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1. Genetic Structure of the Spanish Population

Author

Gutiérrez Marta, Ochoa María, Molero Eva, Ochoa Carolina, Carrasco José M, Velasco Juan, Moreno-Rey Concha, Royo Jose, Morón Francisco J, Ramírez-Lorca Reposo, Salinas Ana, Rivero M Carmen, Zabena Carina, Martínez-Larrad María, Sáez María, González-Pérez Antonio, Galan José J, Gayán Javier, Reina Mercedes, Pascual Rocío, Romo-Astorga Alejandro, Susillo-González Juan, Vázquez Enrique, Real Luis M, Ruiz Agustín, and Serrano-Ríos Manuel

Subjects
Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background Genetic admixture is a common caveat for genetic association analysis. Therefore, it is important to characterize the genetic structure of the population under study to control for this kind of potential bias. Results In this study we have sampled over 800 unrelated individuals from the population of Spain, and have genotyped them with a genome-wide coverage. We have carried out linkage disequilibrium, haplotype, population structure and copy-number variation (CNV) analyses, and have compared these estimates of the Spanish population with existing data from similar efforts. Conclusions In general, the Spanish population is similar to the Western and Northern Europeans, but has a more diverse haplotypic structure. Moreover, the Spanish population is also largely homogeneous within itself, although patterns of micro-structure may be able to predict locations of origin from distant regions. Finally, we also present the first characterization of a CNV map of the Spanish population. These results and original data are made available to the scientific community.

Published
2010
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2. Calpain-5 gene variants are associated with diastolic blood pressure and cholesterol levels

Author

Morón Francisco J, González Alejandro, Martinez-Calatrava María J, Zabena Carina, González-Sánchez José L, Ramírez-Lorca Reposo, Martínez-Larrad María T, Sáez María E, Ruiz Agustín, and Serrano-Ríos Manuel

Subjects
Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background Genes implicated in common complex disorders such as obesity, type 2 diabetes mellitus (T2DM) or cardiovascular diseases are not disease specific, since clinically related disorders also share genetic components. Cysteine protease Calpain 10 (CAPN10) has been associated with T2DM, hypertension, hypercholesterolemia, increased body mass index (BMI) and polycystic ovary syndrome (PCOS), a reproductive disorder of women in which isunlin resistance seems to play a pathogenic role. The calpain 5 gene (CAPN5) encodes a protein homologue of CAPN10. CAPN5 has been previously associated with PCOS by our group. In this new study, we have analysed the association of four CAPN5 gene variants(rs948976A>G, rs4945140G>A, rs2233546C>T and rs2233549G>A) with several cardiovascular risk factors related to metabolic syndrome in general population. Methods Anthropometric measurements, blood pressure, insulin, glucose and lipid profiles were determined in 606 individuals randomly chosen from a cross-sectional population-based epidemiological survey in the province of Segovia in Central Spain (Castille), recruited to investigate the prevalence of anthropometric and physiological parameters related to obesity and other components of the metabolic syndrome. Genotypes at the four polymorphic loci in CAPN5 gene were detected by polymerase chain reaction (PCR). Results Genotype association analysis was significant for BMI (p ≤ 0.041), diastolic blood pressure (p = 0.015) and HDL-cholesterol levels (p = 0.025). Different CAPN5 haplotypes were also associated with diastolic blood pressure (DBP) (0.0005 ≤ p ≤ 0.006) and total cholesterol levels (0.001 ≤ p ≤ 0.029). In addition, the AACA haplotype, over-represented in obese individuals, is also more frequent in individuals with metabolic syndrome defined by ATPIII criteria (p = 0.029). Conclusion As its homologue CAPN10, CAPN5 seems to influence traits related to increased risk for cardiovascular diseases. Our results also may suggest CAPN5 as a candidate gene for metabolic syndrome.

Published
2007
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3. Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

Author

Strawbridge, Rona J, Dupuis, Josée, Prokopenko, Inga, Barker, Adam, Ahlqvist, Emma, Rybin, Denis, Petrie, John R, Travers, Mary E, Bouatia-Naji, Nabila, Dimas, Antigone S, Nica, Alexandra, Wheeler, Eleanor, Chen, Han, Voight, Benjamin F, Taneera, Jalal, Kanoni, Stavroula, Peden, John F, Turrini, Fabiola, Gustafsson, Stefan, Zabena, Carina, Almgren, Peter, Barker, David JP, Barnes, Daniel, Dennison, Elaine M, Eriksson, Johan G, Eriksson, Per, Eury, Elodie, Folkersen, Lasse, Fox, Caroline S, Frayling, Timothy M, Goel, Anuj, Gu, Harvest F, Horikoshi, Momoko, Isomaa, Bo, Jackson, Anne U, Jameson, Karen A, Kajantie, Eero, Kerr-Conte, Julie, Kuulasmaa, Teemu, Kuusisto, Johanna, Loos, Ruth JF, Luan, Jian'an, Makrilakis, Konstantinos, Manning, Alisa K, Martínez-Larrad, María Teresa, Narisu, Narisu, Nastase Mannila, Maria, Ohrvik, John, Osmond, Clive, Pascoe, Laura, Payne, Felicity, Sayer, Avan A, Sennblad, Bengt, Silveira, Angela, Stancáková, Alena, Stirrups, Kathy, Swift, Amy J, Syvänen, Ann-Christine, Tuomi, Tiinamaija, van 't Hooft, Ferdinand M, Walker, Mark, Weedon, Michael N, Xie, Weijia, Zethelius, Björn, DIAGRAM Consortium, GIANT Consortium, MuTHER Consortium, CARDIoGRAM Consortium, C4D Consortium, Ongen, Halit, Mälarstig, Anders, Hopewell, Jemma C, Saleheen, Danish, Chambers, John, Parish, Sarah, Danesh, John, Kooner, Jaspal, Ostenson, Claes-Göran, Lind, Lars, Cooper, Cyrus C, Serrano-Ríos, Manuel, Ferrannini, Ele, Forsen, Tom J, Clarke, Robert, Franzosi, Maria Grazia, Seedorf, Udo, Watkins, Hugh, Froguel, Philippe, Johnson, Paul, Deloukas, Panos, Collins, Francis S, Laakso, Markku, Dermitzakis, Emmanouil T, Boehnke, Michael, McCarthy, Mark I, Wareham, Nicholas J, Groop, Leif, Pattou, François, Gloyn, Anna L, and Dedoussis, George V

Subjects
DIAGRAM Consortium, GIANT Consortium, MuTHER Consortium, CARDIoGRAM Consortium, C4D Consortium, Humans, Diabetes Mellitus, Type 2, Insulin, Proinsulin, Fasting, Genotype, Polymorphism, Single Nucleotide, Genome, Human, Adult, Female, Male, Genetic Variation, Diabetes Mellitus, Type 2, Polymorphism, Single Nucleotide, Genome, Human, Endocrinology & Metabolism, Medical and Health Sciences
Abstract

ObjectiveProinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology.Research design and methodsWe have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates.ResultsNine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets.ConclusionsWe have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

Published
2011

10. Elaboració de la primera Guia de Bones Pràctiques d'Informació Mèdica a la Indústria Farmacèutica Espanyola

Author

Guardiola, Elena, Fragoso, Jaime, Abril, Monica Rojo, Balmy, Sylvaine, Cabo, Lurdes, Díaz, Lourdes, Escudero, Nuria, Flores, Ángeles, García-Ortiz, Daniel, M Ángeles Hernández, Iglesias, Inmaculada, Ortega, Patricia, Pozo, Tamara, Pulido, Fernanda, Zabena, Carina, [Guardiola E] BayerHispania SL, Sant Joan Despí, Spain, Grupo de Información Médica de AMIFE, Madrid, Spain. [Fragoso J] SermesConsulting-GSK, Tres Cantos, Spain, Grupo de Información Médica de AMIFE, Madrid, Spain. [Rojo M] GrünenthalPharma SA, Madrid, Spain, Grupo de Información Médica de AMIFE, Madrid, Spain. [Balmy S] BoironSIHSA, Alcobendas, Spain, Grupo de Información Médica de AMIFE, Madrid, Spain. [Cabo L] SanofiEspaña, Barcelona, Spain, Grupo de Información Médica de AMIFE, Madrid, Spain. [Díaz L] EisaiFarmacéutica, Madrid, Spain, Grupo de Información Médica de AMIFE, Madrid, Spain. [Escudero N] Meisys, San Sebastián de los Reyes, Spain, Grupo de Información Médica de AMIFE, Madrid, Spain. [Flores Á] Lilly SA, Madrid, Spain, Grupo de Información Médica de AMIFE, Madrid, Spain. [García-Ortiz D] TevaPharma SL, Alcobendas, Spain, Grupo de Información Médica de AMIFE, Madrid, Spain. [Hernández MÁ] GileadSciences, Maddrid, Spain, Grupo de Información Médica de AMIFE, Madrid, Spain. [Iglesias I] Janssen-CilagSA, Madrid, Spain, Grupo de Información Médica de AMIFE, Madrid, Spain. [Ortega P] Meisys, SL, San Sebastián de los Reyes, Spain, Grupo de Información Médica de AMIFE, Madrid, Spain. [Pozo T] Takeda Farmacéutica España, SAU, Madrid, Spain, Grupo de Información Médica de AMIFE, Madrid, Spain. [Pulido F] AnaxomicsBiotechSL, Barcelona, Spain, Grupo de Información Médica de AMIFE, Madrid, Spain. [Zabena C] PRAHealth Sciences, Madrid, Spain, Grupo de Información Médica de AMIFE, Madrid, Spain, and Departament de Salut

Subjects
Health Surveillance of Products::Drug and Narcotic Control::Chemical Industry::Drug Industry [HEALTH SURVEILLANCE], Environmental Health::Science::Social Sciences::Information Science::Information Services [PUBLIC HEALTH], Treball en equip, salud ambiental::ciencia::ciencias sociales::Ciencias de la información::servicios de información [SALUD PÚBLICA], Indústria farmacèutica - Serveis d'informació, control sanitario de productos::control de medicamentos y estupefacientes::industria química::industria farmacéutica [VIGILANCIA SANITARIA]
Abstract

Informació mèdica; Indústria farmacèutica; Bones pràctiques Información médica; Industria farmacéutica; Buenas prácticas Medical information; Pharmaceutical industry; Good practices Introducció. La indústria farmacèutica (IF) és un important proveïdor d'informació i documentació mèdica. La Informació Mèdica (IM) és una activitat necessària per tal que els medicaments i productes sanitaris comercialitzats per les empreses farmacèutiques s'utilitzin de forma segura i eficaç. Per aquest motiu, han de proporcionar informació fiable, precisa, equilibrada i imparcial a professionals de la salut i pacients. El Grup d'IM d'AMIFE es creà el 2014 com a fòrum de debat sobre la situació actual i el futur de la IM, dels seus professionals i dels serveis que proporciona. Objectiu. En no haver-hi legislació específica, el Grup es plantejà la importància de definir i orientar les obligacions i activitats d'IM a la IF. Encara que hi ha algunes guies internacionals, es considerà imprescindible elaborar una guia espanyola de bones pràctiques. Mètode. Coordinat per dos membres del Grup, es convidà tot el Grup a participar en el projecte, tant en la planificació com en la redacció, avaluació d'experts i edició dels capítols. Es va elaborar l'índex i s'assignaren els autors. Cada capítol havia d'incloure una revisió del tema i observacions o conclusions que, consensuades, donarien lloc a recomanacions. Resultats. S'ha redactat, i es publicarà molt aviat, la Guia de Bones Pràctiques d'Informació Mèdica a la Indústria Farmacèutica Espanyola. En 12 capítols es tracta de la importància de la IM, les característiques dels departaments d'IM i els seus professionals, i els procediments normalitzats de treball així com de temes legals, d'ètica, de propietat intel·lectual, de medicina basada en l'evidència i d'avaluació de la qualitat, i es plantegen els reptes futurs. Conclusions. És important disposar d'una Guia de Bones Pràctiques d'IM a la IF. Aquest treball ha permès aprofundir en el tema, redactar la primera guia espanyola i elaborar conclusions i recomanacions així com establir una xarxa col·laborativa entre els professionals d'IM de la IF. Introducción. La industria farmacéutica (IF) es un importante proveedor de información y documentación médica. La Información Médica (IM) es una actividad necesaria para que los medicamentos y productos sanitarios comercializados por las empresas farmacéuticas se utilicen de forma segura y eficaz. Por este motivo, deben proporcionar información fiable, precisa, equilibrada e imparcial a profesionales de la salud y pacientes. El Grupo de IM de AMIFE se creó en 2014 como foro de debate sobre la situación actual y el futuro de la IM, de sus profesionales y de los servicios que proporciona. Introduction. The pharmaceutical industry is a leading provider of medical information and documentation. The Medical Information is a necessary activity so that the medicines and sanitary products marketed by the pharmaceutical companies are used safely and efficiently. For this reason, they must provide reliable, accurate, balanced and unbiased information to healthcare professionals and patients. The AMIFE IM Group was created in 2014 as a forum for debate on the current situation and the future of the IM, its professionals and the services it provides

