G6PC2 result in a loss of protein function and lower fasting glucose levels.
doi:10.1371/journal.pgen.1004876
PMCID: PMC4307976  PMID: 25625282
2.  Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture 
Berndt, Sonja I. | Gustafsson, Stefan | Mägi, Reedik | Ganna, Andrea | Wheeler, Eleanor | Feitosa, Mary F. | Justice, Anne E. | Monda, Keri L. | Croteau-Chonka, Damien C. | Day, Felix R. | Esko, Tõnu | Fall, Tove | Ferreira, Teresa | Gentilini, Davide | Jackson, Anne U. | Luan, Jian’an | Randall, Joshua C. | Vedantam, Sailaja | Willer, Cristen J. | Winkler, Thomas W. | Wood, Andrew R. | Workalemahu, Tsegaselassie | Hu, Yi-Juan | Lee, Sang Hong | Liang, Liming | Lin, Dan-Yu | Min, Josine L. | Neale, Benjamin M. | Thorleifsson, Gudmar | Yang, Jian | Albrecht, Eva | Amin, Najaf | Bragg-Gresham, Jennifer L. | Cadby, Gemma | den Heijer, Martin | Eklund, Niina | Fischer, Krista | Goel, Anuj | Hottenga, Jouke-Jan | Huffman, Jennifer E. | Jarick, Ivonne | Johansson, Åsa | Johnson, Toby | Kanoni, Stavroula | Kleber, Marcus E. | König, Inke R. | Kristiansson, Kati | Kutalik, Zoltán | Lamina, Claudia | Lecoeur, Cecile | Li, Guo | Mangino, Massimo | McArdle, Wendy L. | Medina-Gomez, Carolina | Müller-Nurasyid, Martina | Ngwa, Julius S. | Nolte, Ilja M. | Paternoster, Lavinia | Pechlivanis, Sonali | Perola, Markus | Peters, Marjolein J. | Preuss, Michael | Rose, Lynda M. | Shi, Jianxin | Shungin, Dmitry | Smith, Albert Vernon | Strawbridge, Rona J. | Surakka, Ida | Teumer, Alexander | Trip, Mieke D. | Tyrer, Jonathan | Van Vliet-Ostaptchouk, Jana V. | Vandenput, Liesbeth | Waite, Lindsay L. | Zhao, Jing Hua | Absher, Devin | Asselbergs, Folkert W. | Atalay, Mustafa | Attwood, Antony P. | Balmforth, Anthony J. | Basart, Hanneke | Beilby, John | Bonnycastle, Lori L. | Brambilla, Paolo | Bruinenberg, Marcel | Campbell, Harry | Chasman, Daniel I. | Chines, Peter S. | Collins, Francis S. | Connell, John M. | Cookson, William | de Faire, Ulf | de Vegt, Femmie | Dei, Mariano | Dimitriou, Maria | Edkins, Sarah | Estrada, Karol | Evans, David M. | Farrall, Martin | Ferrario, Marco M. | Ferrières, Jean | Franke, Lude | Frau, Francesca | Gejman, Pablo V. | Grallert, Harald | Grönberg, Henrik | Gudnason, Vilmundur | Hall, Alistair S. | Hall, Per | Hartikainen, Anna-Liisa | Hayward, Caroline | Heard-Costa, Nancy L. | Heath, Andrew C. | Hebebrand, Johannes | Homuth, Georg | Hu, Frank B. | Hunt, Sarah E. | Hyppönen, Elina | Iribarren, Carlos | Jacobs, Kevin B. | Jansson, John-Olov | Jula, Antti | Kähönen, Mika | Kathiresan, Sekar | Kee, Frank | Khaw, Kay-Tee | Kivimaki, Mika | Koenig, Wolfgang | Kraja, Aldi T. | Kumari, Meena | Kuulasmaa, Kari | Kuusisto, Johanna | Laitinen, Jaana H. | Lakka, Timo A. | Langenberg, Claudia | Launer, Lenore J. | Lind, Lars | Lindström, Jaana | Liu, Jianjun | Liuzzi, Antonio | Lokki, Marja-Liisa | Lorentzon, Mattias | Madden, Pamela A. | Magnusson, Patrik K. | Manunta, Paolo | Marek, Diana | März, Winfried | Mateo Leach, Irene | McKnight, Barbara | Medland, Sarah E. | Mihailov, Evelin | Milani, Lili | Montgomery, Grant W. | Mooser, Vincent | Mühleisen, Thomas W. | Munroe, Patricia B. | Musk, Arthur W. | Narisu, Narisu | Navis, Gerjan | Nicholson, George | Nohr, Ellen A. | Ong, Ken K. | Oostra, Ben A. | Palmer, Colin N.A. | Palotie, Aarno | Peden, John F. | Pedersen, Nancy | Peters, Annette | Polasek, Ozren | Pouta, Anneli | Pramstaller, Peter P. | Prokopenko, Inga | Pütter, Carolin | Radhakrishnan, Aparna | Raitakari, Olli | Rendon, Augusto | Rivadeneira, Fernando | Rudan, Igor | Saaristo, Timo E. | Sambrook, Jennifer G. | Sanders, Alan R. | Sanna, Serena | Saramies, Jouko | Schipf, Sabine | Schreiber, Stefan | Schunkert, Heribert | Shin, So-Youn | Signorini, Stefano | Sinisalo, Juha | Skrobek, Boris | Soranzo, Nicole | Stančáková, Alena | Stark, Klaus | Stephens, Jonathan C. | Stirrups, Kathleen | Stolk, Ronald P. | Stumvoll, Michael | Swift, Amy J. | Theodoraki, Eirini V. | Thorand, Barbara | Tregouet, David-Alexandre | Tremoli, Elena | Van der Klauw, Melanie M. | van Meurs, Joyce B.J. | Vermeulen, Sita H. | Viikari, Jorma | Virtamo, Jarmo | Vitart, Veronique | Waeber, Gérard | Wang, Zhaoming | Widén, Elisabeth | Wild, Sarah H. | Willemsen, Gonneke | Winkelmann, Bernhard R. | Witteman, Jacqueline C.M. | Wolffenbuttel, Bruce H.R. | Wong, Andrew | Wright, Alan F. | Zillikens, M. Carola | Amouyel, Philippe | Boehm, Bernhard O. | Boerwinkle, Eric | Boomsma, Dorret I. | Caulfield, Mark J. | Chanock, Stephen J. | Cupples, L. Adrienne | Cusi, Daniele | Dedoussis, George V. | Erdmann, Jeanette | Eriksson, Johan G. | Franks, Paul W. | Froguel, Philippe | Gieger, Christian | Gyllensten, Ulf | Hamsten, Anders | Harris, Tamara B. | Hengstenberg, Christian | Hicks, Andrew A. | Hingorani, Aroon | Hinney, Anke | Hofman, Albert | Hovingh, Kees G. | Hveem, Kristian | Illig, Thomas | Jarvelin, Marjo-Riitta | Jöckel, Karl-Heinz | Keinanen-Kiukaanniemi, Sirkka M. | Kiemeney, Lambertus A. | Kuh, Diana | Laakso, Markku | Lehtimäki, Terho | Levinson, Douglas F. | Martin, Nicholas G. | Metspalu, Andres | Morris, Andrew D. | Nieminen, Markku S. | Njølstad, Inger | Ohlsson, Claes | Oldehinkel, Albertine J. | Ouwehand, Willem H. | Palmer, Lyle J. | Penninx, Brenda | Power, Chris | Province, Michael A. | Psaty, Bruce M. | Qi, Lu | Rauramaa, Rainer | Ridker, Paul M. | Ripatti, Samuli | Salomaa, Veikko | Samani, Nilesh J. | Snieder, Harold | Sørensen, Thorkild I.A. | Spector, Timothy D. | Stefansson, Kari | Tönjes, Anke | Tuomilehto, Jaakko | Uitterlinden, André G. | Uusitupa, Matti | van der Harst, Pim | Vollenweider, Peter | Wallaschofski, Henri | Wareham, Nicholas J. | Watkins, Hugh | Wichmann, H.-Erich | Wilson, James F. | Abecasis, Goncalo R. | Assimes, Themistocles L. | Barroso, Inês | Boehnke, Michael | Borecki, Ingrid B. | Deloukas, Panos | Fox, Caroline S. | Frayling, Timothy | Groop, Leif C. | Haritunian, Talin | Heid, Iris M. | Hunter, David | Kaplan, Robert C. | Karpe, Fredrik | Moffatt, Miriam | Mohlke, Karen L. | O’Connell, Jeffrey R. | Pawitan, Yudi | Schadt, Eric E. | Schlessinger, David | Steinthorsdottir, Valgerdur | Strachan, David P. | Thorsteinsdottir, Unnur | van Duijn, Cornelia M. | Visscher, Peter M. | Di Blasio, Anna Maria | Hirschhorn, Joel N. | Lindgren, Cecilia M. | Morris, Andrew P. | Meyre, David | Scherag, André | McCarthy, Mark I. | Speliotes, Elizabeth K. | North, Kari E. | Loos, Ruth J.F. | Ingelsson, Erik
Nature genetics  2013;45(5):501-512.
Approaches exploiting extremes of the trait distribution may reveal novel loci for common traits, but it is unknown whether such loci are generalizable to the general population. In a genome-wide search for loci associated with upper vs. lower 5th percentiles of body mass index, height and waist-hip ratio, as well as clinical classes of obesity including up to 263,407 European individuals, we identified four new loci (IGFBP4, H6PD, RSRC1, PPP2R2A) influencing height detected in the tails and seven new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3, ZZZ3) for clinical classes of obesity. Further, we show that there is large overlap in terms of genetic structure and distribution of variants between traits based on extremes and the general population and little etiologic heterogeneity between obesity subgroups.
doi:10.1038/ng.2606
PMCID: PMC3973018  PMID: 23563607
3.  Multiple type 2 diabetes susceptibility genes following genome-wide association scan in UK samples 
Science (New York, N.Y.)  2007;316(5829):1336-1341.
