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245 results on '"Lecoeur, Cécile"'

1. Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation

Author

Mahajan, Anubha, Spracklen, Cassandra N, Zhang, Weihua, Ng, Maggie CY, Petty, Lauren E, Kitajima, Hidetoshi, Yu, Grace Z, Rüeger, Sina, Speidel, Leo, Kim, Young Jin, Horikoshi, Momoko, Mercader, Josep M, Taliun, Daniel, Moon, Sanghoon, Kwak, Soo-Heon, Robertson, Neil R, Rayner, Nigel W, Loh, Marie, Kim, Bong-Jo, Chiou, Joshua, Miguel-Escalada, Irene, della Briotta Parolo, Pietro, Lin, Kuang, Bragg, Fiona, Preuss, Michael H, Takeuchi, Fumihiko, Nano, Jana, Guo, Xiuqing, Lamri, Amel, Nakatochi, Masahiro, Scott, Robert A, Lee, Jung-Jin, Huerta-Chagoya, Alicia, Graff, Mariaelisa, Chai, Jin-Fang, Parra, Esteban J, Yao, Jie, Bielak, Lawrence F, Tabara, Yasuharu, Hai, Yang, Steinthorsdottir, Valgerdur, Cook, James P, Kals, Mart, Grarup, Niels, Schmidt, Ellen M, Pan, Ian, Sofer, Tamar, Wuttke, Matthias, Sarnowski, Chloe, Gieger, Christian, Nousome, Darryl, Trompet, Stella, Long, Jirong, Sun, Meng, Tong, Lin, Chen, Wei-Min, Ahmad, Meraj, Noordam, Raymond, Lim, Victor JY, Tam, Claudia HT, Joo, Yoonjung Yoonie, Chen, Chien-Hsiun, Raffield, Laura M, Lecoeur, Cécile, Prins, Bram Peter, Nicolas, Aude, Yanek, Lisa R, Chen, Guanjie, Jensen, Richard A, Tajuddin, Salman, Kabagambe, Edmond K, An, Ping, Xiang, Anny H, Choi, Hyeok Sun, Cade, Brian E, Tan, Jingyi, Flanagan, Jack, Abaitua, Fernando, Adair, Linda S, Adeyemo, Adebowale, Aguilar-Salinas, Carlos A, Akiyama, Masato, Anand, Sonia S, Bertoni, Alain, Bian, Zheng, Bork-Jensen, Jette, Brandslund, Ivan, Brody, Jennifer A, Brummett, Chad M, Buchanan, Thomas A, Canouil, Mickaël, Chan, Juliana CN, Chang, Li-Ching, Chee, Miao-Li, Chen, Ji, Chen, Shyh-Huei, Chen, Yuan-Tsong, Chen, Zhengming, Chuang, Lee-Ming, and Cushman, Mary

Subjects
Genetics, Diabetes, Human Genome, Metabolic and endocrine, Diabetes Mellitus, Type 2, Ethnicity, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Risk Factors, FinnGen, eMERGE Consortium, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P 50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.

Published
2022

4. Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.

Author

Mahajan, Anubha, Wessel, Jennifer, Willems, Sara M, Zhao, Wei, Robertson, Neil R, Chu, Audrey Y, Gan, Wei, Kitajima, Hidetoshi, Taliun, Daniel, Rayner, N William, Guo, Xiuqing, Lu, Yingchang, Li, Man, Jensen, Richard A, Hu, Yao, Huo, Shaofeng, Lohman, Kurt K, Zhang, Weihua, Cook, James P, Prins, Bram Peter, Flannick, Jason, Grarup, Niels, Trubetskoy, Vassily Vladimirovich, Kravic, Jasmina, Kim, Young Jin, Rybin, Denis V, Yaghootkar, Hanieh, Müller-Nurasyid, Martina, Meidtner, Karina, Li-Gao, Ruifang, Varga, Tibor V, Marten, Jonathan, Li, Jin, Smith, Albert Vernon, An, Ping, Ligthart, Symen, Gustafsson, Stefan, Malerba, Giovanni, Demirkan, Ayse, Tajes, Juan Fernandez, Steinthorsdottir, Valgerdur, Wuttke, Matthias, Lecoeur, Cécile, Preuss, Michael, Bielak, Lawrence F, Graff, Marielisa, Highland, Heather M, Justice, Anne E, Liu, Dajiang J, Marouli, Eirini, Peloso, Gina Marie, Warren, Helen R, ExomeBP Consortium, MAGIC Consortium, GIANT Consortium, Afaq, Saima, Afzal, Shoaib, Ahlqvist, Emma, Almgren, Peter, Amin, Najaf, Bang, Lia B, Bertoni, Alain G, Bombieri, Cristina, Bork-Jensen, Jette, Brandslund, Ivan, Brody, Jennifer A, Burtt, Noël P, Canouil, Mickaël, Chen, Yii-Der Ida, Cho, Yoon Shin, Christensen, Cramer, Eastwood, Sophie V, Eckardt, Kai-Uwe, Fischer, Krista, Gambaro, Giovanni, Giedraitis, Vilmantas, Grove, Megan L, de Haan, Hugoline G, Hackinger, Sophie, Hai, Yang, Han, Sohee, Tybjærg-Hansen, Anne, Hivert, Marie-France, Isomaa, Bo, Jäger, Susanne, Jørgensen, Marit E, Jørgensen, Torben, Käräjämäki, Annemari, Kim, Bong-Jo, Kim, Sung Soo, Koistinen, Heikki A, Kovacs, Peter, Kriebel, Jennifer, Kronenberg, Florian, Läll, Kristi, Lange, Leslie A, Lee, Jung-Jin, Lehne, Benjamin, Li, Huaixing, and Lin, Keng-Hung