Published
2017

11. A Genome-Wide Association Search for Type 2 Diabetes Genes in African Americans

Author

Palmer, Nicholette D, McDonough, Caitrin W, Hicks, Pamela J, Roh, Bong H, Wing, Maria R, An, S Sandy, Hester, Jessica M, Cooke, Jessica N, Bostrom, Meredith A, Rudock, Megan E, Talbert, Matthew E, Lewis, Joshua P, DIAGRAM Consortium, MAGIC Investigators, Ferrara, Assiamira, Lu, Lingyi, Ziegler, Julie T, Sale, Michele M, Divers, Jasmin, Shriner, Daniel, Adeyemo, Adebowale, Rotimi, Charles N, Ng, Maggie CY, Langefeld, Carl D, Freedman, Barry I, Bowden, Donald W, 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, Noël P, Charpentier, Guillaume, Chines, Peter S, Cornelis, Marilyn, Couper, David J, Crawford, Gabe, Doney, Alex SF, 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 RV, Jørgensen, Torben, Kao, Wen HL, 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 RB, 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 NA, Pramstaller, Peter P, Rudan, Igor, Sijbrands, Eric, Stein, Lincoln D, Tuomilehto, Jaakko, Uitterlinden, Andre, Walker, Mark, Wareham, Nicholas J, Watanabe, Richard M, Abecasis, Goncalo 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, Soranzo, Nicole, Wheeler, Eleanor, Glazer, Nicole L, Bouatia-Naji, Nabila, Mägi, Reedik, Randall, Joshua, Johnson, Toby, Elliott, Paul, Rybin, Denis, Henneman, Peter, Dehghan, Abbas, Hottenga, Jouke Jan, Song, Kijoung, Goel, Anuj, Egan, Josephine M, Lajunen, Taina, Doney, Alex, Kanoni, Stavroula, Cavalcanti-Proença, Christine, Kumari, Meena, Timpson, Nicholas J, Zabena, Carina, Ingelsson, Erik, An, Ping, O'Connell, Jeffrey, Luan, Jian'an, Elliott, Amanda, McCarroll, Steven A, Roccasecca, Rosa Maria, Pattou, François, Sethupathy, Praveen, Ariyurek, Yavuz, Barter, Philip, Beilby, John P, Ben-Shlomo, Yoav, Bergmann, Sven, Bochud, Murielle, Bonnefond, Amélie, Borch-Johnsen, Knut, Böttcher, Yvonne, Brunner, Eric, Bumpstead, Suzannah J, Chen, Yii-Der Ida, Chines, Peter, Clarke, Robert, Coin, Lachlan JM, Cooper, Matthew N, Crisponi, Laura, Day, Ian NM, De Geus, Eco JC, Delplanque, Jerome, Fedson, Annette C, Fischer-Rosinsky, Antje, Forouhi, Nita G, Frants, Rune, Franzosi, Maria Grazia, Galan, Pilar, Goodarzi, Mark O, Graessler, Jürgen, Grundy, Scott, Gwilliam, Rhian, Hallmans, Göran, Hammond, Naomi, Han, Xijing, Hartikainen, Anna-Liisa, Hayward, Caroline, Heath, Simon C, Hercberg, Serge, Hicks, Andrew A, Hillman, David R, Hingorani, Aroon D, Hui, Jennie, Hung, Joe, 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, Mahley, Robert, Mangino, Massimo, Manning, Alisa K, Martínez-Larrad, María Teresa, McAteer, Jarred B, McPherson, Ruth, Meisinger, Christa, Melzer, David, Meyre, David, Mitchell, Braxton D, Mukherjee, Sutapa, Naitza, Silvia, Neville, Matthew J, Oostra, Ben A, Orrù, Marco, Pakyz, Ruth, Paolisso, Giuseppe, Pattaro, Cristian, Pearson, Daniel, Peden, John F, Pedersen, Nancy L, Perola, Markus, Pfeiffer, Andreas FH, Pichler, Irene, Polasek, Ozren, Posthuma, Danielle, Potter, Simon C, Pouta, Anneli, Province, Michael A, Psaty, Bruce M, Rayner, Nigel W, Rice, Kenneth, Ripatti, Samuli, Rivadeneira, Fernando, Rolandsson, Olov, Sandbaek, Annelli, Sandhu, Manjinder, Sanna, Serena, Sayer, Avan Aihie, Scheet, Paul, Seedorf, Udo, Sharp, Stephen J, Shields, Beverley, Sijbrands, Eric JG, Silveira, Angela, Simpson, Laila, Singleton, Andrew, Smith, Nicholas L, Sovio, Ulla, Swift, Amy, Syddall, Holly, Syvänen, Ann-Christine, Tanaka, Toshiko, Tönjes, Anke, Uitterlinden, André G, Van Dijk, Ko Willems, Varma, Dhiraj, Visvikis-Siest, Sophie, Vitart, Veronique, Vogelzangs, Nicole, Waeber, Gérard, Wagner, Peter J, Walley, Andrew, Ward, Kim L, Watkins, Hugh, Wild, Sarah H, Willemsen, Gonneke, Witteman, Jaqueline CM, Yarnell, John WG, Zelenika, Diana, Zethelius, Björn, Zhai, Guangju, Zhao, Jing Hua, Zillikens, M Carola, Borecki, Ingrid B, Loos, Ruth JF, Meneton, Pierre, Magnusson, Patrik KE, Nathan, David M, Williams, Gordon H, 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, Lind, Lars, Palmer, Lyle J, Franks, Paul W, Ebrahim, Shah, Marmot, Michael, Kao, WH Linda, Pramstaller, Peter Paul, Wright, Alan F, Stumvoll, Michael, Hamsten, Anders, Buchanan, Thomas A, Valle, Timo T, Rotter, Jerome I, Siscovick, David S, Penninx, Brenda WJH, Boomsma, Dorret I, Deloukas, Panos, Spector, Timothy D, Ferrucci, Luigi, Cao, Antonio, Scuteri, Angelo, Schlessinger, David, Uda, Manuela, Ruokonen, Aimo, Jarvelin, Marjo-Riitta, Waterworth, Dawn M, Vollenweider, Peter, Peltonen, Leena, Mooser, Vincent, Sladek, Robert, Center for Liver, Digestive and Metabolic Diseases (CLDM), Palmer, Nd, Mcdonough, Cw, Hicks, Pj, Roh, Bh, Wing, Mr, An, S, Hester, Jm, Cooke, Jn, Bostrom, Ma, Rudock, Me, Talbert, Me, Lewis, Jp, Diagram, Consortium, Magic, Investigator, Ferrara, A, Lu, L, Ziegler, Jt, Sale, Mm, Divers, J, Shriner, D, Adeyemo, A, Rotimi, Cn, Ng, Mc, Langefeld, Cd, Freedman, Bi, Bowden, Dw, Voight, Bf, Scott, Lj, Steinthorsdottir, V, Morris, Ap, Dina, C, Welch, Rp, Zeggini, E, Huth, C, Aulchenko, Y, Thorleifsson, G, Mcculloch, Lj, Ferreira, T, Grallert, H, Amin, N, Wu, G, Willer, Cj, Raychaudhuri, S, Mccarroll, Sa, Langenberg, C, Hofmann, Om, Dupuis, J, Qi, L, Segrè, Av, van Hoek, M, Navarro, P, Ardlie, K, Balkau, B, Benediktsson, R, Bennett, Aj, Blagieva, R, Boerwinkle, E, Bonnycastle, Ll, Boström, Kb, Bravenboer, B, Bumpstead, S, Burtt, Np, Charpentier, G, Chines, P, Cornelis, M, Couper, Dj, Crawford, G, Doney, A, Elliott, K, Elliott, Al, Erdos, Mr, Fox, C, Franklin, C, Ganser, M, Gieger, C, Grarup, N, Green, T, Griffin, S, Groves, Cj, Guiducci, C, Hadjadj, S, Hassanali, N, Herder, C, Isomaa, B, Jackson, Au, Johnson, Pr, Jørgensen, T, Kao, Wh, Klopp, N, Kong, A, Kraft, P, Kuusisto, J, Lauritzen, T, Li, M, Lieverse, A, Lindgren, Cm, Lyssenko, V, Marre, M, Meitinger, T, Midthjell, K, Morken, Ma, Narisu, N, Nilsson, P, Owen, Kr, Payne, F, Perry, Jr, Petersen, Ak, Platou, C, Proença, C, Prokopenko, I, Rathmann, W, Rayner, Nw, Robertson, Nr, Rocheleau, G, Roden, M, Sampson, Mj, Saxena, R, Shields, Bm, Shrader, P, Sigurdsson, G, Sparsø, T, Strassburger, K, Stringham, Hm, Sun, Q, Swift, Aj, Thorand, B, Tichet, J, Tuomi, T, van Dam, Rm, van Haeften, Tw, van Herpt, T, van Vliet Ostaptchouk, Jv, Walters, Gb, Weedon, Mn, Wijmenga, C, Witteman, J, Bergman, Rn, Cauchi, S, Collins, F, Gloyn, Al, Gyllensten, U, Hansen, T, Hide, Wa, Hitman, Ga, Hofman, A, Hunter, Dj, Hveem, K, Laakso, M, Mohlke, Kl, Morris, Ad, Palmer, Cn, Pramstaller, Pp, Rudan, I, Sijbrands, E, Stein, Ld, Tuomilehto, J, Uitterlinden, A, Walker, M, Wareham, Nj, Watanabe, Rm, Abecasis, Gr, Boehm, Bo, Campbell, H, Daly, Mj, Hattersley, At, Hu, Fb, Meigs, Jb, Pankow, J, Pedersen, O, Wichmann, He, Barroso, I, Florez, Jc, Frayling, Tm, Groop, L, Sladek, R, Thorsteinsdottir, U, Wilson, Jf, Illig, T, Froguel, P, van Duijn, Cm, Stefansson, K, Altshuler, D, Boehnke, M, Mccarthy, Mi, Soranzo, N, Wheeler, E, Glazer, Nl, Bouatia Naji, N, Mägi, R, Randall, J, Johnson, T, Elliott, P, Rybin, D, Henneman, P, Dehghan, A, Hottenga, Jj, Song, K, Goel, A, Egan, Jm, Lajunen, T, Kanoni, S, Cavalcanti Proença, C, Kumari, M, Timpson, Nj, Zabena, C, Ingelsson, E, An, P, O'Connell, J, Luan, J, Elliott, A, Roccasecca, Rm, Pattou, F, Sethupathy, P, Ariyurek, Y, Barter, P, Beilby, Jp, Ben Shlomo, Y, Bergmann, S, Bochud, M, Bonnefond, A, Borch Johnsen, K, Böttcher, Y, Brunner, E, Bumpstead, Sj, Chen, Yd, Clarke, R, Coin, Lj, Cooper, Mn, Crisponi, L, Day, In, de Geus, Ej, Delplanque, J, Fedson, Ac, Fischer Rosinsky, A, Forouhi, Ng, Frants, R, Franzosi, Mg, Galan, P, Goodarzi, Mo, Graessler, J, Grundy, S, Gwilliam, R, Hallmans, G, Hammond, N, Han, X, Hartikainen, Al, Hayward, C, Heath, Sc, Hercberg, S, Hicks, Aa, Hillman, Dr, Hingorani, Ad, Hui, J, Hung, J, Jula, A, Kaakinen, M, Kaprio, J, Kesaniemi, Ya, Kivimaki, M, Knight, B, Koskinen, S, Kovacs, P, Kyvik, Ko, Lathrop, Gm, Lawlor, Da, Le Bacquer, O, Lecoeur, C, Li, Y, Mahley, R, Mangino, M, Manning, Ak, Martínez Larrad, Mt, Mcateer, Jb, Mcpherson, R, Meisinger, C, Melzer, D, Meyre, D, Mitchell, Bd, Mukherjee, S, Naitza, S, Neville, Mj, Oostra, Ba, Orrù, M, Pakyz, R, Paolisso, Giuseppe, Pattaro, C, Pearson, D, Peden, Jf, Pedersen, Nl, Perola, M, Pfeiffer, Af, Pichler, I, Polasek, O, Posthuma, D, Potter, Sc, Pouta, A, Province, Ma, Psaty, Bm, Rice, K, Ripatti, S, Rivadeneira, F, Rolandsson, O, Sandbaek, A, Sandhu, M, Sanna, S, Sayer, Aa, Scheet, P, Seedorf, U, Sharp, Sj, Shields, B, Sijbrands, Ej, Silveira, A, Simpson, L, Singleton, A, Smith, Nl, Sovio, U, Swift, A, Syddall, H, Syvänen, Ac, Tanaka, T, Tönjes, A, Uitterlinden, Ag, van Dijk, Kw, Varma, D, Visvikis Siest, S, Vitart, V, Vogelzangs, N, Waeber, G, Wagner, Pj, Walley, A, Ward, Kl, Watkins, H, Wild, Sh, Willemsen, G, Witteman, Jc, Yarnell, Jw, Zelenika, D, Zethelius, B, Zhai, G, Zhao, Jh, Zillikens, Mc, Borecki, Ib, Loos, Rj, Meneton, P, Magnusson, Pk, Nathan, Dm, Williams, Gh, Silander, K, Salomaa, V, Smith, Gd, Bornstein, Sr, Schwarz, P, Spranger, J, Karpe, F, Shuldiner, Ar, Cooper, C, Dedoussis, Gv, Serrano Ríos, M, Lind, L, Palmer, Lj, Franks, Pw, Ebrahim, S, Marmot, M, Wright, Af, Stumvoll, M, Hamsten, A, Buchanan, Ta, Valle, Tt, Rotter, Ji, Siscovick, D, Penninx, Bw, Boomsma, Di, Deloukas, P, Spector, Td, Ferrucci, L, Cao, A, Scuteri, A, Schlessinger, D, Uda, M, Ruokonen, A, Jarvelin, Mr, Waterworth, Dm, Vollenweider, P, Peltonen, L, Mooser, V, Sladek, R., Medical Research Council (MRC), Human genetics, Psychiatry, NCA - Attention & Cognition, EMGO - Lifestyle, overweight and diabetes, Biological Psychology, Functional Genomics, Neuroscience Campus Amsterdam - Attention & Cognition, EMGO+ - Lifestyle, Overweight and Diabetes, Langenberg, Claudia [0000-0002-5017-7344], Griffin, Simon [0000-0002-2157-4797], Wareham, Nicholas [0000-0003-1422-2993], Soranzo, Nicole [0000-0003-1095-3852], Wheeler, Eleanor [0000-0002-8616-6444], Luan, Jian'an [0000-0003-3137-6337], Forouhi, Nita [0000-0002-5041-248X], Sharp, Stephen [0000-0003-2375-1440], Sovio, Ulla [0000-0002-0799-1105], Apollo - University of Cambridge Repository, DIAGRAM Consortium, MAGIC Investigators, Johnson, T., Bergman, S., Bochud, M., Waeber, G., and Vollenweider, P.