The molecular mechanisms involved in the development of type 2 diabetes are poorly understood. Starting from genome-wide genotype data for 1,924 diabetic cases and 2,938 population controls generated by the Wellcome Trust Case Control Consortium, we set out to detect replicated diabetes association signals through analysis of 3,757 additional cases and 5,346 controls, and by integration of our findings with equivalent data from other international consortia. We detected diabetes susceptibility loci in and around the genes CDKAL1, CDKN2A/CDKN2B and IGF2BP2 and confirmed the recently described associations at HHEX/IDE and SLC30A8. Our findings provide insights into the genetic architecture of type 2 diabetes, emphasizing the contribution of multiple variants of modest effect. The regions identified underscore the importance of pathways influencing pancreatic beta cell development and function in the etiology of type 2 diabetes.
doi:10.1126/science.1142364
PMCID: PMC3772310  PMID: 17463249
4.  Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways 
Scott, Robert A | Lagou, Vasiliki | Welch, Ryan P | Wheeler, Eleanor | Montasser, May E | Luan, Jian’an | Mägi, Reedik | Strawbridge, Rona J | Rehnberg, Emil | Gustafsson, Stefan | Kanoni, Stavroula | Rasmussen-Torvik, Laura J | Yengo, Loïc | Lecoeur, Cecile | Shungin, Dmitry | Sanna, Serena | Sidore, Carlo | Johnson, Paul C D | Jukema, J Wouter | Johnson, Toby | Mahajan, Anubha | Verweij, Niek | Thorleifsson, Gudmar | Hottenga, Jouke-Jan | Shah, Sonia | Smith, Albert V | Sennblad, Bengt | Gieger, Christian | Salo, Perttu | Perola, Markus | Timpson, Nicholas J | Evans, David M | Pourcain, Beate St | Wu, Ying | Andrews, Jeanette S | Hui, Jennie | Bielak, Lawrence F | Zhao, Wei | Horikoshi, Momoko | Navarro, Pau | Isaacs, Aaron | O’Connell, Jeffrey R | Stirrups, Kathleen | Vitart, Veronique | Hayward, Caroline | Esko, Tönu | Mihailov, Evelin | Fraser, Ross M | Fall, Tove | Voight, Benjamin F | Raychaudhuri, Soumya | Chen, Han | Lindgren, Cecilia M | Morris, Andrew P | Rayner, Nigel W | Robertson, Neil | Rybin, Denis | Liu, Ching-Ti | Beckmann, Jacques S | Willems, Sara M | Chines, Peter S | Jackson, Anne U | Kang, Hyun Min | Stringham, Heather M | Song, Kijoung | Tanaka, Toshiko | Peden, John F | Goel, Anuj | Hicks, Andrew A | An, Ping | Müller-Nurasyid, Martina | Franco-Cereceda, Anders | Folkersen, Lasse | Marullo, Letizia | Jansen, Hanneke | Oldehinkel, Albertine J | Bruinenberg, Marcel | Pankow, James S | North, Kari E | Forouhi, Nita G | Loos, Ruth J F | Edkins, Sarah | Varga, Tibor V | Hallmans, Göran | Oksa, Heikki | Antonella, Mulas | Nagaraja, Ramaiah | Trompet, Stella | Ford, Ian | Bakker, Stephan J L | Kong, Augustine | Kumari, Meena | Gigante, Bruna | Herder, Christian | Munroe, Patricia B | Caulfield, Mark | Antti, Jula | Mangino, Massimo | Small, Kerrin | Miljkovic, Iva | Liu, Yongmei | Atalay, Mustafa | Kiess, Wieland | James, Alan L | Rivadeneira, Fernando | Uitterlinden, Andre G | Palmer, Colin N A | Doney, Alex S F | Willemsen, Gonneke | Smit, Johannes H | Campbell, Susan | Polasek, Ozren | Bonnycastle, Lori L | Hercberg, Serge | Dimitriou, Maria | Bolton, Jennifer L | Fowkes, Gerard R | Kovacs, Peter | Lindström, Jaana | Zemunik, Tatijana | Bandinelli, Stefania | Wild, Sarah H | Basart, Hanneke V | Rathmann, Wolfgang | Grallert, Harald | Maerz, Winfried | Kleber, Marcus E | Boehm, Bernhard O | Peters, Annette | Pramstaller, Peter P | Province, Michael A | Borecki, Ingrid B | Hastie, Nicholas D | Rudan, Igor | Campbell, Harry | Watkins, Hugh | Farrall, Martin | Stumvoll, Michael | Ferrucci, Luigi | Waterworth, Dawn M | Bergman, Richard N | Collins, Francis S | Tuomilehto, Jaakko | Watanabe, Richard M | de Geus, Eco J C | Penninx, Brenda W | Hofman, Albert | Oostra, Ben A | Psaty, Bruce M | Vollenweider, Peter | Wilson, James F | Wright, Alan F | Hovingh, G Kees | Metspalu, Andres | Uusitupa, Matti | Magnusson, Patrik K E | Kyvik, Kirsten O | Kaprio, Jaakko | Price, Jackie F | Dedoussis, George V | Deloukas, Panos | Meneton, Pierre | Lind, Lars | Boehnke, Michael | Shuldiner, Alan R | van Duijn, Cornelia M | Morris, Andrew D | Toenjes, Anke | Peyser, Patricia A | Beilby, John P | Körner, Antje | Kuusisto, Johanna | Laakso, Markku | Bornstein, Stefan R | Schwarz, Peter E H | Lakka, Timo A | Rauramaa, Rainer | Adair, Linda S | Smith, George Davey | Spector, Tim D | Illig, Thomas | de Faire, Ulf | Hamsten, Anders | Gudnason, Vilmundur | Kivimaki, Mika | Hingorani, Aroon | Keinanen-Kiukaanniemi, Sirkka M | Saaristo, Timo E | Boomsma, Dorret I | Stefansson, Kari | van der Harst, Pim | Dupuis, Josée | Pedersen, Nancy L | Sattar, Naveed | Harris, Tamara B | Cucca, Francesco | Ripatti, Samuli | Salomaa, Veikko | Mohlke, Karen L | Balkau, Beverley | Froguel, Philippe | Pouta, Anneli | Jarvelin, Marjo-Riitta | Wareham, Nicholas J | Bouatia-Naji, Nabila | McCarthy, Mark I | Franks, Paul W | Meigs, James B | Teslovich, Tanya M | Florez, Jose C | Langenberg, Claudia | Ingelsson, Erik | Prokopenko, Inga | Barroso, Inês
Nature genetics  2012;44(9):991-1005.
Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have raised the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional follow-up of these newly discovered loci will further improve our understanding of glycemic control.
doi:10.1038/ng.2385
PMCID: PMC3433394  PMID: 22885924
5.  Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes 
Morris, Andrew P | Voight, Benjamin F | Teslovich, Tanya M | Ferreira, Teresa | Segrè, Ayellet V | Steinthorsdottir, Valgerdur | Strawbridge, Rona J | Khan, Hassan | Grallert, Harald | Mahajan, Anubha | Prokopenko, Inga | Kang, Hyun Min | Dina, Christian | Esko, Tonu | Fraser, Ross M | Kanoni, Stavroula | Kumar, Ashish | Lagou, Vasiliki | Langenberg, Claudia | Luan, Jian'an | Lindgren, Cecilia M | Müller-Nurasyid, Martina | Pechlivanis, Sonali | Rayner, N William | Scott, Laura J | Wiltshire, Steven | Yengo, Loic | Kinnunen, Leena | Rossin, Elizabeth J | Raychaudhuri, Soumya | Johnson, Andrew D | Dimas, Antigone S | Loos, Ruth J F | Vedantam, Sailaja | Chen, Han | Florez, Jose C | Fox, Caroline | Liu, Ching-Ti | Rybin, Denis | Couper, David J | Kao, Wen Hong L | Li, Man | Cornelis, Marilyn C | Kraft, Peter | Sun, Qi | van Dam, Rob M | Stringham, Heather M | Chines, Peter S | Fischer, Krista | Fontanillas, Pierre | Holmen, Oddgeir L | Hunt, Sarah E | Jackson, Anne U | Kong, Augustine | Lawrence, Robert | Meyer, Julia | Perry, John RB | Platou, Carl GP | Potter, Simon | Rehnberg, Emil | Robertson, Neil | Sivapalaratnam, Suthesh | Stančáková, Alena | Stirrups, Kathleen | Thorleifsson, Gudmar | Tikkanen, Emmi | Wood, Andrew R | Almgren, Peter | Atalay, Mustafa | Benediktsson, Rafn | Bonnycastle, Lori L | Burtt, Noël | Carey, Jason | Charpentier, Guillaume | Crenshaw, Andrew T | Doney, Alex S F | Dorkhan, Mozhgan | Edkins, Sarah | Emilsson, Valur | Eury, Elodie | Forsen, Tom | Gertow, Karl | Gigante, Bruna | Grant, George B | Groves, Christopher J | Guiducci, Candace | Herder, Christian | Hreidarsson, Astradur B | Hui, Jennie | James, Alan | Jonsson, Anna | Rathmann, Wolfgang | Klopp, Norman | Kravic, Jasmina | Krjutškov, Kaarel | Langford, Cordelia | Leander, Karin | Lindholm, Eero | Lobbens, Stéphane | Männistö, Satu | Mirza, Ghazala | Mühleisen, Thomas W | Musk, Bill | Parkin, Melissa | Rallidis, Loukianos | Saramies, Jouko | Sennblad, Bengt | Shah, Sonia | Sigurðsson, Gunnar | Silveira, Angela | Steinbach, Gerald | Thorand, Barbara | Trakalo, Joseph | Veglia, Fabrizio | Wennauer, Roman | Winckler, Wendy | Zabaneh, Delilah | Campbell, Harry | van Duijn, Cornelia | Uitterlinden89-, Andre G | Hofman, Albert | Sijbrands, Eric | Abecasis, Goncalo R | Owen, Katharine R | Zeggini, Eleftheria | Trip, Mieke D | Forouhi, Nita G | Syvänen, Ann-Christine | Eriksson, Johan G | Peltonen, Leena | Nöthen, Markus M | Balkau, Beverley | Palmer, Colin N A | Lyssenko, Valeriya | Tuomi, Tiinamaija | Isomaa, Bo | Hunter, David J | Qi, Lu | Shuldiner, Alan R | Roden, Michael | Barroso, Ines | Wilsgaard, Tom | Beilby, John | Hovingh, Kees | Price, Jackie F | Wilson, James F | Rauramaa, Rainer | Lakka, Timo A | Lind, Lars | Dedoussis, George | Njølstad, Inger | Pedersen, Nancy L | Khaw, Kay-Tee | Wareham, Nicholas J | Keinanen-Kiukaanniemi, Sirkka M | Saaristo, Timo E | Korpi-Hyövälti, Eeva | Saltevo, Juha | Laakso, Markku | Kuusisto, Johanna | Metspalu, Andres | Collins, Francis S | Mohlke, Karen L | Bergman, Richard N | Tuomilehto, Jaakko | Boehm, Bernhard O | Gieger, Christian | Hveem, Kristian | Cauchi, Stephane | Froguel, Philippe | Baldassarre, Damiano | Tremoli, Elena | Humphries, Steve E | Saleheen, Danish | Danesh, John | Ingelsson, Erik | Ripatti, Samuli | Salomaa, Veikko | Erbel, Raimund | Jöckel, Karl-Heinz | Moebus, Susanne | Peters, Annette | Illig, Thomas | de Faire, Ulf | Hamsten, Anders | Morris, Andrew D | Donnelly, Peter J | Frayling, Timothy M | Hattersley, Andrew T | Boerwinkle, Eric | Melander, Olle | Kathiresan, Sekar | Nilsson, Peter M | Deloukas, Panos | Thorsteinsdottir, Unnur | Groop, Leif C | Stefansson, Kari | Hu, Frank | Pankow, James S | Dupuis, Josée | Meigs, James B | Altshuler, David | Boehnke, Michael | McCarthy, Mark I
Nature genetics  2012;44(9):981-990.