Subjects
ExomeBP Consortium, MAGIC Consortium, GIANT Consortium, Humans, Diabetes Mellitus, Type 2, Genetic Predisposition to Disease, Chromosome Mapping, Alleles, European Continental Ancestry Group, Female, Male, Genetic Variation, Genome-Wide Association Study, Whole Exome Sequencing, Diabetes Mellitus, Type 2, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P

Published
2018

5. Mendelian randomization analysis does not support causal associations of birth weight with hypertension risk and blood pressure in adulthood

Author

Zheng, Yan, Huang, Tao, Wang, Tiange, Mei, Zhendong, Sun, Zhonghan, Zhang, Tao, Ellervik, Christina, Chai, Jin-Fang, Sim, Xueling, van Dam, Rob M., Tai, E-Shyong, Koh, Woon-Puay, Dorajoo, Rajkumar, Saw, Seang-Mei, Sabanayagam, Charumathi, Wong, Tien Yin, Gupta, Preeti, Rossing, Peter, Ahluwalia, Tarunveer S., Vinding, Rebecca K., Bisgaard, Hans, Bønnelykke, Klaus, Wang, Yujie, Graff, Mariaelisa, Voortman, Trudy, van Rooij, Frank J. A., Hofman, Albert, van Heemst, Diana, Noordam, Raymond, Estampador, Angela C., Varga, Tibor V., Enzenbach, Cornelia, Scholz, Markus, Thiery, Joachim, Burkhardt, Ralph, Orho-Melander, Marju, Schulz, Christina-Alexandra, Ericson, Ulrika, Sonestedt, Emily, Kubo, Michiaki, Akiyama, Masato, Zhou, Ang, Kilpeläinen, Tuomas O., Hansen, Torben, Kleber, Marcus E., Delgado, Graciela, McCarthy, Mark, Lemaitre, Rozenn N., Felix, Janine F., Jaddoe, Vincent W. V., Wu, Ying, Mohlke, Karen L., Lehtimäki, Terho, Wang, Carol A., Pennell, Craig E., Schunkert, Heribert, Kessler, Thorsten, Zeng, Lingyao, Willenborg, Christina, Peters, Annette, Lieb, Wolfgang, Grote, Veit, Rzehak, Peter, Koletzko, Berthold, Erdmann, Jeanette, Munz, Matthias, Wu, Tangchun, He, Meian, Yu, Caizheng, Lecoeur, Cécile, Froguel, Philippe, Corella, Dolores, Moreno, Luis A., Lai, Chao-Qiang, Pitkänen, Niina, Boreham, Colin A., Ridker, Paul M., Rosendaal, Frits R., de Mutsert, Renée, Power, Chris, Paternoster, Lavinia, Sørensen, Thorkild I. A., Tjønneland, Anne, Overvad, Kim, Djousse, Luc, Rivadeneira, Fernando, Lee, Nanette R., Raitakari, Olli T., Kähönen, Mika, Viikari, Jorma, Langhendries, Jean-Paul, Escribano, Joaquin, Verduci, Elvira, Dedoussis, George, König, Inke, Balkau, Beverley, Coltell, Oscar, Dallongeville, Jean, Meirhaeghe, Aline, Amouyel, Philippe, Gottrand, Frédéric, Pahkala, Katja, Niinikoski, Harri, Hyppönen, Elina, März, Winfried, Mackey, David A., Gruszfeld, Dariusz, Tucker, Katherine L., Fumeron, Frédéric, Estruch, Ramon, Ordovas, Jose M., Arnett, Donna K., Mook-Kanamori, Dennis O., Mozaffarian, Dariush, Psaty, Bruce M., North, Kari E., Chasman, Daniel I., and Qi, Lu

Published
2020

7. Role of astrocyte senescence regulated by the non– canonical autophagy in the neuroinflammation associated to cerebral malaria