Subjects
Netherlands Twin Register (NTR), Male, Adult, African Americans/genetics, Aged, Case-Control Studies, Cohort Studies, Diabetes Mellitus, Type 2/ethnology, Diabetes Mellitus, Type 2/genetics, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Meta-Analysis as Topic, Middle Aged, Polymorphism, Single Nucleotide, Validation Studies as Topic, Medicin och hälsovetenskap, Linkage disequilibrium, Genetic Screens, endocrine system diseases, lcsh:Medicine, Genome-wide association study, Medical and Health Sciences, 0302 clinical medicine, Endocrinology, Genome Sequencing, lcsh:Science, Medicine(all), Genetics, African Americans, 0303 health sciences, education.field_of_study, INSULIN-RESISTANCE, Multidisciplinary, Agricultural and Biological Sciences(all), LARGE-SCALE ASSOCIATION, STAGE RENAL-DISEASE, COMMON VARIANTS, Genomics, Medicine, Research Article, SUSCEPTIBILITY LOCI, General Science & Technology, Population, Single-nucleotide polymorphism, Biology, DIAGRAM Consortium, 03 medical and health sciences, MAGIC Investigators, SDG 3 - Good Health and Well-being, Genetic linkage, MD Multidisciplinary, Genome-Wide Association Studies, SNP, ddc:610, education, Genotyping, 030304 developmental biology, Diabetic Endocrinology, LINKAGE ANALYSIS, Biochemistry, Genetics and Molecular Biology(all), lcsh:R, TCF7L2 GENE, Case-control study, Computational Biology, nutritional and metabolic diseases, Human Genetics, Diabetes Mellitus Type 2, Stage renal-disease, large-scale association, Susceptibility loci, Insulin-resistance, Fasting glucose, Tissue factor, Homeodomain protein, Linkage analysis, Common variants, TCF7L2 gene, Black or African American, Diabetes Mellitus, Type 2, TISSUE FACTOR, Genetics of Disease, HOMEODOMAIN PROTEIN, Genetic Polymorphism, lcsh:Q, Genome Expression Analysis, 030217 neurology & neurosurgery, Population Genetics, FASTING GLUCOSE
Abstract

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P

Published
2012
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12. Common variants at 10 genomic loci influence hemoglobin A1C levels via glycemic and nonglycemic pathways

Author

Soranzo, Nicole, Sanna, Serena, Wheeler, Eleanor, Gieger, Christian, Radke, Dörte, Dupuis, Josée, Bouatia-Naji, Nabila, Langenberg, Claudia, Prokopenko, Inga, Stolerman, Elliot, Sandhu, Manjinder S., Heeney, Matthew M., Devaney, Joseph M., Reilly, Muredach P., Ricketts, Sally L., Stewart, Alexandre F.R., Voight, Benjamin F., Willenborg, Christina, Wright, Benjamin, Altshuler, David, Arking, Dan, Balkau, Beverley, Barnes, Daniel, Boerwinkle, Eric, Böhm, Bernhard, Bonnefond, Amélie, Bonnycastle, Lori L., Boomsma, Dorret I., Bornstein, Stefan R., Böttcher, Yvonne, Bumpstead, Suzannah, Burnett-Miller, Mary Susan, Campbell, Harry, Cao, Antonio, Chamber, John, Clark, Robert, Collins, Francis S., Coresh, Josef, de Geus, Eco J.C., Dei, Mariano, Deloukas, Panos, Döring, Angela, Egan, Josephine M., Elosua, Roberto, Ferrucci, Luigi, Forouhi, Nita, Fox, Caroline S., Franklin, Christopher, Grazia Franzosi, Maria, Gallina, Sophie, Goel, Anuj, Graessler, Jürgen, Grallert, Harald, Greinacher, Andreas, Hadley, David, Hall, Alistair, Hamsten, Anders, Hayward, Caroline, Heath, Simon, Herder, Christian, Homuth, Georg, Hottenga, Jouke-Jan, Hunter-Merrill, Rachel, Illig, Thomas, Jackson, Anne U., Jula, Antti, Kleber, Marcus, Knouff, Christopher W., Kong, Augustine, Kooner, Jaspal, Köttgen, Anna, Kovacs, Peter, Krohn, Knut, Kühnel, Brigitte, Kuusisto, Johanna, Laakso, Markku, Lathrop, Mark, Lecoeur, Cécile, Li, Man, Li, Mingyao, Loos, Ruth J.F., Luan, Jian'an, Lyssenko, Valeriya, Mägi, Reedik, Magnusson, Patrik K.E., Mälarstig, Anders, Mangino, Massimo, Martínez-Larrad, María Teresa, März, Winfried, McArdle, Wendy L., McPherson, Ruth, Meisinger, Christa, Meitinger, Thomas, Melander, Olle, Mohlke, Karen L., Mooser, Vincent E., Morken, Mario A., Narisu, Narisu, Nathan, David M., Nauck, Matthias, O'Donnell, Chris, Oexle, Konrad, Olla, Nazario, Pankow, James S., Payne, Felicity, Peden, John F., Pedersen, Nancy L., Peltonen, Leena, Perola, Markus, Polasek, Ozren, Porcu, Eleonora, Rader, Daniel J., Rathmann, Wolfgang, Ripatti, Samuli, Rocheleau, Ghislain, Roden, Michael, Rudan, Igor, Salomaa, Veikko, Saxena, Richa, Schlessinger, David, Schunkert, Heribert, Schwarz, Peter, Seedorf, Udo, Selvin, Elizabeth, Serrano-Ríos, Manuel, Shrader, Peter, Silveira, Angela, Siscovick, David, Song, Kjioung, Spector, Timothy D., Stefansson, Kari, Steinthorsdottir, Valgerdur, Strachan, David P., Strawbridge, Rona, Stumvoll, Michael, Surakka, Ida, Swift, Amy J., Tanaka, Toshiko, Teumer, Alexander, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tönjes, Anke, Usala, Gianluca, Vitart, Veronique, Völzke, Henry, Wallaschofski, Henri, Waterworth, Dawn M., Watkins, Hugh, Wichmann, H-Erich, Wild, Sarah H., Willemsen, Gonneke, Williams, Gordon H., Wilson, James F., Winkelmann, Juliane, Wright, Alan F., Zabena, Carina, Zhao, Jing Hua, Epstein, Stephen E., Erdmann, Jeanette, Hakonarson, Hakon H., Kathiresan, Sekar, Khaw, Kay-Tee, Roberts, Robert, Samani, Nilesh J., Fleming, Mark D., Sladek, Robert, Abecasis, Gonçalo, Boehnke, Michael, Froguel, Philippe, Groop, Leif, McCarthy, Mark I., Kao, W.H. Linda, Florez, Jose C., Uda, Manuela, Wareham, Nicholas J., Barroso, Inês, and Meigs, James B.

Subjects
endocrine system diseases, nutritional and metabolic diseases
Abstract

OBJECTIVE Glycated hemoglobin (HbA1c), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA1c. We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA1c levels.\ud \ud RESEARCH DESIGN AND METHODS We studied associations with HbA1c in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA1c loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening.\ud \ud RESULTS Ten loci reached genome-wide significant association with HbA1c, including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 × 10−26), HFE (rs1800562/P = 2.6 × 10−20), TMPRSS6 (rs855791/P = 2.7 × 10−14), ANK1 (rs4737009/P = 6.1 × 10−12), SPTA1 (rs2779116/P = 2.8 × 10−9) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 × 10−9), and four known HbA1c loci: HK1 (rs16926246/P = 3.1 × 10−54), MTNR1B (rs1387153/P = 4.0 × 10−11), GCK (rs1799884/P = 1.5 × 10−20) and G6PC2/ABCB11 (rs552976/P = 8.2 × 10−18). We show that associations with HbA1c are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B). The seven nonglycemic loci accounted for a 0.19 (% HbA1c) difference between the extreme 10% tails of the risk score, and would reclassify ∼2% of a general white population screened for diabetes with HbA1c.\ud \ud CONCLUSIONS GWAS identified 10 genetic loci reproducibly associated with HbA1c. Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron storage disorders. Common variants at these loci likely influence HbA1c levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA1c.

Published
2010

13. Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes

Author

Strawbridge, Rona J., Dupuis, Josee, Prokopenko, Inga, Barker, Adam, Ahlqvist, Emma, Rybin, Denis, Petrie, John R., Travers, Mary E., Bouatia-Naji, Nabila, Dimas, Antigone S., Nica, Alexandra, Wheeler, Eleanor, Chen, Han, Voight, Benjamin F., Taneera, Jalal, Kanoni, Stavroula, Peden, John F., Turrini, Fabiola, Gustafsson, Stefan, Zabena, Carina, Almgren, Peter, Barker, David J. P., Barnes, Daniel, Dennison, Elaine M., Eriksson, Johan G., Eriksson, Per, Eury, Elodie, Folkersen, Lasse, Fox, Caroline S., Frayling, Timothy M., Goel, Anuj, Gu, Harvest F., Horikoshi, Momoko, Isomaa, Bo, Jackson, Anne U., Jameson, Karen A., Kajantie, Eero, Kerr-Conte, Julie, Kuulasmaa, Teemu, Kuusisto, Johanna, Loos, Ruth J. F., Luan, Jian'an, Makrilakis, Konstantinos, Manning, Alisa K., Teresa Martinez-Larrad, Maria, Narisu, Narisu, Mannila, Maria Nastase, Ohrvik, John, Osmond, Clive, Pascoe, Laura, Payne, Felicity, Sayer, Avan A., Sennblad, Bengt, Silveira, Angela, Stancakova, Alena, Stirrups, Kathy, Swift, Amy J., Syvänen, Ann-Christine, Tuomi, Tiinamaija, van 't Hooft, Ferdinand M., Walker, Mark, Weedon, Michael N., Xie, Weijia, Zethelius, Björn, Ongen, Halit, Malarstig, Anders, Hopewell, Jemma C., Saleheen, Danish, Chambers, John, Parish, Sarah, Danesh, John, Kooner, Jaspal, Ostenson, Claes-Goran, Lind, Lars, Cooper, Cyrus C., Serrano-Rios, Manuel, Ferrannini, Ele, Forsen, Tom J., Clarke, Robert, Franzosi, Maria Grazia, Seedorf, Udo, Watkins, Hugh, Froguel, Philippe, Johnson, Paul, Deloukas, Panos, Collins, Francis S., Laakso, Markku, Dermitzakis, Emmanouil T., Boehnke, Michael, McCarthy, Mark I., Wareham, Nicholas J., Groop, Leif, Pattou, Francois, Gloyn, Anna L., Dedoussis, George V., Lyssenko, Valeriya, Meigs, James B., Barroso, Ines, Watanabe, Richard M., Ingelsson, Erik, Langenberg, Claudia, Hamsten, Anders, Florez, Jose C., Strawbridge, Rona J., Dupuis, Josee, Prokopenko, Inga, Barker, Adam, Ahlqvist, Emma, Rybin, Denis, Petrie, John R., Travers, Mary E., Bouatia-Naji, Nabila, Dimas, Antigone S., Nica, Alexandra, Wheeler, Eleanor, Chen, Han, Voight, Benjamin F., Taneera, Jalal, Kanoni, Stavroula, Peden, John F., Turrini, Fabiola, Gustafsson, Stefan, Zabena, Carina, Almgren, Peter, Barker, David J. P., Barnes, Daniel, Dennison, Elaine M., Eriksson, Johan G., Eriksson, Per, Eury, Elodie, Folkersen, Lasse, Fox, Caroline S., Frayling, Timothy M., Goel, Anuj, Gu, Harvest F., Horikoshi, Momoko, Isomaa, Bo, Jackson, Anne U., Jameson, Karen A., Kajantie, Eero, Kerr-Conte, Julie, Kuulasmaa, Teemu, Kuusisto, Johanna, Loos, Ruth J. F., Luan, Jian'an, Makrilakis, Konstantinos, Manning, Alisa K., Teresa Martinez-Larrad, Maria, Narisu, Narisu, Mannila, Maria Nastase, Ohrvik, John, Osmond, Clive, Pascoe, Laura, Payne, Felicity, Sayer, Avan A., Sennblad, Bengt, Silveira, Angela, Stancakova, Alena, Stirrups, Kathy, Swift, Amy J., Syvänen, Ann-Christine, Tuomi, Tiinamaija, van 't Hooft, Ferdinand M., Walker, Mark, Weedon, Michael N., Xie, Weijia, Zethelius, Björn, Ongen, Halit, Malarstig, Anders, Hopewell, Jemma C., Saleheen, Danish, Chambers, John, Parish, Sarah, Danesh, John, Kooner, Jaspal, Ostenson, Claes-Goran, Lind, Lars, Cooper, Cyrus C., Serrano-Rios, Manuel, Ferrannini, Ele, Forsen, Tom J., Clarke, Robert, Franzosi, Maria Grazia, Seedorf, Udo, Watkins, Hugh, Froguel, Philippe, Johnson, Paul, Deloukas, Panos, Collins, Francis S., Laakso, Markku, Dermitzakis, Emmanouil T., Boehnke, Michael, McCarthy, Mark I., Wareham, Nicholas J., Groop, Leif, Pattou, Francois, Gloyn, Anna L., Dedoussis, George V., Lyssenko, Valeriya, Meigs, James B., Barroso, Ines, Watanabe, Richard M., Ingelsson, Erik, Langenberg, Claudia, Hamsten, Anders, and Florez, Jose C.