To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip involving 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two demonstrating sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of further common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signalling and cell cycle regulation, in diabetes pathogenesis.
doi:10.1038/ng.2383
PMCID: PMC3442244  PMID: 22885922
6.  Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes 
Morris, Andrew P | Voight, Benjamin F | Teslovich, Tanya M | Ferreira, Teresa | Segré, Ayellet V | Steinthorsdottir, Valgerdur | Strawbridge, Rona J | Khan, Hassan | Grallert, Harald | Mahajan, Anubha | Prokopenko, Inga | Kang, Hyun Min | Dina, Christian | Esko, Tonu | Fraser, Ross M | Kanoni, Stavroula | Kumar, Ashish | Lagou, Vasiliki | Langenberg, Claudia | Luan, Jian’an | Lindgren, Cecilia M | Müller-Nurasyid, Martina | Pechlivanis, Sonali | Rayner, N William | Scott, Laura J | Wiltshire, Steven | Yengo, Loic | Kinnunen, Leena | Rossin, Elizabeth J | Raychaudhuri, Soumya | Johnson, Andrew D | Dimas, Antigone S | Loos, Ruth J F | Vedantam, Sailaja | Chen, Han | Florez, Jose C | Fox, Caroline | Liu, Ching-Ti | Rybin, Denis | Couper, David J | Kao, Wen Hong L | Li, Man | Cornelis, Marilyn C | Kraft, Peter | Sun, Qi | van Dam, Rob M | Stringham, Heather M | Chines, Peter S | Fischer, Krista | Fontanillas, Pierre | Holmen, Oddgeir L | Hunt, Sarah E | Jackson, Anne U | Kong, Augustine | Lawrence, Robert | Meyer, Julia | Perry, John R B | Platou, Carl G P | Potter, Simon | Rehnberg, Emil | Robertson, Neil | Sivapalaratnam, Suthesh | Stančáková, Alena | Stirrups, Kathleen | Thorleifsson, Gudmar | Tikkanen, Emmi | Wood, Andrew R | Almgren, Peter | Atalay, Mustafa | Benediktsson, Rafn | Bonnycastle, Lori L | Burtt, Noël | Carey, Jason | Charpentier, Guillaume | Crenshaw, Andrew T | Doney, Alex S F | Dorkhan, Mozhgan | Edkins, Sarah | Emilsson, Valur | Eury, Elodie | Forsen, Tom | Gertow, Karl | Gigante, Bruna | Grant, George B | Groves, Christopher J | Guiducci, Candace | Herder, Christian | Hreidarsson, Astradur B | Hui, Jennie | James, Alan | Jonsson, Anna | Rathmann, Wolfgang | Klopp, Norman | Kravic, Jasmina | Krjutškov, Kaarel | Langford, Cordelia | Leander, Karin | Lindholm, Eero | Lobbens, Stéphane | Männistö, Satu | Mirza, Ghazala | Mühleisen, Thomas W | Musk, Bill | Parkin, Melissa | Rallidis, Loukianos | Saramies, Jouko | Sennblad, Bengt | Shah, Sonia | Sigurðsson, Gunnar | Silveira, Angela | Steinbach, Gerald | Thorand, Barbara | Trakalo, Joseph | Veglia, Fabrizio | Wennauer, Roman | Winckler, Wendy | Zabaneh, Delilah | Campbell, Harry | van Duijn, Cornelia | Uitterlinden, Andre G | Hofman, Albert | Sijbrands, Eric | Abecasis, Goncalo R | Owen, Katharine R | Zeggini, Eleftheria | Trip, Mieke D | Forouhi, Nita G | Syvänen, Ann-Christine | Eriksson, Johan G | Peltonen, Leena | Nöthen, Markus M | Balkau, Beverley | Palmer, Colin N A | Lyssenko, Valeriya | Tuomi, Tiinamaija | Isomaa, Bo | Hunter, David J | Qi, Lu | Shuldiner, Alan R | Roden, Michael | Barroso, Ines | Wilsgaard, Tom | Beilby, John | Hovingh, Kees | Price, Jackie F | Wilson, James F | Rauramaa, Rainer | Lakka, Timo A | Lind, Lars | Dedoussis, George | Njølstad, Inger | Pedersen, Nancy L | Khaw, Kay-Tee | Wareham, Nicholas J | Keinanen-Kiukaanniemi, Sirkka M | Saaristo, Timo E | Korpi-Hyövälti, Eeva | Saltevo, Juha | Laakso, Markku | Kuusisto, Johanna | Metspalu, Andres | Collins, Francis S | Mohlke, Karen L | Bergman, Richard N | Tuomilehto, Jaakko | Boehm, Bernhard O | Gieger, Christian | Hveem, Kristian | Cauchi, Stephane | Froguel, Philippe | Baldassarre, Damiano | Tremoli, Elena | Humphries, Steve E | Saleheen, Danish | Danesh, John | Ingelsson, Erik | Ripatti, Samuli | Salomaa, Veikko | Erbel, Raimund | Jöckel, Karl-Heinz | Moebus, Susanne | Peters, Annette | Illig, Thomas | de Faire, Ulf | Hamsten, Anders | Morris, Andrew D | Donnelly, Peter J | Frayling, Timothy M | Hattersley, Andrew T | Boerwinkle, Eric | Melander, Olle | Kathiresan, Sekar | Nilsson, Peter M | Deloukas, Panos | Thorsteinsdottir, Unnur | Groop, Leif C | Stefansson, Kari | Hu, Frank | Pankow, James S | Dupuis, Josée | Meigs, James B | Altshuler, David | Boehnke, Michael | McCarthy, Mark I
Nature genetics  2012;44(9):981-990.
To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip involving 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two demonstrating sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of further common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signalling and cell cycle regulation, in diabetes pathogenesis.
doi:10.1038/ng.2383
PMCID: PMC3442244  PMID: 22885922
7.  Stratifying Type 2 Diabetes Cases by BMI Identifies Genetic Risk Variants in LAMA1 and Enrichment for Risk Variants in Lean Compared to Obese Cases 
Perry, John R. B. | Voight, Benjamin F. | Yengo, Loïc | Amin, Najaf | Dupuis, Josée | Ganser, Martha | Grallert, Harald | Navarro, Pau | Li, Man | Qi, Lu | Steinthorsdottir, Valgerdur | Scott, Robert A. | Almgren, Peter | Arking, Dan E. | Aulchenko, Yurii | Balkau, Beverley | Benediktsson, Rafn | Bergman, Richard N. | Boerwinkle, Eric | Bonnycastle, Lori | Burtt, Noël P. | Campbell, Harry | Charpentier, Guillaume | Collins, Francis S. | Gieger, Christian | Green, Todd | Hadjadj, Samy | Hattersley, Andrew T. | Herder, Christian | Hofman, Albert | Johnson, Andrew D. | Kottgen, Anna | Kraft, Peter | Labrune, Yann | Langenberg, Claudia | Manning, Alisa K. | Mohlke, Karen L. | Morris, Andrew P. | Oostra, Ben | Pankow, James | Petersen, Ann-Kristin | Pramstaller, Peter P. | Prokopenko, Inga | Rathmann, Wolfgang | Rayner, William | Roden, Michael | Rudan, Igor | Rybin, Denis | Scott, Laura J. | Sigurdsson, Gunnar | Sladek, Rob | Thorleifsson, Gudmar | Thorsteinsdottir, Unnur | Tuomilehto, Jaakko | Uitterlinden, Andre G. | Vivequin, Sidonie | Weedon, Michael N. | Wright, Alan F. | Hu, Frank B. | Illig, Thomas | Kao, Linda | Meigs, James B. | Wilson, James F. | Stefansson, Kari | van Duijn, Cornelia | Altschuler, David | Morris, Andrew D. | Boehnke, Michael | McCarthy, Mark I. | Froguel, Philippe | Palmer, Colin N. A. | Wareham, Nicholas J. | Groop, Leif | Frayling, Timothy M. | Cauchi, Stéphane
PLoS Genetics  2012;8(5):e1002741.
Common diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a major risk factor for type 2 diabetes, but patients vary appreciably in body mass index. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI<25 Kg/m2) compared to obese cases (BMI≥30 Kg/m2). We performed two case-control genome-wide studies using two accepted cut-offs for defining individuals as overweight or obese. We used 2,112 lean type 2 diabetes cases (BMI<25 kg/m2) or 4,123 obese cases (BMI≥30 kg/m2), and 54,412 un-stratified controls. Replication was performed in 2,881 lean cases or 8,702 obese cases, and 18,957 un-stratified controls. To assess the effects of known signals, we tested the individual and combined effects of SNPs representing 36 type 2 diabetes loci. After combining data from discovery and replication datasets, we identified two signals not previously reported in Europeans. A variant (rs8090011) in the LAMA1 gene was associated with type 2 diabetes in lean cases (P = 8.4×10−9, OR = 1.13 [95% CI 1.09–1.18]), and this association was stronger than that in obese cases (P = 0.04, OR = 1.03 [95% CI 1.00–1.06]). A variant in HMG20A—previously identified in South Asians but not Europeans—was associated with type 2 diabetes in obese cases (P = 1.3×10−8, OR = 1.11 [95% CI 1.07–1.15]), although this association was not significantly stronger than that in lean cases (P = 0.02, OR = 1.09 [95% CI 1.02–1.17]). For 36 known type 2 diabetes loci, 29 had a larger odds ratio in the lean compared to obese (binomial P = 0.0002). In the lean analysis, we observed a weighted per-risk allele OR = 1.13 [95% CI 1.10–1.17], P = 3.2×10−14. This was larger than the same model fitted in the obese analysis where the OR = 1.06 [95% CI 1.05–1.08], P = 2.2×10−16. This study provides evidence that stratification of type 2 diabetes cases by BMI may help identify additional risk variants and that lean cases may have a stronger genetic predisposition to type 2 diabetes.
Author Summary
Individuals with Type 2 diabetes (T2D) can present with variable clinical characteristics. It is well known that obesity is a major risk factor for type 2 diabetes, yet patients can vary considerably—there are many lean diabetes patients and many overweight people without diabetes. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI<25 Kg/m2) compared to obese cases (BMI≥30 Kg/m2). Specifically, as lean T2D patients had lower risk than obese patients, they must have been more genetically susceptible. Using genetic data from multiple genome-wide association studies, we tested genetic markers across the genome in 2,112 lean type 2 diabetes cases (BMI<25 kg/m2), 4,123 obese cases (BMI≥30 kg/m2), and 54,412 healthy controls. We confirmed our results in an additional 2,881 lean cases, 8,702 obese cases, and 18,957 healthy controls. Using these data we found differences in genetic enrichment between lean and obese cases, supporting our original hypothesis. We also searched for genetic variants that may be risk factors only in lean or obese patients and found two novel gene regions not previously reported in European individuals. These findings may influence future study design for type 2 diabetes and provide further insight into the biology of the disease.
doi:10.1371/journal.pgen.1002741
PMCID: PMC3364960  PMID: 22693455
8.  Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis 
Voight, Benjamin F | Scott, Laura J | Steinthorsdottir, Valgerdur | Morris, Andrew P | Dina, Christian | Welch, Ryan P | Zeggini, Eleftheria | Huth, Cornelia | Aulchenko, Yurii S | Thorleifsson, Gudmar | McCulloch, Laura J | Ferreira, Teresa | Grallert, Harald | Amin, Najaf | Wu, Guanming | Willer, Cristen J | Raychaudhuri, Soumya | McCarroll, Steve A | Langenberg, Claudia | Hofmann, Oliver M | Dupuis, Josée | Qi, Lu | Segrè, Ayellet V | van Hoek, Mandy | Navarro, Pau | Ardlie, Kristin | Balkau, Beverley | Benediktsson, Rafn | Bennett, Amanda J | Blagieva, Roza | Boerwinkle, Eric | Bonnycastle, Lori L | Boström, Kristina Bengtsson | Bravenboer, Bert | Bumpstead, Suzannah | Burtt, Noisël P | Charpentier, Guillaume | Chines, Peter S | Cornelis, Marilyn | Couper, David J | Crawford, Gabe | Doney, Alex S F | Elliott, Katherine S | Elliott, Amanda L | Erdos, Michael R | Fox, Caroline S | Franklin, Christopher S | Ganser, Martha | Gieger, Christian | Grarup, Niels | Green, Todd | Griffin, Simon | Groves, Christopher J | Guiducci, Candace | Hadjadj, Samy | Hassanali, Neelam | Herder, Christian | Isomaa, Bo | Jackson, Anne U | Johnson, Paul R V | Jørgensen, Torben | Kao, Wen H L | Klopp, Norman | Kong, Augustine | Kraft, Peter | Kuusisto, Johanna | Lauritzen, Torsten | Li, Man | Lieverse, Aloysius | Lindgren, Cecilia M | Lyssenko, Valeriya | Marre, Michel | Meitinger, Thomas | Midthjell, Kristian | Morken, Mario A | Narisu, Narisu | Nilsson, Peter | Owen, Katharine R | Payne, Felicity | Perry, John R B | Petersen, Ann-Kristin | Platou, Carl | Proença, Christine | Prokopenko, Inga | Rathmann, Wolfgang | Rayner, N William | Robertson, Neil R | Rocheleau, Ghislain | Roden, Michael | Sampson, Michael J | Saxena, Richa | Shields, Beverley M | Shrader, Peter | Sigurdsson, Gunnar | Sparsø, Thomas | Strassburger, Klaus | Stringham, Heather M | Sun, Qi | Swift, Amy J | Thorand, Barbara | Tichet, Jean | Tuomi, Tiinamaija | van Dam, Rob M | van Haeften, Timon W | van Herpt, Thijs | van Vliet-Ostaptchouk, Jana V | Walters, G Bragi | Weedon, Michael N | Wijmenga, Cisca | Witteman, Jacqueline | Bergman, Richard N | Cauchi, Stephane | Collins, Francis S | Gloyn, Anna L | Gyllensten, Ulf | Hansen, Torben | Hide, Winston A | Hitman, Graham A | Hofman, Albert | Hunter, David J | Hveem, Kristian | Laakso, Markku | Mohlke, Karen L | Morris, Andrew D | Palmer, Colin N A | Pramstaller, Peter P | Rudan, Igor | Sijbrands, Eric | Stein, Lincoln D | Tuomilehto, Jaakko | Uitterlinden, Andre | Walker, Mark | Wareham, Nicholas J | Watanabe, Richard M | Abecasis, Gonçalo R | Boehm, Bernhard O | Campbell, Harry | Daly, Mark J | Hattersley, Andrew T | Hu, Frank B | Meigs, James B | Pankow, James S | Pedersen, Oluf | Wichmann, H-Erich | Barroso, Inês | Florez, Jose C | Frayling, Timothy M | Groop, Leif | Sladek, Rob | Thorsteinsdottir, Unnur | Wilson, James F | Illig, Thomas | Froguel, Philippe | van Duijn, Cornelia M | Stefansson, Kari | Altshuler, David | Boehnke, Michael | McCarthy, Mark I
Nature genetics  2010;42(7):579-589.
By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combinedP < 5 × 10−8. These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.