Abstract

OBJECTIVE-Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired beta-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS-We have conducted a meta-analysis of genome-wide association tests of similar to 2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS-Nine SNPs at eight loci were associated with proinsulin levels (P < 5 x 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC3OA8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 x 10(-4)), improved beta-cell function (P = 1.1 x 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 x 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS-We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

Published
2011
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14. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Author

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 J C, 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, Sigurethsson, Gunnar, Sijbrands, Eric 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, 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 I, 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, 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 J C, 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, Sigurethsson, Gunnar, Sijbrands, Eric 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, 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 I, 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, and Barroso, Inês

Abstract

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. 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 type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

Published
2010
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15. Common Variants of the Liver Fatty Acid Binding Protein Gene Influence the Risk of Type 2 Diabetes and Insulin Resistance in Spanish Population

Author

Mansego, Maria Luisa, primary, Martínez, Fernando, additional, Martínez-Larrad, Maria Teresa, additional, Zabena, Carina, additional, Rojo, Gemma, additional, Morcillo, Sonsoles, additional, Soriguer, Federico, additional, Martín-Escudero, Juan Carlos, additional, Serrano-Ríos, Manuel, additional, Redon, Josep, additional, and Chaves, Felipe Javier, additional

Published
2012
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16. Genetic Structure of the Spanish Population

Author

Gayán, Javier, primary, Galan, José J, additional, González-Pérez, Antonio, additional, Sáez, María Eugenia, additional, Martínez-Larrad, María Teresa, additional, Zabena, Carina, additional, Rivero, M Carmen, additional, Salinas, Ana, additional, Ramírez-Lorca, Reposo, additional, Morón, Francisco J, additional, Royo, Jose Luis, additional, Moreno-Rey, Concha, additional, Velasco, Juan, additional, Carrasco, José M, additional, Molero, Eva, additional, Ochoa, Carolina, additional, Ochoa, María Dolores, additional, Gutiérrez, Marta, additional, Reina, Mercedes, additional, Pascual, Rocío, additional, Romo-Astorga, Alejandro, additional, Susillo-González, Juan Luis, additional, Vázquez, Enrique, additional, Real, Luis M, additional, Ruiz, Agustín, additional, and Serrano-Ríos, Manuel, additional

Published
2010
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17. Erratum: New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Author

Dupuis, Josée, primary, Langenberg, Claudia, additional, Prokopenko, Inga, additional, Saxena, Richa, additional, Soranzo, Nicole, additional, Jackson, Anne U, additional, Wheeler, Eleanor, additional, Glazer, Nicole L, additional, Bouatia-Naji, Nabila, additional, Gloyn, Anna L, additional, Lindgren, Cecilia M, additional, Mägi, Reedik, additional, Morris, Andrew P, additional, Randall, Joshua, additional, Johnson, Toby, additional, Elliott, Paul, additional, Rybin, Denis, additional, Thorleifsson, Gudmar, additional, Steinthorsdottir, Valgerdur, additional, Henneman, Peter, additional, Grallert, Harald, additional, Dehghan, Abbas, additional, Hottenga, Jouke Jan, additional, Franklin, Christopher S, additional, Navarro, Pau, additional, Song, Kijoung, additional, Goel, Anuj, additional, Perry, John R B, additional, Egan, Josephine M, additional, Lajunen, Taina, additional, Grarup, Niels, additional, Sparsø, Thomas, additional, Doney, Alex, additional, Voight, Benjamin F, additional, Stringham, Heather M, additional, Li, Man, additional, Kanoni, Stavroula, additional, Shrader, Peter, additional, Cavalcanti-Proença, Christine, additional, Kumari, Meena, additional, Qi, Lu, additional, Timpson, Nicholas J, additional, Gieger, Christian, additional, Zabena, Carina, additional, Rocheleau, Ghislain, additional, Ingelsson, Erik, additional, An, Ping, additional, O'Connell, Jeffrey, additional, Luan, Jian'an, additional, Elliott, Amanda, additional, McCarroll, Steven A, additional, Payne, Felicity, additional, Roccasecca, Rosa Maria, additional, Pattou, François, additional, Sethupathy, Praveen, additional, Ardlie, Kristin, additional, Ariyurek, Yavuz, additional, Balkau, Beverley, additional, Barter, Philip, additional, Beilby, John P, additional, Ben-Shlomo, Yoav, additional, Benediktsson, Rafn, additional, Bennett, Amanda J, additional, Bergmann, Sven, additional, Bochud, Murielle, additional, Boerwinkle, Eric, additional, Bonnefond, Amélie, additional, Bonnycastle, Lori L, additional, Borch-Johnsen, Knut, additional, Böttcher, Yvonne, additional, Brunner, Eric, additional, Bumpstead, Suzannah J, additional, Charpentier, Guillaume, additional, Chen, Yii-Der Ida, additional, Chines, Peter, additional, Clarke, Robert, additional, Coin, Lachlan J M, additional, Cooper, Matthew N, additional, Cornelis, Marilyn, additional, Crawford, Gabe, additional, Crisponi, Laura, additional, Day, Ian N M, additional, de Geus, Eco J C, additional, Delplanque, Jerome, additional, Dina, Christian, additional, Erdos, Michael R, additional, Fedson, Annette C, additional, Fischer-Rosinsky, Antje, additional, Forouhi, Nita G, additional, Fox, Caroline S, additional, Frants, Rune, additional, Franzosi, Maria Grazia, additional, Galan, Pilar, additional, Goodarzi, Mark O, additional, Graessler, Jürgen, additional, Groves, Christopher J, additional, Grundy, Scott, additional, Gwilliam, Rhian, additional, Gyllensten, Ulf, additional, Hadjadj, Samy, additional, Hallmans, Göran, additional, Hammond, Naomi, additional, Han, Xijing, additional, Hartikainen, Anna-Liisa, additional, Hassanali, Neelam, additional, Hayward, Caroline, additional, Heath, Simon C, additional, Hercberg, Serge, additional, Herder, Christian, additional, Hicks, Andrew A, additional, Hillman, David R, additional, Hingorani, Aroon D, additional, Hofman, Albert, additional, Hui, Jennie, additional, Hung, Joe, additional, Isomaa, Bo, additional, Johnson, Paul R V, additional, Jørgensen, Torben, additional, Jula, Antti, additional, Kaakinen, Marika, additional, Kaprio, Jaakko, additional, Kesaniemi, Y Antero, additional, Kivimaki, Mika, additional, Knight, Beatrice, additional, Koskinen, Seppo, additional, Kovacs, Peter, additional, Kyvik, Kirsten Ohm, additional, Lathrop, G Mark, additional, Lawlor, Debbie A, additional, Le Bacquer, Olivier, additional, Lecoeur, Cécile, additional, Li, Yun, additional, Lyssenko, Valeriya, additional, Mahley, Robert, additional, Mangino, Massimo, additional, Manning, Alisa K, additional, Martínez-Larrad, María Teresa, additional, McAteer, Jarred B, additional, McCulloch, Laura J, additional, McPherson, Ruth, additional, Meisinger, Christa, additional, Melzer, David, additional, Meyre, David, additional, Mitchell, Braxton D, additional, Morken, Mario A, additional, Mukherjee, Sutapa, additional, Naitza, Silvia, additional, Narisu, Narisu, additional, Neville, Matthew J, additional, Oostra, Ben A, additional, Orrù, Marco, additional, Pakyz, Ruth, additional, Palmer, Colin N A, additional, Paolisso, Giuseppe, additional, Pattaro, Cristian, additional, Pearson, Daniel, additional, Peden, John F, additional, Pedersen, Nancy L, additional, Perola, Markus, additional, Pfeiffer, Andreas F H, additional, Pichler, Irene, additional, Polasek, Ozren, additional, Posthuma, Danielle, additional, Potter, Simon C, additional, Pouta, Anneli, additional, Province, Michael A, additional, Psaty, Bruce M, additional, Rathmann, Wolfgang, additional, Rayner, Nigel W, additional, Rice, Kenneth, additional, Ripatti, Samuli, additional, Rivadeneira, Fernando, additional, Roden, Michael, additional, Rolandsson, Olov, additional, Sandbaek, Annelli, additional, Sandhu, Manjinder, additional, Sanna, Serena, additional, Sayer, Avan Aihie, additional, Scheet, Paul, additional, Scott, Laura J, additional, Seedorf, Udo, additional, Sharp, Stephen J, additional, Shields, Beverley, additional, SigurÐsson, Gunnar, additional, Sijbrands, Eric J G, additional, Silveira, Angela, additional, Simpson, Laila, additional, Singleton, Andrew, additional, Smith, Nicholas L, additional, Sovio, Ulla, additional, Swift, Amy, additional, Syddall, Holly, additional, Syvänen, Ann-Christine, additional, Tanaka, Toshiko, additional, Thorand, Barbara, additional, Tichet, Jean, additional, Tönjes, Anke, additional, Tuomi, Tiinamaija, additional, Uitterlinden, André G, additional, van Dijk, Ko Willems, additional, van Hoek, Mandy, additional, Varma, Dhiraj, additional, Visvikis-Siest, Sophie, additional, Vitart, Veronique, additional, Vogelzangs, Nicole, additional, Waeber, Gérard, additional, Wagner, Peter J, additional, Walley, Andrew, additional, Walters, G Bragi, additional, Ward, Kim L, additional, Watkins, Hugh, additional, Weedon, Michael N, additional, Wild, Sarah H, additional, Willemsen, Gonneke, additional, Witteman, Jaqueline C M, additional, Yarnell, John W G, additional, Zeggini, Eleftheria, additional, Zelenika, Diana, additional, Zethelius, Björn, additional, Zhai, Guangju, additional, Zhao, Jing Hua, additional, Zillikens, M Carola, additional, Consortium, DIAGRAM, additional, Consortium, GIANT, additional, Consortium, Global BPgen, additional, Borecki, Ingrid B, additional, Loos, Ruth J F, additional, Meneton, Pierre, additional, Magnusson, Patrik K E, additional, Nathan, David M, additional, Williams, Gordon H, additional, Hattersley, Andrew T, additional, Silander, Kaisa, additional, Salomaa, Veikko, additional, Smith, George Davey, additional, Bornstein, Stefan R, additional, Schwarz, Peter, additional, Spranger, Joachim, additional, Karpe, Fredrik, additional, Shuldiner, Alan R, additional, Cooper, Cyrus, additional, Dedoussis, George V, additional, Serrano-Ríos, Manuel, additional, Morris, Andrew D, additional, Lind, Lars, additional, Palmer, Lyle J, additional, Hu, Frank B, additional, Franks, Paul W, additional, Ebrahim, Shah, additional, Marmot, Michael, additional, Kao, W H Linda, additional, Pankow, James S, additional, Sampson, Michael J, additional, Kuusisto, Johanna, additional, Laakso, Markku, additional, Hansen, Torben, additional, Pedersen, Oluf, additional, Pramstaller, Peter Paul, additional, Wichmann, H Erich, additional, Illig, Thomas, additional, Rudan, Igor, additional, Wright, Alan F, additional, Stumvoll, Michael, additional, Campbell, Harry, additional, Wilson, James F, additional, Hamsten, Anders, additional, Bergman, Richard N, additional, Buchanan, Thomas A, additional, Collins, Francis S, additional, Mohlke, Karen L, additional, Tuomilehto, Jaakko, additional, Valle, Timo T, additional, Altshuler, David, additional, Rotter, Jerome I, additional, Siscovick, David S, additional, Penninx, Brenda W J H, additional, Boomsma, Dorret I, additional, Deloukas, Panos, additional, Spector, Timothy D, additional, Frayling, Timothy M, additional, Ferrucci, Luigi, additional, Kong, Augustine, additional, Thorsteinsdottir, Unnur, additional, Stefansson, Kari, additional, van Duijn, Cornelia M, additional, Aulchenko, Yurii S, additional, Cao, Antonio, additional, Scuteri, Angelo, additional, Schlessinger, David, additional, Uda, Manuela, additional, Ruokonen, Aimo, additional, Jarvelin, Marjo-Riitta, additional, Waterworth, Dawn M, additional, Vollenweider, Peter, additional, Peltonen, Leena, additional, Mooser, Vincent, additional, Abecasis, Goncalo R, additional, Wareham, Nicholas J, additional, Sladek, Robert, additional, Froguel, Philippe, additional, Watanabe, Richard M, additional, Meigs, James B, additional, Groop, Leif, additional, Boehnke, Michael, additional, McCarthy, Mark I, additional, Florez, Jose C, additional, and Barroso, Inês, additional

Published
2010
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22. Interaction of the −308G/A Promoter Polymorphism of the Tumor Necrosis Factor-α Gene with Single-Nucleotide Polymorphism 45 of the Adiponectin Gene: Effect on Serum Adiponectin Concentrations in a Spanish Population

Author

González-Sánchez, José L, primary, Martínez-Calatrava, María J, primary, Martínez-Larrad, María T, primary, Zabena, Carina, primary, Fernández-Pérez, Cristina, primary, Laakso, Markku, primary, and Serrano-Ríos, Manuel, primary

Published
2006
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24. Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes.