doi:10.1038/ng.609
PMCID: PMC3080658  PMID: 20581827
9.  New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk 
Dupuis, Josée | Langenberg, Claudia | Prokopenko, Inga | Saxena, Richa | Soranzo, Nicole | Jackson, Anne U | Wheeler, Eleanor | Glazer, Nicole L | Bouatia-Naji, Nabila | Gloyn, Anna L | Lindgren, Cecilia M | Mägi, Reedik | Morris, Andrew P | Randall, Joshua | Johnson, Toby | Elliott, Paul | Rybin, Denis | Thorleifsson, Gudmar | Steinthorsdottir, Valgerdur | Henneman, Peter | Grallert, Harald | Dehghan, Abbas | Hottenga, Jouke Jan | Franklin, Christopher S | Navarro, Pau | Song, Kijoung | Goel, Anuj | Perry, John R B | Egan, Josephine M | Lajunen, Taina | Grarup, Niels | Sparsø, Thomas | Doney, Alex | Voight, Benjamin F | Stringham, Heather M | Li, Man | Kanoni, Stavroula | Shrader, Peter | Cavalcanti-Proença, Christine | Kumari, Meena | Qi, Lu | Timpson, Nicholas J | Gieger, Christian | Zabena, Carina | Rocheleau, Ghislain | Ingelsson, Erik | An, Ping | O’Connell, Jeffrey | Luan, Jian'an | Elliott, Amanda | McCarroll, Steven A | Payne, Felicity | Roccasecca, Rosa Maria | Pattou, François | Sethupathy, Praveen | Ardlie, Kristin | Ariyurek, Yavuz | Balkau, Beverley | Barter, Philip | Beilby, John P | Ben-Shlomo, Yoav | Benediktsson, Rafn | Bennett, Amanda J | Bergmann, Sven | Bochud, Murielle | Boerwinkle, Eric | Bonnefond, Amélie | Bonnycastle, Lori L | Borch-Johnsen, Knut | Böttcher, Yvonne | Brunner, Eric | Bumpstead, Suzannah J | Charpentier, Guillaume | Chen, Yii-Der Ida | Chines, Peter | Clarke, Robert | Coin, Lachlan J M | Cooper, Matthew N | Cornelis, Marilyn | Crawford, Gabe | Crisponi, Laura | Day, Ian N M | de Geus, Eco | Delplanque, Jerome | Dina, Christian | Erdos, Michael R | Fedson, Annette C | Fischer-Rosinsky, Antje | Forouhi, Nita G | Fox, Caroline S | Frants, Rune | Franzosi, Maria Grazia | Galan, Pilar | Goodarzi, Mark O | Graessler, Jürgen | Groves, Christopher J | Grundy, Scott | Gwilliam, Rhian | Gyllensten, Ulf | Hadjadj, Samy | Hallmans, Göran | Hammond, Naomi | Han, Xijing | Hartikainen, Anna-Liisa | Hassanali, Neelam | Hayward, Caroline | Heath, Simon C | Hercberg, Serge | Herder, Christian | Hicks, Andrew A | Hillman, David R | Hingorani, Aroon D | Hofman, Albert | Hui, Jennie | Hung, Joe | Isomaa, Bo | Johnson, Paul R V | Jørgensen, Torben | Jula, Antti | Kaakinen, Marika | Kaprio, Jaakko | Kesaniemi, Y Antero | Kivimaki, Mika | Knight, Beatrice | Koskinen, Seppo | Kovacs, Peter | Kyvik, Kirsten Ohm | Lathrop, G Mark | Lawlor, Debbie A | Le Bacquer, Olivier | Lecoeur, Cécile | Li, Yun | Lyssenko, Valeriya | Mahley, Robert | Mangino, Massimo | Manning, Alisa K | Martínez-Larrad, María Teresa | McAteer, Jarred B | McCulloch, Laura J | McPherson, Ruth | Meisinger, Christa | Melzer, David | Meyre, David | Mitchell, Braxton D | Morken, Mario A | Mukherjee, Sutapa | Naitza, Silvia | Narisu, Narisu | Neville, Matthew J | Oostra, Ben A | Orrù, Marco | Pakyz, Ruth | Palmer, Colin N A | Paolisso, Giuseppe | Pattaro, Cristian | Pearson, Daniel | Peden, John F | Pedersen, Nancy L. | Perola, Markus | Pfeiffer, Andreas F H | Pichler, Irene | Polasek, Ozren | Posthuma, Danielle | Potter, Simon C | Pouta, Anneli | Province, Michael A | Psaty, Bruce M | Rathmann, Wolfgang | Rayner, Nigel W | Rice, Kenneth | Ripatti, Samuli | Rivadeneira, Fernando | Roden, Michael | Rolandsson, Olov | Sandbaek, Annelli | Sandhu, Manjinder | Sanna, Serena | Sayer, Avan Aihie | Scheet, Paul | Scott, Laura J | Seedorf, Udo | Sharp, Stephen J | Shields, Beverley | Sigurðsson, Gunnar | Sijbrands, Erik J G | Silveira, Angela | Simpson, Laila | Singleton, Andrew | Smith, Nicholas L | Sovio, Ulla | Swift, Amy | Syddall, Holly | Syvänen, Ann-Christine | Tanaka, Toshiko | Thorand, Barbara | Tichet, Jean | Tönjes, Anke | Tuomi, Tiinamaija | Uitterlinden, André G | van Dijk, Ko Willems | van Hoek, Mandy | Varma, Dhiraj | Visvikis-Siest, Sophie | Vitart, Veronique | Vogelzangs, Nicole | Waeber, Gérard | Wagner, Peter J | Walley, Andrew | Walters, G Bragi | Ward, Kim L | Watkins, Hugh | Weedon, Michael N | Wild, Sarah H | Willemsen, Gonneke | Witteman, Jaqueline C M | Yarnell, John W G | Zeggini, Eleftheria | Zelenika, Diana | Zethelius, Björn | Zhai, Guangju | Zhao, Jing Hua | Zillikens, M Carola | Borecki, Ingrid B | Loos, Ruth J F | Meneton, Pierre | Magnusson, Patrik K E | Nathan, David M | Williams, Gordon H | Hattersley, Andrew T | Silander, Kaisa | Salomaa, Veikko | Smith, George Davey | Bornstein, Stefan R | Schwarz, Peter | Spranger, Joachim | Karpe, Fredrik | Shuldiner, Alan R | Cooper, Cyrus | Dedoussis, George V | Serrano-Ríos, Manuel | Morris, Andrew D | Lind, Lars | Palmer, Lyle J | Hu, Frank B. | Franks, Paul W | Ebrahim, Shah | Marmot, Michael | Kao, W H Linda | Pankow, James S | Sampson, Michael J | Kuusisto, Johanna | Laakso, Markku | Hansen, Torben | Pedersen, Oluf | Pramstaller, Peter Paul | Wichmann, H Erich | Illig, Thomas | Rudan, Igor | Wright, Alan F | Stumvoll, Michael | Campbell, Harry | Wilson, James F | Hamsten, Anders | Bergman, Richard N | Buchanan, Thomas A | Collins, Francis S | Mohlke, Karen L | Tuomilehto, Jaakko | Valle, Timo T | Altshuler, David | Rotter, Jerome I | Siscovick, David S | Penninx, Brenda W J H | Boomsma, Dorret | Deloukas, Panos | Spector, Timothy D | Frayling, Timothy M | Ferrucci, Luigi | Kong, Augustine | Thorsteinsdottir, Unnur | Stefansson, Kari | van Duijn, Cornelia M | Aulchenko, Yurii S | Cao, Antonio | Scuteri, Angelo | Schlessinger, David | Uda, Manuela | Ruokonen, Aimo | Jarvelin, Marjo-Riitta | Waterworth, Dawn M | Vollenweider, Peter | Peltonen, Leena | Mooser, Vincent | Abecasis, Goncalo R | Wareham, Nicholas J | Sladek, Robert | Froguel, Philippe | Watanabe, Richard M | Meigs, James B | Groop, Leif | Boehnke, Michael | McCarthy, Mark I | Florez, Jose C | Barroso, Inês
Nature genetics  2010;42(2):105-116.
Circulating glucose levels are tightly regulated. To identify novel glycemic loci, we performed meta-analyses of 21 genome-wide associations studies informative for fasting glucose (FG), fasting insulin (FI) and indices of β-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 non-diabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with FG/HOMA-B and two associated with FI/HOMA-IR. These include nine new FG loci (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and FAM148B) and one influencing FI/HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB/TMEM195 with type 2 diabetes (T2D). Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify T2D risk loci, as well as loci that elevate FG modestly, but do not cause overt diabetes.
doi:10.1038/ng.520
PMCID: PMC3018764  PMID: 20081858
10.  Underlying Genetic Models of Inheritance in Established Type 2 Diabetes Associations 
American Journal of Epidemiology  2009;170(5):537-545.
For most associations of common single nucleotide polymorphisms (SNPs) with common diseases, the genetic model of inheritance is unknown. The authors extended and applied a Bayesian meta-analysis approach to data from 19 studies on 17 replicated associations with type 2 diabetes. For 13 SNPs, the data fitted very well to an additive model of inheritance for the diabetes risk allele; for 4 SNPs, the data were consistent with either an additive model or a dominant model; and for 2 SNPs, the data were consistent with an additive or recessive model. Results were robust to the use of different priors and after exclusion of data for which index SNPs had been examined indirectly through proxy markers. The Bayesian meta-analysis model yielded point estimates for the genetic effects that were very similar to those previously reported based on fixed- or random-effects models, but uncertainty about several of the effects was substantially larger. The authors also examined the extent of between-study heterogeneity in the genetic model and found generally small between-study deviation values for the genetic model parameter. Heterosis could not be excluded for 4 SNPs. Information on the genetic model of robustly replicated association signals derived from genome-wide association studies may be useful for predictive modeling and for designing biologic and functional experiments.
doi:10.1093/aje/kwp145
PMCID: PMC2732984  PMID: 19602701
Bayes theorem; diabetes mellitus, type 2; meta-analysis; models, genetic; polymorphism, genetic; population characteristics
11.  Underlying genetic models of inheritance in established type 2 diabetes associations 
American journal of epidemiology  2009;170(5):537-545.
For most associations of common polymorphisms with common diseases, the genetic model of inheritance is unknown. We extended and applied a Bayesian meta-analysis approach to data from 19 studies on 17 replicated associations for type 2 diabetes. For 13 polymorphisms, the data fit very well to an additive model, for 4 polymorphisms the data were consistent with either an additive or dominant model, and for 2 polymorphisms with an additive or recessive model of inheritance for the diabetes risk allele. Results were robust to using different priors and after excluding data where index polymorphisms had been examined indirectly through proxy markers. The Bayesian meta-analysis model yielded point estimates for the genetic effects that are very similar to those previously reported based on fixed or random effects models, but uncertainty about several of the effects was substantially larger. We also examined the extent of between-study heterogeneity in the genetic model and found generally small values of the between-study deviation for the genetic model parameter. Heterosis could not be excluded in 4 SNPs. Information on the genetic model of robustly replicated GWA-derived association signals may be useful for predictive modeling, and for designing biological and functional experiments.