Author

Dupuis, Josée, Prokopenko, Inga, Barker, Adam, Ahlqvist, Emma, Rybin, Denis, Petrie, John R., Travers, Mary E., Bouatia-Naji, Nabila, Dimas, Antigone S., Nica, Alexandra, Wheeler, Eleanor, Chen, Han, Voight, Benjamin F., Taneera, Jalal, Kanoni, Stavroula, Peden, John F., Turrini, Fabiola, Gustafsson, Stefan, Zabena, Carina, and Almgren, Peter

Subjects
PROINSULIN, INSULIN, C-peptide, B cells, GENOMES
Abstract

OBJECTIVE-Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired b-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS-We have conducted a meta-analysis of genome-wide association tests of ~2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS-Nine SNPs at eight loci were associated with proinsulin levels (P < 5 x 10-8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/ C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 X 10-4), improved b-cell function (P = 1.1 X 10-5), and lower risk of T2D (odds ratio 0.88; P = 7.8 X 10-6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS-We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis. [ABSTRACT FROM AUTHOR]

Published
2011
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26. Is the plasminogen activator inhibitor-1 gene a candidate gene predisposing to hypertension Results from a population-based study in Spain

Author

Martínez-Calatrava, María J, González-Sánchez, José L, Zabena, Carina, Martínez-Larrad, María T, Luque-Otero, Manuel, and Serrano-Ríos, Manuel

Abstract

Studies in humans and mice suggest that plasminogen activator inhibitor-1 (PAI-1) might be a candidate gene for arterial hypertension. Our aims were to analyse whether the functional 4G/5G PAI-1 polymorphism represents a risk marker for the development of arterial hypertension regardless of hypertension-related metabolic variables.

Published
2007
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27. Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals

Author

Dastani, Zari, Hivert, Marie-France, Timpson, Nicholas, Perry, John RB, Yuan, Xin, Scott, Robert A, Henneman, Peter, Heid, Iris M, Kizer, Jorge R, Lyytikäinen, Leo-Pekka, Fuchsberger, Christian, Tanaka, Toshiko, Morris, Andrew P, Small, Kerrin, Isaacs, Aaron, Beekman, Marian, Coassin, Stefan, Lohman, Kurt, Qi, Lu, Kanoni, Stavroula, Pankow, James S, Uh, Hae-Won, Wu, Ying, Bidulescu, Aurelian, Rasmussen-Torvik, Laura J, Greenwood, Celia MT, Ladouceur, Martin, Grimsby, Jonna, Manning, Alisa K, Liu, Ching-Ti, Kooner, Jaspal, Mooser, Vincent E, Vollenweider, Peter, Kapur, Karen A, Chambers, John, Wareham, Nicholas J, Langenberg, Claudia, Frants, Rune, Willems-Vandijk, Ko, Oostra, Ben A, Willems, Sara M, Lamina, Claudia, Winkler, Thomas W, Psaty, Bruce M, Tracy, Russell P, Brody, Jennifer, Chen, Ida, Viikari, Jorma, Kähönen, Mika, Pramstaller, Peter P, Evans, David M, St Pourcain, Beate, Sattar, Naveed, Wood, Andrew R, Bandinelli, Stefania, Carlson, Olga D, Egan, Josephine M, Böhringer, Stefan, Van Heemst, Diana, Kedenko, Lyudmyla, Kristiansson, Kati, Nuotio, Marja-Liisa, Loo, Britt-Marie, Harris, Tamara, Garcia, Melissa, Kanaya, Alka, Haun, Margot, Klopp, Norman, Wichmann, H-Erich, Deloukas, Panos, Katsareli, Efi, Couper, David J, Duncan, Bruce B, Kloppenburg, Margreet, Adair, Linda S, Borja, Judith B, DIAGRAM+ Consortium, MAGIC Consortium, GLGC Investigators, MuTHER Consortium, Wilson, James G, Musani, Solomon, Guo, Xiuqing, Johnson, Toby, Semple, Robert, Teslovich, Tanya M, Allison, Matthew A, Redline, Susan, Buxbaum, Sarah G, Mohlke, Karen L, Meulenbelt, Ingrid, Ballantyne, Christie M, Dedoussis, George V, Hu, Frank B, Liu, Yongmei, Paulweber, Bernhard, Spector, Timothy D, Slagboom, P Eline, Ferrucci, Luigi, Jula, Antti, Perola, Markus, Raitakari, Olli, Florez, Jose C, Salomaa, Veikko, Eriksson, Johan G, Frayling, Timothy M, Hicks, Andrew A, Lehtimäki, Terho, Smith, George Davey, Siscovick, David S, Kronenberg, Florian, Van Duijn, Cornelia, Loos, Ruth JF, Waterworth, Dawn M, Meigs, James B, Dupuis, Josee, Richards, J Brent, Voight, Benjamin F, Scott, Laura J, Steinthorsdottir, Valgerdur, 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, Hofmann, Oliver M, 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, Noël P, Charpentier, Guillaume, Chines, Peter S, Cornelis, Marilyn, Crawford, Gabe, Doney, Alex SF, 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 RV, Jørgensen, Torben, Kao, Wen HL, 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, 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, Morris, Andrew D, Palmer, Colin NA, Rudan, Igor, Sijbrands, Eric, Stein, Lincoln D, Tuomilehto, Jaakko, Uitterlinden, Andre, Walker, Mark, Watanabe, Richard M, Abecasis, Goncalo R, Boehm, Bernhard O, Campbell, Harry, Daly, Mark J, Hattersley, Andrew T, Pedersen, Oluf, Barroso, Inês, 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, Soranzo, Nicole, Wheeler, Eleanor, Glazer, Nicole L, Bouatia-Naji, Nabila, Mägi, Reedik, Randall, Joshua, Elliott, Paul, Rybin, Denis, Dehghan, Abbas, Hottenga, Jouke Jan, Song, Kijoung, Goel, Anuj, Lajunen, Taina, Doney, Alex, Cavalcanti-Proença, Christine, Kumari, Meena, Timpson, Nicholas J, Zabena, Carina, Ingelsson, Erik, An, Ping, O'Connell, Jeffrey, Luan, Jian'an, Elliott, Amanda, McCarroll, Steven A, Roccasecca, Rosa Maria, Pattou, François, Sethupathy, Praveen, Ariyurek, Yavuz, Barter, Philip, Beilby, John P, Ben-Shlomo, Yoav, Bergmann, Sven, Bochud, Murielle, Bonnefond, Amélie, Borch-Johnsen, Knut, Böttcher, Yvonne, Brunner, Eric, Bumpstead, Suzannah J, Chen, Yii-Der Ida, Chines, Peter, Clarke, Robert, Coin, Lachlan JM, Cooper, Matthew N, Crisponi, Laura, Day, Ian NM, De Geus, Eco JC, Delplanque, Jerome, Fedson, Annette C, Fischer-Rosinsky, Antje, Forouhi, Nita G, Franzosi, Maria Grazia, Galan, Pilar, Goodarzi, Mark O, Graessler, Jürgen, Grundy, Scott, Gwilliam, Rhian, Hallmans, Göran, Hammond, Naomi, Han, Xijing, Hartikainen, Anna-Liisa, Hayward, Caroline, Heath, Simon C, Hercberg, Serge, Hillman, David R, Hingorani, Aroon D, Hui, Jennie, Hung, Joe, 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, Mahley, Robert, Mangino, Massimo, Martínez-Larrad, María Teresa, McAteer, Jarred B, McPherson, Ruth, Meisinger, Christa, Melzer, David, Meyre, David, Mitchell, Braxton D, Mukherjee, Sutapa, Naitza, Silvia, Neville, Matthew J, Orrù, Marco, Pakyz, Ruth, Paolisso, Giuseppe, Pattaro, Cristian, Pearson, Daniel, Peden, John F, Pedersen, Nancy L, Pfeiffer, Andreas FH, Pichler, Irene, Polasek, Ozren, Posthuma, Danielle, Potter, Simon C, Pouta, Anneli, Province, Michael A, Rayner, Nigel W, Rice, Kenneth, Ripatti, Samuli, Rivadeneira, Fernando, Rolandsson, Olov, Sandbaek, Annelli, Sandhu, Manjinder, Sanna, Serena, Sayer, Avan Aihie, Scheet, Paul, Seedorf, Udo, Sharp, Stephen J, Shields, Beverley, Sigurðsson, Gunnar, Sijbrands, Eric JG, Silveira, Angela, Simpson, Laila, Singleton, Andrew, Smith, Nicholas L, Sovio, Ulla, Swift, Amy, Syddall, Holly, Syvänen, Ann-Christine, Tönjes, Anke, Uitterlinden, André G, Van Dijk, Ko Willems, Varma, Dhiraj, Visvikis-Siest, Sophie, Vitart, Veronique, Vogelzangs, Nicole, Waeber, Gérard, Wagner, Peter J, Walley, Andrew, Ward, Kim L, Watkins, Hugh, Wild, Sarah H, Willemsen, Gonneke, Witteman, Jaqueline CM, Yarnell, John WG, Zelenika, Diana, Zethelius, Björn, Zhai, Guangju, Zhao, Jing Hua, Zillikens, M Carola, DIAGRAM Consortium, GIANT Consortium, Global B Pgen Consortium, Borecki, Ingrid B, Meneton, Pierre, Magnusson, Patrik KE, Nathan, David M, Williams, Gordon H, Silander, Kaisa, Bornstein, Stefan R, Schwarz, Peter, Spranger, Joachim, Karpe, Fredrik, Shuldiner, Alan R, Cooper, Cyrus, Serrano-Ríos, Manuel, Lind, Lars, Palmer, Lyle J, Franks, Paul W, Ebrahim, Shah, Marmot, Michael, Kao, WH Linda, Pramstaller, Peter Paul, Wright, Alan F, Stumvoll, Michael, Hamsten, Anders, Procardis Consortium, Buchanan, Thomas A, Valle, Timo T, Rotter, Jerome I, Penninx, Brenda WJH, Boomsma, Dorret I, Cao, Antonio, Scuteri, Angelo, Schlessinger, David, Uda, Manuela, Ruokonen, Aimo, Jarvelin, Marjo-Riitta, Peltonen, Leena, Mooser, Vincent, Sladek, Robert, MAGIC Investigators, GLGC Consortium, Musunuru, Kiran, Smith, Albert V, Edmondson, Andrew C, Stylianou, Ioannis M, Koseki, Masahiro, Pirruccello, James P, Chasman, Daniel I, Johansen, Christopher T, Fouchier, Sigrid W, Peloso, Gina M, Barbalic, Maja, Ricketts, Sally L, Bis, Joshua C, Feitosa, Mary F, Orho-Melander, Marju, Melander, Olle, Li, Xiaohui, Li, Mingyao, Cho, Yoon Shin, Go, Min Jin, Kim, Young Jin, Lee, Jong-Young, Park, Taesung, Kim, Kyunga, Sim, Xueling, Ong, Rick Twee-Hee, Croteau-Chonka, Damien C, Lange, Leslie A, Smith, Joshua D, Ziegler, Andreas, Zhang, Weihua, Zee, Robert YL, Whitfield, John B, Thompson, John R, Surakka, Ida, Spector, Tim D, Smit, Johannes H, Sinisalo, Juha, Scott, James, Saharinen, Juha, Sabatti, Chiara, Rose, Lynda M, Roberts, Robert, Rieder, Mark, Parker, Alex N, Pare, Guillaume, O'Donnell, Christopher J, Nieminen, Markku S, Nickerson, Deborah A, Montgomery, Grant W, McArdle, Wendy, Masson, David, Martin, Nicholas G, Marroni, Fabio, Lucas, Gavin, Luben, Robert, Lokki, Marja-Liisa, Lettre, Guillaume, Launer, Lenore J, Lakatta, Edward G, Laaksonen, Reijo, Kyvik, Kirsten O, König, Inke R, Khaw, Kay-Tee, Kaplan, Lee M, Johansson, Åsa, Janssens, A Cecile JW, Igl, Wilmar, Hovingh, G Kees, Hengstenberg, Christian, Havulinna, Aki S, Hastie, Nicholas D, Harris, Tamara B, Haritunians, Talin, Hall, Alistair S, Groop, Leif C, Gonzalez, Elena, Freimer, Nelson B, Erdmann, Jeanette, Ejebe, Kenechi G, Döring, Angela, Dominiczak, Anna F, Demissie, Serkalem, Deloukas, Panagiotis, De Faire, Ulf, Crawford, Gabriel, Chen, Yii-Der I, Caulfield, Mark J, Boekholdt, S Matthijs, Assimes, Themistocles L, Quertermous, Thomas, Seielstad, Mark, Wong, Tien Y, Tai, E-Shyong, Feranil, Alan B, Kuzawa, Christopher W, Taylor, Herman A, Gabriel, Stacey B, Holm, Hilma, Gudnason, Vilmundur, Krauss, Ronald M, Ordovas, Jose M, Munroe, Patricia B, Kooner, Jaspal S, Tall, Alan R, Hegele, Robert A, Kastelein, John JP, Schadt, Eric E, Strachan, David P, Reilly, Muredach P, Samani, Nilesh J, Schunkert, Heribert, Cupples, L Adrienne, Sandhu, Manjinder S, Ridker, Paul M, Rader, Daniel J, and Kathiresan, Sekar