doi:10.1093/aje/kwp145
PMCID: PMC2732984  PMID: 19602701
12.  Correction: Genome-Wide Association Scan Meta-Analysis Identifies Three Loci Influencing Adiposity and Fat Distribution 
Lindgren, Cecilia M. | Heid, Iris M. | Randall, Joshua C. | Lamina, Claudia | Steinthorsdottir, Valgerdur | Qi, Lu | Speliotes, Elizabeth K. | Thorleifsson, Gudmar | Willer, Cristen J. | Herrera, Blanca M. | Jackson, Anne U. | Lim, Noha | Scheet, Paul | Soranzo, Nicole | Amin, Najaf | Aulchenko, Yurii S. | Chambers, John C. | Drong, Alexander | Luan, Jian'an | Lyon, Helen N. | Rivadeneira, Fernando | Sanna, Serena | Timpson, Nicholas J. | Zillikens, M. Carola | Zhao, Jing Hua | Almgren, Peter | Bandinelli, Stefania | Bennett, Amanda J. | Bergman, Richard N. | Bonnycastle, Lori L. | Bumpstead, Suzannah J. | Chanock, Stephen J. | Cherkas, Lynn | Chines, Peter | Coin, Lachlan | Cooper, Cyrus | Crawford, Gabriel | Doering, Angela | Dominiczak, Anna | Doney, Alex S. F. | Ebrahim, Shah | Elliott, Paul | Erdos, Michael R. | Estrada, Karol | Ferrucci, Luigi | Fischer, Guido | Forouhi, Nita G. | Gieger, Christian | Grallert, Harald | Groves, Christopher J. | Grundy, Scott | Guiducci, Candace | Hadley, David | Hamsten, Anders | Havulinna, Aki S. | Hofman, Albert | Holle, Rolf | Holloway, John W. | Illig, Thomas | Isomaa, Bo | Jacobs, Leonie C. | Jameson, Karen | Jousilahti, Pekka | Karpe, Fredrik | Kuusisto, Johanna | Laitinen, Jaana | Lathrop, G. Mark | Lawlor, Debbie A. | Mangino, Massimo | McArdle, Wendy L. | Meitinger, Thomas | Morken, Mario A. | Morris, Andrew P. | Munroe, Patricia | Narisu, Narisu | Nordström, Anna | Nordström, Peter | Oostra, Ben A. | Palmer, Colin N. A. | Payne, Felicity | Peden, John F. | Prokopenko, Inga | Renström, Frida | Ruokonen, Aimo | Salomaa, Veikko | Sandhu, Manjinder S. | Scott, Laura J. | Scuteri, Angelo | Silander, Kaisa | Song, Kijoung | Yuan, Xin | Stringham, Heather M. | Swift, Amy J. | Tuomi, Tiinamaija | Uda, Manuela | Vollenweider, Peter | Waeber, Gerard | Wallace, Chris | Walters, G. Bragi | Weedon, Michael N. | Witteman, Jacqueline C. M. | Zhang, Cuilin | Zhang, Weihua | Caulfield, Mark J. | Collins, Francis S. | Davey Smith, George | Day, Ian N. M. | Franks, Paul W. | Hattersley, Andrew T. | Hu, Frank B. | Jarvelin, Marjo-Riitta | Kong, Augustine | Kooner, Jaspal S. | Laakso, Markku | Lakatta, Edward | Mooser, Vincent | Morris, Andrew D. | Peltonen, Leena | Samani, Nilesh J. | Spector, Timothy D. | Strachan, David P. | Tanaka, Toshiko | Tuomilehto, Jaakko | Uitterlinden, André G. | van Duijn, Cornelia M. | Wareham, Nicholas J. | Watkins for the PROCARDIS consortia, Hugh | Waterworth, Dawn M. | Boehnke, Michael | Deloukas, Panos | Groop, Leif | Hunter, David J. | Thorsteinsdottir, Unnur | Schlessinger, David | Wichmann, H.-Erich | Frayling, Timothy M. | Abecasis, Gonçalo R. | Hirschhorn, Joel N. | Loos, Ruth J. F. | Stefansson, Kari | Mohlke, Karen L. | Barroso, Inês | McCarthy for the GIANT consortium, Mark I.
PLoS Genetics  2009;5(7):10.1371/annotation/b6e8f9f6-2496-4a40-b0e3-e1d1390c1928.
doi:10.1371/annotation/b6e8f9f6-2496-4a40-b0e3-e1d1390c1928
PMCID: PMC2722420
13.  Genome-Wide Association Scan Meta-Analysis Identifies Three Loci Influencing Adiposity and Fat Distribution 
Lindgren, Cecilia M. | Heid, Iris M. | Randall, Joshua C. | Lamina, Claudia | Steinthorsdottir, Valgerdur | Qi, Lu | Speliotes, Elizabeth K. | Thorleifsson, Gudmar | Willer, Cristen J. | Herrera, Blanca M. | Jackson, Anne U. | Lim, Noha | Scheet, Paul | Soranzo, Nicole | Amin, Najaf | Aulchenko, Yurii S. | Chambers, John C. | Drong, Alexander | Luan, Jian'an | Lyon, Helen N. | Rivadeneira, Fernando | Sanna, Serena | Timpson, Nicholas J. | Zillikens, M. Carola | Zhao, Jing Hua | Almgren, Peter | Bandinelli, Stefania | Bennett, Amanda J. | Bergman, Richard N. | Bonnycastle, Lori L. | Bumpstead, Suzannah J. | Chanock, Stephen J. | Cherkas, Lynn | Chines, Peter | Coin, Lachlan | Cooper, Cyrus | Crawford, Gabriel | Doering, Angela | Dominiczak, Anna | Doney, Alex S. F. | Ebrahim, Shah | Elliott, Paul | Erdos, Michael R. | Estrada, Karol | Ferrucci, Luigi | Fischer, Guido | Forouhi, Nita G. | Gieger, Christian | Grallert, Harald | Groves, Christopher J. | Grundy, Scott | Guiducci, Candace | Hadley, David | Hamsten, Anders | Havulinna, Aki S. | Hofman, Albert | Holle, Rolf | Holloway, John W. | Illig, Thomas | Isomaa, Bo | Jacobs, Leonie C. | Jameson, Karen | Jousilahti, Pekka | Karpe, Fredrik | Kuusisto, Johanna | Laitinen, Jaana | Lathrop, G. Mark | Lawlor, Debbie A. | Mangino, Massimo | McArdle, Wendy L. | Meitinger, Thomas | Morken, Mario A. | Morris, Andrew P. | Munroe, Patricia | Narisu, Narisu | Nordström, Anna | Nordström, Peter | Oostra, Ben A. | Palmer, Colin N. A. | Payne, Felicity | Peden, John F. | Prokopenko, Inga | Renström, Frida | Ruokonen, Aimo | Salomaa, Veikko | Sandhu, Manjinder S. | Scott, Laura J. | Scuteri, Angelo | Silander, Kaisa | Song, Kijoung | Yuan, Xin | Stringham, Heather M. | Swift, Amy J. | Tuomi, Tiinamaija | Uda, Manuela | Vollenweider, Peter | Waeber, Gerard | Wallace, Chris | Walters, G. Bragi | Weedon, Michael N. | Witteman, Jacqueline C. M. | Zhang, Cuilin | Zhang, Weihua | Caulfield, Mark J. | Collins, Francis S. | Davey Smith, George | Day, Ian N. M. | Franks, Paul W. | Hattersley, Andrew T. | Hu, Frank B. | Jarvelin, Marjo-Riitta | Kong, Augustine | Kooner, Jaspal S. | Laakso, Markku | Lakatta, Edward | Mooser, Vincent | Morris, Andrew D. | Peltonen, Leena | Samani, Nilesh J. | Spector, Timothy D. | Strachan, David P. | Tanaka, Toshiko | Tuomilehto, Jaakko | Uitterlinden, André G. | van Duijn, Cornelia M. | Wareham, Nicholas J. | Watkins for the PROCARDIS consortia, Hugh | Waterworth, Dawn M. | Boehnke, Michael | Deloukas, Panos | Groop, Leif | Hunter, David J. | Thorsteinsdottir, Unnur | Schlessinger, David | Wichmann, H.-Erich | Frayling, Timothy M. | Abecasis, Gonçalo R. | Hirschhorn, Joel N. | Loos, Ruth J. F. | Stefansson, Kari | Mohlke, Karen L. | Barroso, Inês | McCarthy for the GIANT consortium, Mark I.
PLoS Genetics  2009;5(6):e1000508.
To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist–hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9×10−11) and MSRA (WC, P = 8.9×10−9). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6×10−8). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.
Author Summary
Here, we describe a meta-analysis of genome-wide association data from 38,580 individuals, followed by large-scale replication (in up to 70,689 individuals) designed to uncover variants influencing anthropometric measures of central obesity and fat distribution, namely waist circumference (WC) and waist–hip ratio (WHR). This work complements parallel efforts that have been successful in defining variants impacting overall adiposity and focuses on the visceral fat accumulation which has particularly strong relationships to metabolic and cardiovascular disease. Our analyses have identified two loci (TFAP2B and MSRA) associated with WC, and a further locus, near LYPLAL1, which shows gender-specific relationships with WHR (all to levels of genome-wide significance). These loci vary in the strength of their associations with overall adiposity, and LYPLAL1 in particular appears to have a specific effect on patterns of fat distribution. All in all, these three loci provide novel insights into human physiology and the development of obesity.
doi:10.1371/journal.pgen.1000508
PMCID: PMC2695778  PMID: 19557161
14.  Mullinamides A and B, New Cyclopeptides Produced by the Ruth Mullins Coal Mine Fire Isolate Streptomyces sp. RM-27-46 
The Journal of antibiotics  2014;67(8):571-575.
Two new cyclopeptides, mullinamides A [cyclo-(-l-Gly-l-Glu-l-Val-l-Ile-l-Pro-)] and B [cyclo-(-l-Glu-l-Met-l-Pro-)] were isolated from the crude extract of terrestrial Streptomyces sp. RM-27-46 along with the three known cyclopeptides surugamide A [cyclo-(-l-Ile-d-Ile-l-Lys-l-Ile-d-Phe-d-Leu-l-Ile-d-Ala-)], cyclo-(-l-Pro-l-Phe-) and cyclo-(-l-Pro-l-Leu-). The structures of the new compounds were elucidated by the cumulative analyses of NMR spectroscopy and high resolution mass spectrometry. While mullinamides A and B displayed no appreciable antimicrobial/fungal activity or cytotoxicity, this study highlights the first reported antibacterial activity of surugamide A.
doi:10.1038/ja.2014.37
PMCID: PMC4146655  PMID: 24713874
surugamide; cyclopeptide; natural product; pharmacognosy; bioprospecting; antibiotic
15.  EGCG stimulates Nrf2 and heme oxygenase-1 via caveolin-1 displacement 
Flavonoids, such as the tea catechin epigallocatechin-gallate (EGCG), can protect against atherosclerosis by decreasing vascular endothelial cell inflammation. Heme oxygenase (HO-1) is an enzyme that plays an important role in vascular physiology, and its induction may provide protection against atherosclerosis. HO-1 can be compartmentalized in caveolae in endothelial cells. Caveolae are plasma microdomains important in vesicular transport and the regulation of signaling pathways associated with the pathology of vascular diseases. We hypothesize that caveolae play a role in the uptake and transport of EGCG and mechanisms associated with the anti-inflammatory properties of this flavonoid. To test this hypothesis, we explored the effect of EGCG on the induction of Nrf2 and HO-1 in endothelial cells with or without functional caveolae. Treatment with EGCG activated Nrf2 and increased HO-1 expression and cellular production of bilirubin. In addition, EGCG rapidly accumulated in caveolae, which was associated with caveolin-1 displacement from the plasma membrane towards the cytosol. Similar to EGCG treatment, silencing of caveolin-1 by siRNA technique also resulted in upregulation of Nrf2, HO-1 and bilirubin production. These data suggest that EGCG-induced caveolin-1 displacement may reduce endothelial inflammation.
doi:10.1016/j.jnutbio.2010.12.002
PMCID: PMC4309924  PMID: 21447442
EGCG; Nrf2; Caveolae; Endothelial Cells; Atherosclerosis
16.  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
17.  A national survey of the diagnosis and management of suspected ventilator-associated pneumonia 
BMJ Open Respiratory Research  2014;1(1):e000066.
Background
Ventilator-associated pneumonia (VAP) affects up to 20% of patients admitted to intensive care units (ICU). It is associated with increased morbidity, mortality and healthcare costs. Despite published guidelines, variability in diagnosis and management exists, the extent of which remains unclear. We sought to characterise consultant opinions surrounding diagnostic and management practice for VAP in the UK.
Methods
An online survey was sent to all consultant members of the UK Intensive Care Society (n=∼1500). Data were collected regarding respondents’ individual practice in the investigation and management of suspected VAP including use of diagnostic criteria, microbiological sampling, chest X-ray (CXR), bronchoscopy and antibiotic treatments.
Results
339 (23%) responses were received from a broadly representative spectrum of ICU consultants. All respondents indicated that microbiological confirmation should be sought, the majority (57.8%) stating they would take an endotracheal aspirate prior to starting empirical antibiotics. Microbiology reporting services were described as qualitative only by 29.7%. Only 17% of respondents had access to routine reporting of CXRs by a radiologist. Little consensus exists regarding technique for bronchoalveolar lavage (BAL) with the reported volume of saline used ranging from 5 to 500 mL. 24.5% of consultants felt inadequately trained in bronchoscopy.
Conclusions
There is wide variability in the approach to diagnosis and management of VAP among UK consultants. Such variability challenges the reliability of the diagnosis of VAP and its reported incidence as a performance indicator in healthcare systems. The data presented suggest increased radiological and microbiological support, and standardisation of BAL technique, might improve this situation.
doi:10.1136/bmjresp-2014-000066
PMCID: PMC4275666  PMID: 25553248
Respiratory Infection; Pneumonia; Assisted Ventilation
18.  The Role of the O-GlcNAc Modification in Regulating Eukaryotic Gene Expression 
O-linked β-N-acetylglucosamine (O-GlcNAc) modification of proteins has been shown to be involved in many different cellular processes, such as cell cycle control, nutrient sensing, signal transduction, stress response and transcriptional regulation. Cells have developed complex regulatory systems in order to regulate gene expression appropriately in response to environmental and intracellular cues. Control of eukaryotic gene transcription often involves post-translational modification of a multitude of proteins including transcription factors, basal transcription machinery, and chromatin remodeling complexes to modulate their functions in a variety of manners. In this review we describe the emerging functional roles for and techniques to detect and modulate the O-GlcNAc modification and illustrate that the O-GlcNAc modification is intricately involved in at least seven different general mechanisms for the control of gene transcription.
doi:10.2174/157436210790226465
PMCID: PMC4255977  PMID: 25484640
O-GlcNAc; transcriptional regulation; post-translational modification; review
19.  Glycemic Exposure and Blood Pressure Influencing Progression and Remission of Diabetic Retinopathy 
Diabetes Care  2013;36(12):3979-3984.
OBJECTIVE
This study sought to investigate the progression and regression of diabetic retinopathy (DR) and the effects of population risk factors on the rates of transition across retinopathy stages.
RESEARCH DESIGN AND METHODS
The study cohort consisted of 44,871 observed DR events between the calendar years 1990 and 2011 for 4,758 diabetic patients who were diagnosed at 35 years of age or older. The first retinal observation was recorded within a year from diagnosis, and the result was recorded as free of retinopathy. A multistate Markov model was applied for analyzing the development of DR and its relation to the patterns of changes in risk factors.
RESULTS
We observed a consistent risk effect of HbA1c on the progression (no retinopathy to mild background DR [BDR] hazard ratio per SD of HbA1c [HR] 1.42 [95% CI 1.32–1.52], mild BDR to observable BDR HR 1.32 [95% CI 1.08–1.60], and observable BDR to severe nonproliferative/proliferative DR HR 2.23 [95% CI 1.16–4.29]). Similarly, systolic blood pressure (SBP) and diastolic blood pressure increased the risk for the transition from the asymptomatic phase to mild BDR (HR 1.20 [95% CI 1.11–1.30]) and the mild BDR to observable BDR (HR 1.87 [95% CI 1.46–2.40]), respectively. Regression from mild BDR to no DR was associated with lower SBP (HR 0.79 [95% CI 0.64–0.97]) and lower HbA1c (HR 0.76 [95% CI 0.64–0.89]).
CONCLUSIONS
Progression and regression of DR were strongly associated with blood pressure and glycemic exposure.
doi:10.2337/dc12-2392
PMCID: PMC3836116  PMID: 24170761
20.  Resveratrol protects against polychlorinated biphenyl-mediated impairment of glucose homeostasis in adipocytes 
Resveratrol (RSV) is a plant polyphenol that exhibits several favorable effects on glucose homeostasis in adipocytes. Recent studies from our laboratory demonstrated that coplanar polychlorinated biphenyls (PCBs) that are ligands of the aryl hydrocarbon receptor (AhR) impair glucose homeostasis in mice. PCB-induced impairment of glucose homeostasis was associated with augmented expression of inflammatory cytokines in adipose tissue, a site for accumulation of lipophilic PCBs. This study determined if RSV protects against PCB-77 induced impairment of glucose disposal in vitro and in vivo, and if these beneficial effects are associated with enhanced nuclear factor erythoid 2-related factor 2 (Nrf2) signaling in adipose tissue. PCB-77 increased oxidative stress and abolished insulin stimulated 2-deoxy-D-glucose (2DG) uptake in 3T3-L1 adipocytes. These effects were restored by RSV, which resulted in a concentration-dependent increase in NAD(P)H:quinone oxidoreductase 1 (NQO1), the downstream target of Nrf2 signaling. We quantified glucose and insulin tolerance and components of Nrf2 and insulin signaling cascades in adipose tissue of male C57BL/6 mice administered vehicle or PCB-77 (50 mg/kg) and fed a diet with or without resVida® (0.1%, or 160 mg/kg/day). PCB-77 impaired glucose and insulin tolerance, and these effects were reversed by RSV. PCB-77 induced reductions in insulin signaling in adipose tissue were also abolished by RSV, which increased NQO1 expression. These results demonstrate that coplanar PCB-induced impairment of glucose homeostasis in mice can be prevented by RSV, potentially through stimulation of Nrf2 signaling and enhanced insulin stimulated glucose disposal in adipose tissue.
doi:10.1016/j.jnutbio.2013.08.009
PMCID: PMC4066417  PMID: 24231106
Resveratrol; adipocyte; polychlorinated biphenyl; diabetes; Nrf2
21.  Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins 
Postmus, Iris | Trompet, Stella | Deshmukh, Harshal A. | Barnes, Michael R. | Li, Xiaohui | Warren, Helen R. | Chasman, Daniel I. | Zhou, Kaixin | Arsenault, Benoit J. | Donnelly, Louise A. | Wiggins, Kerri L. | Avery, Christy L. | Griffin, Paula | Feng, QiPing | Taylor, Kent D. | Li, Guo | Evans, Daniel S. | Smith, Albert V. | de Keyser, Catherine E. | Johnson, Andrew D. | de Craen, Anton J. M. | Stott, David J. | Buckley, Brendan M. | Ford, Ian | Westendorp, Rudi G. J. | Eline Slagboom, P. | Sattar, Naveed | Munroe, Patricia B. | Sever, Peter | Poulter, Neil | Stanton, Alice | Shields, Denis C. | O’Brien, Eoin | Shaw-Hawkins, Sue | Ida Chen, Y.-D. | Nickerson, Deborah A. | Smith, Joshua D. | Pierre Dubé, Marie | Matthijs Boekholdt, S. | Kees Hovingh, G. | Kastelein, John J. P. | McKeigue, Paul M. | Betteridge, John | Neil, Andrew | Durrington, Paul N. | Doney, Alex | Carr, Fiona | Morris, Andrew | McCarthy, Mark I. | Groop, Leif | Ahlqvist, Emma | Bis, Joshua C. | Rice, Kenneth | Smith, Nicholas L. | Lumley, Thomas | Whitsel, Eric A. | Stürmer, Til | Boerwinkle, Eric | Ngwa, Julius S. | O’Donnell, Christopher J. | Vasan, Ramachandran S. | Wei, Wei-Qi | Wilke, Russell A. | Liu, Ching-Ti | Sun, Fangui | Guo, Xiuqing | Heckbert, Susan R | Post, Wendy | Sotoodehnia, Nona | Arnold, Alice M. | Stafford, Jeanette M. | Ding, Jingzhong | Herrington, David M. | Kritchevsky, Stephen B. | Eiriksdottir, Gudny | Launer, Leonore J. | Harris, Tamara B. | Chu, Audrey Y. | Giulianini, Franco | MacFadyen, Jean G. | Barratt, Bryan J. | Nyberg, Fredrik | Stricker, Bruno H. | Uitterlinden, André G. | Hofman, Albert | Rivadeneira, Fernando | Emilsson, Valur | Franco, Oscar H. | Ridker, Paul M. | Gudnason, Vilmundur | Liu, Yongmei | Denny, Joshua C. | Ballantyne, Christie M. | Rotter, Jerome I. | Adrienne Cupples, L. | Psaty, Bruce M. | Palmer, Colin N. A. | Tardif, Jean-Claude | Colhoun, Helen M. | Hitman, Graham | Krauss, Ronald M. | Wouter Jukema, J | Caulfield, Mark J.