Subjects
2. Zero hunger, Male, Waist-Hip Ratio, Cholesterol, HDL, Gene Expression, Glucose Tolerance Test, Polymorphism, Single Nucleotide, White People, 3. Good health, Black or African American, Asian People, Diabetes Mellitus, Type 2, Humans, Female, Genetic Predisposition to Disease, Adiponectin, Insulin Resistance, Metabolic Networks and Pathways, Genome-Wide Association Study
Abstract

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p

28. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Author

Global BPgen Consrotium, Sovio, Ulla, Shuldiner, Alan R., Dedoussis, George V., Bonnycastle, Lori L., Hercberg, Serge, Chen, Yii-Der Ida, Visvikis-Siest, Sophie, Kumari, Meena, Meneton, Pierre, Ariyurek, Yavuz, Egan, Josephine M., Ben-Shlomo, Yoav, Forouhi, Nita G., Graessler, Jurgen, Rudan, Igor, Pedersen, Nancy L., Lindgren, Cecilia M., Chines, Peter, Stringham, Heather M., Meisinger, Christa, Pattaro, Cristian, Vogelzangs, Nicole, DIAGRAM Consortium, Illig, Thomas, Langenberg, Claudia, Zethelius, Bjorn, Sayer, Avan Aihie, Laakso, Markku, Li, Man, Clarke, Robert, Isomaa, Bo, McAteer, Jarred B., Doney, Alex, Pedersen, Oluf, Jorgensen, Torben, Bottcher, Yvonne, Ebrahim, Shah, Schwarz, Peter, Lecoeur, Cecile, Psaty, Bruce M., Shrader, Peter, Knight, Beatrice, Beilby, John P., Gieger, Christian, Ripatti, Samuli, Zhao, Jing Hua, Herder, Christian, Morken, Mario A., Kesaniemi, Y. Antero, Orru, Marco, Mitchell, Braxton D., Thorand, Barbara, Lyssenko, Valeriya, Manning, Alisa K., Sethupathy, Praveen, Meyre, David, Hansen, Torben, Rayner, Nigel W., Hammond, Naomi, Timpson, Nicholas J., Sanna, Serena, Brunner, Eric, Zhai, Guangju, Witteman, Jacqueline C.M., Rybin, Denis, Cornelis, Marilyn, Zabena, Carina, Willemson, Gonneke, Kaakinen, Marika, Perry, John R.B., Zelenika, Diana, Walters, G. Bragi, Heath, Simon C., Oostra, Ben A., Salomaa, Veikko, Ward, Kim L., van Dijk, Ko Willems, Williams, Gordon H., Karpe, Fredrik, Wagner, Peter J., Magi, Reedik, Fischer-Rosinsky, Antje, Hallmans, Goran, Lajunen, Taina, Qi, Lu, Navarro, Paul, Grallert, Harald, Pramstaller, Peter Paul, Kaprio, Jaakko, Smith, Nicholas L., Hayward, Caroline, Sandbaek, Annelli, Sparso, Thomas, Dina, Christian, Paolisso, Giuseppe, Wright, Alan F., Mangino, Massimo, Henneman, Peter, Smith, George Davey, Boerwinkle, Eric, Prokopenko, Inga, Jackson, Anne U., Grarup, Niels, Walley, Andrew, Hofman, Albert, Hadjadj, Samy, Hu, Frank B., Hung, Joe, Li, Yun, Gwilliam, Rhian, Thorleifsson, Gudmar, Singleton, Andrew, Ardlie, Kristin, Kivimaki, Mika, Syvanen, Ann-Christine, Zillikens, M. Carola, Day, Ian N.M., Rice, Kenneth, Silander, Kaisa, Bergmann, Sven, Simpson, Laila, Scott, Laura J., Melzer, David, Neville, Matthew J., Watkins, Hugh, Ingelsson, Erik, Lathrop, G. Mark, Scheet, Paul, Hottenga, Jouke Jan, Song, Kijoung, Benediktsson, Rafn, de Geus, Eco J. C., Le Bacquer, Olivier, Hillman, David R., Koskinen, Seppo, Frants, Rune, Lind, Lars, Kanoni, Stavroula, Sandhu, Manjinder, Crawford, Gabe, Sigurdsson, Gunnar, Pfeiffer, Andreas F.H., Pattou, Francois, Pankow, James S., Wilson, James F., Bennett, Amanda J., Dupuis, Josee, Potter, Simon C., Elliott, Amanda, Province, Michael A., Perola, Markus, Serrano-Rios, Manuel, Kyvik, Kirsten Ohm, Yarnell, John W.G., Pakyz, Ruth, Johnson, Paul R.V., Borch-Johnsen, Knut, Saxena, Richa, Steinthorsdottir, Valgerdur, Tanaka, Toshiko, Campbell, Harry, Barter, Philip, Franzosi, Maria Grazia, GIANT Consortium, Han, Xijing, Cavalcanti-Proenca, Christine, Glazer, Nicole L., Kovacs, Peter, Stumvoll, Michael, Syddall, Holly, Hingorani, Aroon D., Morris, Andrew P., O'Connell, Jeffrey, Payne, Felicity, Galan, Pilar, Rivadeneira, Fernando, Wild, Sarah H., McPherson, Ruth, Sijbrands, Eric J.G., Hicks, Andrew A., Dehghan, Abbas, Elliott, Paul, Cooper, Matthew N., Sharp, Stephen J., Balkau, Beverley, Voight, Benjamin F., Roden, Michael, Tuomi, Tiinamaija, Franklin, Christopher S., Swift, Amy, Pichler, Irene, Narisu, Narisu, Goodarzi, Mark O., Franks, Paul W., An, Ping, Bumpstead, Suzannah J., Bochud, Murielle, Rathmann, Wolfgang, Randall, Joshua, Bouatia-Naji, Nabila, von Hoek, Mandy, Kuusisto, Johanna, Sampson, Michael J., Wichmann, H. Erich, Vitart, Veronique, Tichet, Jean, Spranger, Joachim, Fedson, Annette C., Waeber, Gerard, Wheeler, Eleanor, Polasek, Ozren, Coin, Lachlan J.M., Varma, Dhiraj, Pearson, Daniel, Hartikainen, Anna-Liisa, Loos, Ruth J.F., Grundy, Scott, Martinez-Larrad, Maria Teresa, Jula, Antti, Palmer, Colin N.A., Mukherjee, Sutapa, Bornstein, Stefan R., Gyllensten, Ulf, Roccasecca, Rosa Maria, Johnson, Toby, Crisponi, Laura, Weedon, Michael N., Hamsten, Anders, Bonnefond, Amelie, Nathan, David M., Silveira, Angela, Borecki, Ingrid B., Hassanali, Neelam, Pouta, Anneli, Fox, Caroline S., Cooper, Cyrus, McCulloch, Laura J., Hattersley, Andrew T., Seedorf, Udo, Zeggini, Eleftheria, Lawlor, Debbie A., Uitterlinden, Andre G., Rocheleau, Ghislain, Kao, W.H. Linda, Goel, Anuj, Palmer, Lyel J., Magnusson, Patrik K.E., Shields, Beverley, Tonjes, Anke, Soranzo, Nicole, Groves, Christopher J., Gloyn, Anna L., Charpentier, Guillaume, Erdos, Michael R., Posthuma, Danielle, Marmot, Michael, Morris, Andrew D., Luan, Jian'an, Delplanque, Jerome, Naitza, Silvia, Mahley, Robert, McCarroll, Steven A., Hui, Jennie, Rolandsson, Olov, and Peden, John F.

Subjects
3. Good health
Abstract

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. 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 type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

29. Insulin Resistance in Haart HIV Treated Patients and PRO12ALA PPARg-2: The Genetic Impact Is Related to Duration of Treatment.

Author

Zabena, Carina, Estrada, Vicente, Gonzalez-Sanchez, Jose L., Martínez-Calatrava, Maria J., Martínez-Larrad, Maria T., Perez-Barba, Milagros, and Serrano-Ríos, Manuel

Subjects
*PEROXISOMES, *GENETIC polymorphisms, *TYPE 2 diabetes, *INSULIN resistance, *METABOLIC disorders, *HIV-positive persons, *ANTIRETROVIRAL agents
Abstract

The article discusses a study which investigated the potential associations of the Pro12Ala peroxisome proliferator-activated receptor (PPARγ-2) polymorphism on type 2 diabetes, insulin resistance (IR) and metabolic derangements in HIV-infected patients on Highly Active Antiretroviral Therapy (HAART). Results of the study suggest that a higher time of treatment had a greater impact on IR than a potentially protective effect of Ala12 allele of PPARγ-2 gene.

Published
2007

30. PPARγ2 Pro12A1a and TNFα-308 G/A Interaction on Features of Metabolic Syndrome.

Author

Gonzalez-Sanchez, Jose L., Zabena, Carina, Martínez-Larrad, Maria T., Martínez-Calatrava, Maria J., Perez-Barba, Milagros, and Serrano-Ríos, Manuel

Subjects
*NUCLEAR receptors (Biochemistry), *GENETIC polymorphisms, *INSULIN resistance, *METABOLIC syndrome, *GENES, *TYPE 2 diabetes, *OBESITY
Abstract

To determine whether the Pro12A1a polymorphism of the PPARγ2 gene was associated with increased risk for the development of insulin resistance and other features of the metabolic syndrome in a representative sample of Spanish population and its interaction with the TNF-α-308 G/A polymorphism, we genotyped 783 unrelated subjects recruited from a cross-sectional population-based epidemiological survey in Segovia, Spain (The Segovia Study Group). Anthropometric parameters: BMI, waist to hip ratio (WHR). OGTT, fasting and 2 hrs glucose; serum insulin, adiponectin levels (RIA); lipid profile. Plasma PAI-1 and plasma soluble TNF-αreceptor 2 (sTNFR2) levels by ELISA. Insulin resistance was assessed by HOMA-IR. Categories of glucose tolerance (ADA Clinical Practice Recommendations 2006) MS was defined according to the 2005 IDF criteria. Pro12A1a PPARγand -308G/A TNF-α genotypes determined by PCR-RFLP. PPARγ genotype distribution: Pro12Pro 87.2%, Pro12A1a 12.4%, A1a12A1a: 0.4%. Impaired glucose tolerance (IGT) was higher in Pro 12Pro homozygous compared to carriers of the A1a12 allele (16.8% vs 8.1%, p=027) even after adjustment for sex, age, BMI, WHR and insulin resistance (OR: 2.5, CI 95% 1.04-6.25, p=0.049) in a logistic regression model. Plasma levels of sTNFR2 were positively correlated with BMI, and waist circumference among type 2 diabetic subjects. Interestingly diabetic subjects carrying the -308A allele had higher sTNFR2 levels,. WHR, insulin 2 hours PAI levels,and lower adiponectin concentrations as compared with G-308G homozygous. A gene-gene interaction was detected. Subjects simultaneously having the Ala12 allele of the PPARγ2 gene and the -308A allele of the TNF-α gene had higher waist to hip ratio than those carrying only either one of these gene polymorphisms alone (P<0.001), independently of sex, age, and glucose tolerance status. Our findings indicate a gene-gene interaction between the PPARγPro12Ala polymorphism and the TNF-α-308Apolymorphism, which may result in higher risk for abdominal obesity, but not for type 2 diabetes. [ABSTRACT FROM AUTHOR]

Published
2007

31. Effect of ENPP1 (PC-1) K121Q Polymorphism on Type 2 Diabetes and Its Interactions with SNPs 45/276 of the Adiponectin Gene.

Author

Gonzalez-Sanchez, Jose L., Martinez-Larrad, Maria T., Zabena, Carina, Martínez-Calatrava, Maria J., and Serrano-Ríos, Manuel

Subjects
PHOSPHODIESTERASES, GENETIC polymorphisms, TYPE 2 diabetes, MUSCLE proteins, GENETICS of diabetes, INSULIN resistance
Abstract

To determine whether the K121Q polymorphism of the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene, also known as PC-1 was associated with features of Metabolic Syndrome (MS) in a representative sample of Spanish population and its interaction with adiponectin gene (APM) polymorphisms, we genotyped 842 unrelated subjects recruited from a cross-sectional population-based epidemiological survey in Segovia, Spain (The Segovia Study Group). Anthropometric parameters: BMI, waist circumference (WC). OGTT, fasting and 2 hrs glucose; serum insulin, leptin levels (RIA); lipid profile. Insulin resistance was assessed by HOMA-IR. Categories of glucose tolerance (ADA Clinical Practice Recommendations 2006). MS was defined according to the 2005 IDF criteria. SNPs 45 and 276 of the adiponectin gene screened by PCR/ SnaPshot reactions (ABI Prism 310 Genetic Analyzer). ENPP1 K121Q genotypes determined by PCR-RFLP. ENPP1 genotype distribution: K121K 73.2%, K121Q 24.8%, Q121Q: 2.0%. Among subjects with MS those carrying the 121Q allele had higher BMI, and WC than carriers of the K121K genotype, even after adjustment for sex, age, and degree of glucose tolerance. Among type 2 diabetic subjects, the genotype frequency of K121Q was higher in obese (31.4%) as compared with non-obese subjects (13.2%). The Q allele was also associated with higher BMI (32 ± 4 vs. 29 ± 4, p=0.009), and higher leptin (22 ±13 vs. 114 ± p=0.030) concentrations. Multiple linear regression analysis showed that these differences were also significant even after the adjustment for sex, and age (p=0.012); and for sex, age, BMI and waist circumference (p=0.026). The G allele of SNP45 and the G/G genotype of SNP276 of the APM gene were associated with impaired glucose tolerance (p=0.020 and p0=.042, respectively). No Gene-gene interaction between ENPP1 and APM genotypes was detected for features of the metabolic syndrome but for HDL-cholesterol. Subjects carrying the ENPP1 121Q allele and the G allele of SNP45 had decreased HDL-cholesterol as compared with others groups (p=0.003). The K121Q ENPP1 polymorphism is not associated with insulin resistance in the Spanish population. However among subjects with MS and type 2 diabetes the 121Q allele was associated with obesity-related markers such as a higher BMI, WC, and hyperleptinemia. [ABSTRACT FROM AUTHOR]

Published
2007

32. Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

Author

Dastani Z, Hivert MF, Timpson N, Perry JR, Yuan X, Scott RA, Henneman P, Heid IM, Kizer JR, Lyytikäinen LP, Fuchsberger C, Tanaka T, Morris AP, Small K, Isaacs A, Beekman M, Coassin S, Lohman K, Qi L, Kanoni S, Pankow JS, Uh HW, Wu Y, Bidulescu A, Rasmussen-Torvik LJ, Greenwood CM, Ladouceur M, Grimsby J, Manning AK, Liu CT, Kooner J, Mooser VE, Vollenweider P, Kapur KA, Chambers J, Wareham NJ, Langenberg C, Frants R, Willems-Vandijk K, Oostra BA, Willems SM, Lamina C, Winkler TW, Psaty BM, Tracy RP, Brody J, Chen I, Viikari J, Kähönen M, Pramstaller PP, Evans DM, St Pourcain B, Sattar N, Wood AR, Bandinelli S, Carlson OD, Egan JM, Böhringer S, van Heemst D, Kedenko L, Kristiansson K, Nuotio ML, Loo BM, Harris T, Garcia M, Kanaya A, Haun M, Klopp N, Wichmann HE, Deloukas P, Katsareli E, Couper DJ, Duncan BB, Kloppenburg M, Adair LS, Borja JB, Wilson JG, Musani S, Guo X, Johnson T, Semple R, Teslovich TM, Allison MA, Redline S, Buxbaum SG, Mohlke KL, Meulenbelt I, Ballantyne CM, Dedoussis GV, Hu FB, Liu Y, Paulweber B, Spector TD, Slagboom PE, Ferrucci L, Jula A, Perola M, Raitakari O, Florez JC, Salomaa V, Eriksson JG, Frayling TM, Hicks AA, Lehtimäki T, Smith GD, Siscovick DS, Kronenberg F, van Duijn C, Loos RJ, Waterworth DM, Meigs JB, Dupuis J, Richards JB, Voight BF, Scott LJ, Steinthorsdottir V, Dina C, Welch RP, Zeggini E, Huth C, Aulchenko YS, Thorleifsson G, McCulloch LJ, Ferreira T, Grallert H, Amin N, Wu G, Willer CJ, Raychaudhuri S, McCarroll SA, Hofmann OM, Segrè AV, van Hoek M, Navarro P, Ardlie K, Balkau B, Benediktsson R, Bennett AJ, Blagieva R, Boerwinkle E, Bonnycastle LL, Boström KB, Bravenboer B, Bumpstead S, Burtt NP, Charpentier G, Chines PS, Cornelis M, Crawford G, Doney AS, Elliott KS, Elliott AL, Erdos MR, Fox CS, Franklin CS, Ganser M, Gieger C, Grarup N, Green T, Griffin S, Groves CJ, Guiducci C, Hadjadj S, Hassanali N, Herder C, Isomaa B, Jackson AU, Johnson PR, Jørgensen T, Kao WH, Kong A, Kraft P, Kuusisto J, Lauritzen T, Li M, Lieverse A, Lindgren CM, Lyssenko V, Marre M, Meitinger T, Midthjell K, Morken MA, Narisu N, Nilsson P, Owen KR, Payne F, Petersen AK, Platou C, Proença C, Prokopenko I, Rathmann W, Rayner NW, Robertson NR, Rocheleau G, Roden M, Sampson MJ, Saxena R, Shields BM, Shrader P, Sigurdsson G, Sparsø T, Strassburger K, Stringham HM, Sun Q, Swift AJ, Thorand B, Tichet J, Tuomi T, van Dam RM, van Haeften TW, van Herpt T, van Vliet-Ostaptchouk JV, Walters GB, Weedon MN, Wijmenga C, Witteman J, Bergman RN, Cauchi S, Collins FS, Gloyn AL, Gyllensten U, Hansen T, Hide WA, Hitman GA, Hofman A, Hunter DJ, Hveem K, Laakso M, Morris AD, Palmer CN, Rudan I, Sijbrands E, Stein LD, Tuomilehto J, Uitterlinden A, Walker M, Watanabe RM, Abecasis GR, Boehm BO, Campbell H, Daly MJ, Hattersley AT, Pedersen O, Barroso I, Groop L, Sladek R, Thorsteinsdottir U, Wilson JF, Illig T, Froguel P, van Duijn CM, Stefansson K, Altshuler D, Boehnke M, McCarthy MI, Soranzo N, Wheeler E, Glazer NL, Bouatia-Naji N, Mägi R, Randall J, Elliott P, Rybin D, Dehghan A, Hottenga JJ, Song K, Goel A, Lajunen T, Doney A, Cavalcanti-Proença C, Kumari M, Timpson NJ, Zabena C, Ingelsson E, An P, O'Connell J, Luan J, Elliott A, McCarroll SA, Roccasecca RM, Pattou F, Sethupathy P, Ariyurek Y, Barter P, Beilby JP, Ben-Shlomo Y, Bergmann S, Bochud M, Bonnefond A, Borch-Johnsen K, Böttcher Y, Brunner E, Bumpstead SJ, Chen YD, Chines P, Clarke R, Coin LJ, Cooper MN, Crisponi L, Day IN, de Geus EJ, Delplanque J, Fedson AC, Fischer-Rosinsky A, Forouhi NG, Franzosi MG, Galan P, Goodarzi MO, Graessler J, Grundy S, Gwilliam R, Hallmans G, Hammond N, Han X, Hartikainen AL, Hayward C, Heath SC, Hercberg S, Hillman DR, Hingorani AD, Hui J, Hung J, Kaakinen M, Kaprio J, Kesaniemi YA, Kivimaki M, Knight B, Koskinen S, Kovacs P, Kyvik KO, Lathrop GM, Lawlor DA, Le Bacquer O, Lecoeur C, Li Y, Mahley R, Mangino M, Martínez-Larrad MT, McAteer JB, McPherson R, Meisinger C, Melzer D, Meyre D, Mitchell BD, Mukherjee S, Naitza S, Neville MJ, Orrù M, Pakyz R, Paolisso G, Pattaro C, Pearson D, Peden JF, Pedersen NL, Pfeiffer AF, Pichler I, Polasek O, Posthuma D, Potter SC, Pouta A, Province MA, Rayner NW, Rice K, Ripatti S, Rivadeneira F, Rolandsson O, Sandbaek A, Sandhu M, Sanna S, Sayer AA, Scheet P, Seedorf U, Sharp SJ, Shields B, Sigurðsson G, Sijbrands EJ, Silveira A, Simpson L, Singleton A, Smith NL, Sovio U, Swift A, Syddall H, Syvänen AC, Tönjes A, Uitterlinden AG, van Dijk KW, Varma D, Visvikis-Siest S, Vitart V, Vogelzangs N, Waeber G, Wagner PJ, Walley A, Ward KL, Watkins H, Wild SH, Willemsen G, Witteman JC, Yarnell JW, Zelenika D, Zethelius B, Zhai G, Zhao JH, Zillikens MC, Borecki IB, Meneton P, Magnusson PK, Nathan DM, Williams GH, Silander K, Bornstein SR, Schwarz P, Spranger J, Karpe F, Shuldiner AR, Cooper C, Serrano-Ríos M, Lind L, Palmer LJ, Hu FB 1st, Franks PW, Ebrahim S, Marmot M, Kao WH, Pramstaller PP, Wright AF, Stumvoll M, Hamsten A, Buchanan TA, Valle TT, Rotter JI, Penninx BW, Boomsma DI, Cao A, Scuteri A, Schlessinger D, Uda M, Ruokonen A, Jarvelin MR, Peltonen L, Mooser V, Sladek R, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M, Pirruccello JP, Chasman DI, Johansen CT, Fouchier SW, Peloso GM, Barbalic M, Ricketts SL, Bis JC, Feitosa MF, Orho-Melander M, Melander O, Li X, Li M, Cho YS, Go MJ, Kim YJ, Lee JY, Park T, Kim K, Sim X, Ong RT, Croteau-Chonka DC, Lange LA, Smith JD, Ziegler A, Zhang W, Zee RY, Whitfield JB, Thompson JR, Surakka I, Spector TD, Smit JH, Sinisalo J, Scott J, Saharinen J, Sabatti C, Rose LM, Roberts R, Rieder M, Parker AN, Pare G, O'Donnell CJ, Nieminen MS, Nickerson DA, Montgomery GW, McArdle W, Masson D, Martin NG, Marroni F, Lucas G, Luben R, Lokki ML, Lettre G, Launer LJ, Lakatta EG, Laaksonen R, Kyvik KO, König IR, Khaw KT, Kaplan LM, Johansson Å, Janssens AC, Igl W, Hovingh GK, Hengstenberg C, Havulinna AS, Hastie ND, Harris TB, Haritunians T, Hall AS, Groop LC, Gonzalez E, Freimer NB, Erdmann J, Ejebe KG, Döring A, Dominiczak AF, Demissie S, Deloukas P, de Faire U, Crawford G, Chen YD, Caulfield MJ, Boekholdt SM, Assimes TL, Quertermous T, Seielstad M, Wong TY, Tai ES, Feranil AB, Kuzawa CW, Taylor HA Jr, Gabriel SB, Holm H, Gudnason V, Krauss RM, Ordovas JM, Munroe PB, Kooner JS, Tall AR, Hegele RA, Kastelein JJ, Schadt EE, Strachan DP, Reilly MP, Samani NJ, Schunkert H, Cupples LA, Sandhu MS, Ridker PM, Rader DJ, and Kathiresan S

Subjects
Adiponectin genetics, Black or African American, Asian People, Cholesterol, HDL genetics, Female, Gene Expression, Genetic Predisposition to Disease, Glucose Tolerance Test, Humans, Insulin Resistance genetics, Male, Metabolic Networks and Pathways, Polymorphism, Single Nucleotide, Waist-Hip Ratio, White People, Adiponectin blood, Diabetes Mellitus, Type 2 genetics, Genome-Wide Association Study
Abstract

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance., Competing Interests: DM Waterworth, X Yuan, and VE Mooser are full-time employees of GlaxoSmithKline. P Vollenweider received grant money from GlaxoSmithKline to fund the CoLaus study. The other authors declare no competing financial interests.