Nature Communications  2014;5:5068.
Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.
Statins are effectively used to prevent and manage cardiovascular disease, but patient response to these drugs is highly variable. Here, the authors identify two new genes associated with the response of LDL cholesterol to statins and advance our understanding of the genetic basis of drug response.
doi:10.1038/ncomms6068
PMCID: PMC4220464  PMID: 25350695
22.  Platelets protect from septic shock by inhibiting macrophage-dependent inflammation via the cyclooxygenase 1 signaling pathway 
Nature communications  2013;4:2657.
While it has been long known that patients with sepsis often have thrombocytopenia and that septic patients with severe thrombocytopenia have a poor prognosis and higher mortality, the role of platelets in the pathogenesis of sepsis is poorly understood. Here we report a protective role of platelets in septic shock. We show that experimental thrombocytopenia by intraperitoneal injection of an anti-glycoprotein Ibα monoclonal antibody increases mortality and aggravates organ failure whereas transfusion of platelets reduces mortality in Lipopolysaccharide-induced endotoxemia and a bacterial infusion mouse sepsis model. Plasma concentrations of proinflammatory cytokines TNF-α and IL-6 are elevated by thrombocytopenia and decreased by platelet transfusion in septic mice. Furthermore, we identify that platelets protect from septic shock by inhibiting macrophage-dependent inflammation via the COX1/PGE2/EP4 dependent pathway. Thus, these findings demonstrate a previously unappreciated role for platelets in septic shock and suggest that platelet transfusion may be effective in treating severe septic patients.
doi:10.1038/ncomms3657
PMCID: PMC4217311  PMID: 24150174
23.  A diastereoselective oxa-Pictet-Spengler-based strategy for (+)-frenolicin B and epi-(+)-frenolicin synthesis 
Organic letters  2013;15(21):10.1021/ol4027649.
An efficient diastereoselective oxa-Pictet-Spengler reaction strategy was developed to construct benzoisochroman diastereomers. The utility of the reaction was demonstrated in the context of both the total synthesis of naturally-occurring pyranonaphthoquinones (+)-frenolicin B and epi-(+)-frenolicin B as well as a range of frenolicin precursor analogs. The method is versatile and offers exquisite stereocontrol and, as such, offers a synthetic advance for the synthesis of pyranonaphthoquinone analogs.
doi:10.1021/ol4027649
PMCID: PMC3877857  PMID: 24151973
24.  Autotaxin Production of Lysophosphatidic Acid Mediates Allergic Asthmatic Inflammation 
Rationale: Bioactive lipid mediators, derived from membrane lipid precursors, are released into the airway and airspace where they bind high-affinity cognate receptors and may mediate asthma pathogenesis. Lysophosphatidic acid (LPA), a bioactive lipid mediator generated by the enzymatic activity of extracellular autotaxin (ATX), binds LPA receptors, resulting in an array of biological actions on cell proliferation, migration, survival, differentiation, and motility, and therefore could mediate asthma pathogenesis.
Objectives: To define a role for the ATX-LPA pathway in human asthma pathogenesis and a murine model of allergic lung inflammation.
Methods: We investigated the profiles of LPA molecular species and the level of ATX exoenzyme in bronchoalveolar lavage fluids of human patients with asthma subjected to subsegmental bronchoprovocation with allergen. We interrogated the role of the ATX-LPA pathway in allergic lung inflammation using a murine allergic asthma model in ATX-LPA pathway–specific genetically modified mice.
Measurements and Main Results: Subsegmental bronchoprovocation with allergen in patients with mild asthma resulted in a remarkable increase in bronchoalveolar lavage fluid levels of LPA enriched in polyunsaturated 22:5 and 22:6 fatty acids in association with increased concentrations of ATX protein. Using a triple-allergen mouse asthma model, we showed that ATX-overexpressing transgenic mice had a more severe asthmatic phenotype, whereas blocking ATX activity and knockdown of the LPA2 receptor in mice produced a marked attenuation of Th2 cytokines and allergic lung inflammation.
Conclusions: The ATX-LPA pathway plays a critical role in the pathogenesis of asthma. These preclinical data indicate that targeting the ATX-LPA pathway could be an effective antiasthma treatment strategy.
doi:10.1164/rccm.201306-1014OC
PMCID: PMC3826286  PMID: 24050723
asthma; lysophosphatidic acid; autotaxin; allergic airway inflammation
25.  Mendelian Randomization Studies Do Not Support a Causal Role for Reduced Circulating Adiponectin Levels in Insulin Resistance and Type 2 Diabetes 
Yaghootkar, Hanieh | Lamina, Claudia | Scott, Robert A. | Dastani, Zari | Hivert, Marie-France | Warren, Liling L. | Stancáková, Alena | Buxbaum, Sarah G. | Lyytikäinen, Leo-Pekka | Henneman, Peter | Wu, Ying | Cheung, Chloe Y.Y. | Pankow, James S. | Jackson, Anne U. | Gustafsson, Stefan | Zhao, Jing Hua | Ballantyne, Christie M. | Xie, Weijia | Bergman, Richard N. | Boehnke, Michael | el Bouazzaoui, Fatiha | Collins, Francis S. | Dunn, Sandra H. | Dupuis, Josee | Forouhi, Nita G. | Gillson, Christopher | Hattersley, Andrew T. | Hong, Jaeyoung | Kähönen, Mika | Kuusisto, Johanna | Kedenko, Lyudmyla | Kronenberg, Florian | Doria, Alessandro | Assimes, Themistocles L. | Ferrannini, Ele | Hansen, Torben | Hao, Ke | Häring, Hans | Knowles, Joshua W. | Lindgren, Cecilia M. | Nolan, John J. | Paananen, Jussi | Pedersen, Oluf | Quertermous, Thomas | Smith, Ulf | Lehtimäki, Terho | Liu, Ching-Ti | Loos, Ruth J.F. | McCarthy, Mark I. | Morris, Andrew D. | Vasan, Ramachandran S. | Spector, Tim D. | Teslovich, Tanya M. | Tuomilehto, Jaakko | van Dijk, Ko Willems | Viikari, Jorma S. | Zhu, Na | Langenberg, Claudia | Ingelsson, Erik | Semple, Robert K. | Sinaiko, Alan R. | Palmer, Colin N.A. | Walker, Mark | Lam, Karen S.L. | Paulweber, Bernhard | Mohlke, Karen L. | van Duijn, Cornelia | Raitakari, Olli T. | Bidulescu, Aurelian | Wareham, Nick J. | Laakso, Markku | Waterworth, Dawn M. | Lawlor, Debbie A. | Meigs, James B. | Richards, J. Brent | Frayling, Timothy M.
Diabetes  2013;62(10):3589-3598.
Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes, but its causal role remains controversial. We used a Mendelian randomization approach to test the hypothesis that adiponectin causally influences insulin resistance and type 2 diabetes. We used genetic variants at the ADIPOQ gene as instruments to calculate a regression slope between adiponectin levels and metabolic traits (up to 31,000 individuals) and a combination of instrumental variables and summary statistics–based genetic risk scores to test the associations with gold-standard measures of insulin sensitivity (2,969 individuals) and type 2 diabetes (15,960 case subjects and 64,731 control subjects). In conventional regression analyses, a 1-SD decrease in adiponectin levels was correlated with a 0.31-SD (95% CI 0.26–0.35) increase in fasting insulin, a 0.34-SD (0.30–0.38) decrease in insulin sensitivity, and a type 2 diabetes odds ratio (OR) of 1.75 (1.47–2.13). The instrumental variable analysis revealed no evidence of a causal association between genetically lower circulating adiponectin and higher fasting insulin (0.02 SD; 95% CI −0.07 to 0.11; N = 29,771), nominal evidence of a causal relationship with lower insulin sensitivity (−0.20 SD; 95% CI −0.38 to −0.02; N = 1,860), and no evidence of a relationship with type 2 diabetes (OR 0.94; 95% CI 0.75–1.19; N = 2,777 case subjects and 13,011 control subjects). Using the ADIPOQ summary statistics genetic risk scores, we found no evidence of an association between adiponectin-lowering alleles and insulin sensitivity (effect per weighted adiponectin-lowering allele: −0.03 SD; 95% CI −0.07 to 0.01; N = 2,969) or type 2 diabetes (OR per weighted adiponectin-lowering allele: 0.99; 95% CI 0.95–1.04; 15,960 case subjects vs. 64,731 control subjects). These results do not provide any consistent evidence that interventions aimed at increasing adiponectin levels will improve insulin sensitivity or risk of type 2 diabetes.
doi:10.2337/db13-0128
PMCID: PMC3781444  PMID: 23835345

Results 1-25 (253)