Published
2012
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33. Common variants at 10 genomic loci influence hemoglobin A₁(C) levels via glycemic and nonglycemic pathways.

Author

Soranzo N, Sanna S, Wheeler E, Gieger C, Radke D, Dupuis J, Bouatia-Naji N, Langenberg C, Prokopenko I, Stolerman E, Sandhu MS, Heeney MM, Devaney JM, Reilly MP, Ricketts SL, Stewart AF, Voight BF, Willenborg C, Wright B, Altshuler D, Arking D, Balkau B, Barnes D, Boerwinkle E, Böhm B, Bonnefond A, Bonnycastle LL, Boomsma DI, Bornstein SR, Böttcher Y, Bumpstead S, Burnett-Miller MS, Campbell H, Cao A, Chambers J, Clark R, Collins FS, Coresh J, de Geus EJ, Dei M, Deloukas P, Döring A, Egan JM, Elosua R, Ferrucci L, Forouhi N, Fox CS, Franklin C, Franzosi MG, Gallina S, Goel A, Graessler J, Grallert H, Greinacher A, Hadley D, Hall A, Hamsten A, Hayward C, Heath S, Herder C, Homuth G, Hottenga JJ, Hunter-Merrill R, Illig T, Jackson AU, Jula A, Kleber M, Knouff CW, Kong A, Kooner J, Köttgen A, Kovacs P, Krohn K, Kühnel B, Kuusisto J, Laakso M, Lathrop M, Lecoeur C, Li M, Li M, Loos RJ, Luan J, Lyssenko V, Mägi R, Magnusson PK, Mälarstig A, Mangino M, Martínez-Larrad MT, März W, McArdle WL, McPherson R, Meisinger C, Meitinger T, Melander O, Mohlke KL, Mooser VE, Morken MA, Narisu N, Nathan DM, Nauck M, O'Donnell C, Oexle K, Olla N, Pankow JS, Payne F, Peden JF, Pedersen NL, Peltonen L, Perola M, Polasek O, Porcu E, Rader DJ, Rathmann W, Ripatti S, Rocheleau G, Roden M, Rudan I, Salomaa V, Saxena R, Schlessinger D, Schunkert H, Schwarz P, Seedorf U, Selvin E, Serrano-Ríos M, Shrader P, Silveira A, Siscovick D, Song K, Spector TD, Stefansson K, Steinthorsdottir V, Strachan DP, Strawbridge R, Stumvoll M, Surakka I, Swift AJ, Tanaka T, Teumer A, Thorleifsson G, Thorsteinsdottir U, Tönjes A, Usala G, Vitart V, Völzke H, Wallaschofski H, Waterworth DM, Watkins H, Wichmann HE, Wild SH, Willemsen G, Williams GH, Wilson JF, Winkelmann J, Wright AF, Zabena C, Zhao JH, Epstein SE, Erdmann J, Hakonarson HH, Kathiresan S, Khaw KT, Roberts R, Samani NJ, Fleming MD, Sladek R, Abecasis G, Boehnke M, Froguel P, Groop L, McCarthy MI, Kao WH, Florez JC, Uda M, Wareham NJ, Barroso I, and Meigs JB

Subjects
Adult, Blood Glucose metabolism, Body Mass Index, Chromosome Mapping, Cohort Studies, Female, Genome-Wide Association Study, Humans, Male, Meta-Analysis as Topic, Middle Aged, Polymorphism, Single Nucleotide, White People genetics, Genetic Variation, Glycated Hemoglobin genetics
Abstract

Objective: Glycated hemoglobin (HbA₁(c)), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA₁(c). We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA₁(c) levels., Research Design and Methods: We studied associations with HbA₁(c) in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA₁(c) loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening., Results: Ten loci reached genome-wide significant association with HbA(1c), including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 × 10⁻²⁶), HFE (rs1800562/P = 2.6 × 10⁻²⁰), TMPRSS6 (rs855791/P = 2.7 × 10⁻¹⁴), ANK1 (rs4737009/P = 6.1 × 10⁻¹²), SPTA1 (rs2779116/P = 2.8 × 10⁻⁹) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 × 10⁻⁹), and four known HbA₁(c) loci: HK1 (rs16926246/P = 3.1 × 10⁻⁵⁴), MTNR1B (rs1387153/P = 4.0 × 10⁻¹¹), GCK (rs1799884/P = 1.5 × 10⁻²⁰) and G6PC2/ABCB11 (rs552976/P = 8.2 × 10⁻¹⁸). We show that associations with HbA₁(c) are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B). The seven nonglycemic loci accounted for a 0.19 (% HbA₁(c)) difference between the extreme 10% tails of the risk score, and would reclassify ∼2% of a general white population screened for diabetes with HbA₁(c)., Conclusions: GWAS identified 10 genetic loci reproducibly associated with HbA₁(c). Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron storage disorders. Common variants at these loci likely influence HbA₁(c) levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA₁(c).

Published
2010
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34. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Author

Dupuis J, Langenberg C, Prokopenko I, Saxena R, Soranzo N, Jackson AU, Wheeler E, Glazer NL, Bouatia-Naji N, Gloyn AL, Lindgren CM, Mägi R, Morris AP, Randall J, Johnson T, Elliott P, Rybin D, Thorleifsson G, Steinthorsdottir V, Henneman P, Grallert H, Dehghan A, Hottenga JJ, Franklin CS, Navarro P, Song K, Goel A, Perry JR, Egan JM, Lajunen T, Grarup N, Sparsø T, Doney A, Voight BF, Stringham HM, Li M, Kanoni S, Shrader P, Cavalcanti-Proença C, Kumari M, Qi L, Timpson NJ, Gieger C, Zabena C, Rocheleau G, Ingelsson E, An P, O'Connell J, Luan J, Elliott A, McCarroll SA, Payne F, Roccasecca RM, Pattou F, Sethupathy P, Ardlie K, Ariyurek Y, Balkau B, Barter P, Beilby JP, Ben-Shlomo Y, Benediktsson R, Bennett AJ, Bergmann S, Bochud M, Boerwinkle E, Bonnefond A, Bonnycastle LL, Borch-Johnsen K, Böttcher Y, Brunner E, Bumpstead SJ, Charpentier G, Chen YD, Chines P, Clarke R, Coin LJ, Cooper MN, Cornelis M, Crawford G, Crisponi L, Day IN, de Geus EJ, Delplanque J, Dina C, Erdos MR, Fedson AC, Fischer-Rosinsky A, Forouhi NG, Fox CS, Frants R, Franzosi MG, Galan P, Goodarzi MO, Graessler J, Groves CJ, Grundy S, Gwilliam R, Gyllensten U, Hadjadj S, Hallmans G, Hammond N, Han X, Hartikainen AL, Hassanali N, Hayward C, Heath SC, Hercberg S, Herder C, Hicks AA, Hillman DR, Hingorani AD, Hofman A, Hui J, Hung J, Isomaa B, Johnson PR, Jørgensen T, Jula A, Kaakinen M, Kaprio J, Kesaniemi YA, Kivimaki M, Knight B, Koskinen S, Kovacs P, Kyvik KO, Lathrop GM, Lawlor DA, Le Bacquer O, Lecoeur C, Li Y, Lyssenko V, Mahley R, Mangino M, Manning AK, Martínez-Larrad MT, McAteer JB, McCulloch LJ, McPherson R, Meisinger C, Melzer D, Meyre D, Mitchell BD, Morken MA, Mukherjee S, Naitza S, Narisu N, Neville MJ, Oostra BA, Orrù M, Pakyz R, Palmer CN, Paolisso G, Pattaro C, Pearson D, Peden JF, Pedersen NL, Perola M, Pfeiffer AF, Pichler I, Polasek O, Posthuma D, Potter SC, Pouta A, Province MA, Psaty BM, Rathmann W, Rayner NW, Rice K, Ripatti S, Rivadeneira F, Roden M, Rolandsson O, Sandbaek A, Sandhu M, Sanna S, Sayer AA, Scheet P, Scott LJ, Seedorf U, Sharp SJ, Shields B, Sigurethsson G, Sijbrands EJ, Silveira A, Simpson L, Singleton A, Smith NL, Sovio U, Swift A, Syddall H, Syvänen AC, Tanaka T, Thorand B, Tichet J, Tönjes A, Tuomi T, Uitterlinden AG, van Dijk KW, van Hoek M, Varma D, Visvikis-Siest S, Vitart V, Vogelzangs N, Waeber G, Wagner PJ, Walley A, Walters GB, Ward KL, Watkins H, Weedon MN, Wild SH, Willemsen G, Witteman JC, Yarnell JW, Zeggini E, Zelenika D, Zethelius B, Zhai G, Zhao JH, Zillikens MC, Borecki IB, Loos RJ, Meneton P, Magnusson PK, Nathan DM, Williams GH, Hattersley AT, Silander K, Salomaa V, Smith GD, Bornstein SR, Schwarz P, Spranger J, Karpe F, Shuldiner AR, Cooper C, Dedoussis GV, Serrano-Ríos M, Morris AD, Lind L, Palmer LJ, Hu FB, Franks PW, Ebrahim S, Marmot M, Kao WH, Pankow JS, Sampson MJ, Kuusisto J, Laakso M, Hansen T, Pedersen O, Pramstaller PP, Wichmann HE, Illig T, Rudan I, Wright AF, Stumvoll M, Campbell H, Wilson JF, Bergman RN, Buchanan TA, Collins FS, Mohlke KL, Tuomilehto J, Valle TT, Altshuler D, Rotter JI, Siscovick DS, Penninx BW, Boomsma DI, Deloukas P, Spector TD, Frayling TM, Ferrucci L, Kong A, Thorsteinsdottir U, Stefansson K, van Duijn CM, Aulchenko YS, Cao A, Scuteri A, Schlessinger D, Uda M, Ruokonen A, Jarvelin MR, Waterworth DM, Vollenweider P, Peltonen L, Mooser V, Abecasis GR, Wareham NJ, Sladek R, Froguel P, Watanabe RM, Meigs JB, Groop L, Boehnke M, McCarthy MI, Florez JC, and Barroso I

Subjects
Adolescent, Adult, Alleles, Child, DNA Copy Number Variations genetics, Databases, Genetic, Delta-5 Fatty Acid Desaturase, Gene Expression Regulation, Genome-Wide Association Study, Humans, Meta-Analysis as Topic, Polymorphism, Single Nucleotide genetics, Quantitative Trait Loci genetics, Quantitative Trait, Heritable, Reproducibility of Results, Blood Glucose genetics, Blood Glucose metabolism, Diabetes Mellitus, Type 2 genetics, Fasting blood, Genetic Loci genetics, Genetic Predisposition to Disease, Homeostasis genetics
Abstract

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. 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 type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

Published
2010
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35. Interaction of the -308G/A promoter polymorphism of the tumor necrosis factor-alpha gene with single-nucleotide polymorphism 45 of the adiponectin gene: effect on serum adiponectin concentrations in a Spanish population.

Author

González-Sánchez JL, Martínez-Calatrava MJ, Martínez-Larrad MT, Zabena C, Fernández-Pérez C, Laakso M, and Serrano-Ríos M

Subjects
Abdomen anatomy & histology, Adiponectin blood, Adult, Aged, Anthropometry, Body Mass Index, Diabetes Mellitus, Type 2 blood, Female, Genotype, Glucose Tolerance Test, Heterozygote, Humans, Insulin blood, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Receptors, Tumor Necrosis Factor, Type II blood, Serum, Solubility, Spain, Waist-Hip Ratio, Adiponectin genetics, Polymorphism, Genetic, Promoter Regions, Genetic, Tumor Necrosis Factor-alpha genetics
Abstract

Background: We investigated whether interactions of the -308G/A polymorphism in the promoter region of the tumor necrosis factor-alpha (TNF-alpha) gene with single-nucleotide polymorphisms (SNPs) 45 and 276 of the adiponectin gene are associated with circulating adiponectin and soluble TNF-alpha receptor 2 (sTNFR2) concentrations in a Spanish population., Methods: We performed anthropometric and physiologic measurements in 809 unrelated participants recruited with a simple random sampling approach from respondents to a cross-sectional population-based epidemiologic survey in the province of Segovia in central Spain (Castille)., Results: The 2-h postload glucose and serum insulin concentrations were higher in -308A allele carriers than in -308G/G individuals homozygous for the TNF-alpha gene. Plasma concentrations of sTNFR2 were positively correlated with body mass index, waist-to-hip ratio, and sagittal abdominal diameter among individuals with type 2 diabetes. Individuals with type 2 diabetes and the -308A allele had higher sTNFR2 and lower adiponectin concentrations than -308G homozygotes. Moreover, individuals carrying both the TNF-alpha -308A allele and the G allele of SNP 45 in the adiponectin gene had the highest prevalence of impaired glucose tolerance (adjusted odds ratio, 1.26; 95% confidence interval, 1.01-1.56; P = 0.038) and had lower adiponectin concentrations (beta = -0.090; P = 0.005) than individuals without these genotypes., Conclusions: Our findings are the first to indicate that a higher incidence of impaired glucose tolerance and low circulating adiponectin concentration may be associated with interaction between the -308G/A promoter polymorphism of the TNF-alpha gene and SNP 45 in the adiponectin gene.

Published
2006
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