Author

Hellani, Fatima, primary, Leleu, Inès, additional, Saidi, Nasreddine, additional, Martin, Nathalie, additional, Lecoeur, Cécile, additional, Werkmeister, Elisabeth, additional, Koffi, David, additional, Trottein, François, additional, Yapo-Etté, Hélène, additional, Das, Bidyut, additional, Abbadie, Corinne, additional, and Pied, Sylviane, additional

Published
2023
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8. The expression of genes in top obesity-associated loci is enriched in insula and substantia nigra brain regions involved in addiction and reward

Author

Ndiaye, Fatou K., Huyvaert, Marlène, Ortalli, Ana, Canouil, Mickaël, Lecoeur, Cécile, Verbanck, Marie, Lobbens, Stéphane, Khamis, Amna, Marselli, Lorella, Marchetti, Piero, Kerr-Conte, Julie, Pattou, François, Marre, Michel, Roussel, Ronan, Balkau, Beverley, Froguel, Philippe, and Bonnefond, Amélie

Published
2020
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9. Impact of Type 2 Diabetes Susceptibility Variants on Quantitative Glycemic Traits Reveals Mechanistic Heterogeneity

Author

Dimas, Antigone S, Lagou, Vasiliki, Barker, Adam, Knowles, Joshua W, Mägi, Reedik, Hivert, Marie-France, Benazzo, Andrea, Rybin, Denis, Jackson, Anne U, Stringham, Heather M, Song, Ci, Fischer-Rosinsky, Antje, Boesgaard, Trine Welløv, Grarup, Niels, Abbasi, Fahim A, Assimes, Themistocles L, Hao, Ke, Yang, Xia, Lecoeur, Cécile, Barroso, Inês, Bonnycastle, Lori L, Böttcher, Yvonne, Bumpstead, Suzannah, Chines, Peter S, Erdos, Michael R, Graessler, Jurgen, Kovacs, Peter, Morken, Mario A, Narisu, Narisu, Payne, Felicity, Stancakova, Alena, Swift, Amy J, Tönjes, Anke, Bornstein, Stefan R, Cauchi, Stéphane, Froguel, Philippe, Meyre, David, Schwarz, Peter EH, Häring, Hans-Ulrich, Smith, Ulf, Boehnke, Michael, Bergman, Richard N, Collins, Francis S, Mohlke, Karen L, Tuomilehto, Jaakko, Quertemous, Thomas, Lind, Lars, Hansen, Torben, Pedersen, Oluf, Walker, Mark, Pfeiffer, Andreas FH, Spranger, Joachim, Stumvoll, Michael, Meigs, James B, Wareham, Nicholas J, Kuusisto, Johanna, Laakso, Markku, Langenberg, Claudia, Dupuis, Josée, Watanabe, Richard M, Florez, Jose C, Ingelsson, Erik, McCarthy, Mark I, Prokopenko, Inga, and Investigators, on behalf of the MAGIC

Subjects
Biomedical and Clinical Sciences, Genetics, Diabetes, Autoimmune Disease, Clinical Research, Prevention, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Alleles, Cluster Analysis, Diabetes Mellitus, Type 2, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Insulin, Insulin Resistance, Insulin Secretion, Insulin-Secreting Cells, Male, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, Transcription Factors, MAGIC Investigators, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences
Abstract

Patients with established type 2 diabetes display both β-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci, and indices of proinsulin processing, insulin secretion, and insulin sensitivity. We included data from up to 58,614 nondiabetic subjects with basal measures and 17,327 with dynamic measures. We used additive genetic models with adjustment for sex, age, and BMI, followed by fixed-effects, inverse-variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second cluster (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without a detectable change in fasting glucose levels. The final group contained 20 risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.

Published
2014

10. No Interactions Between Previously Associated 2-Hour Glucose Gene Variants and Physical Activity or BMI on 2-Hour Glucose Levels

Author

Scott, Robert A, Chu, Audrey Y, Grarup, Niels, Manning, Alisa K, Hivert, Marie-France, Shungin, Dmitry, Tönjes, Anke, Yesupriya, Ajay, Barnes, Daniel, Bouatia-Naji, Nabila, Glazer, Nicole L, Jackson, Anne U, Kutalik, Zoltán, Lagou, Vasiliki, Marek, Diana, Rasmussen-Torvik, Laura J, Stringham, Heather M, Tanaka, Toshiko, Aadahl, Mette, Arking, Dan E, Bergmann, Sven, Boerwinkle, Eric, Bonnycastle, Lori L, Bornstein, Stefan R, Brunner, Eric, Bumpstead, Suzannah J, Brage, Soren, Carlson, Olga D, Chen, Han, Chen, Yii-Der Ida, Chines, Peter S, Collins, Francis S, Couper, David J, Dennison, Elaine M, Dowling, Nicole F, Egan, Josephine S, Ekelund, Ulf, Erdos, Michael R, Forouhi, Nita G, Fox, Caroline S, Goodarzi, Mark O, Grässler, Jürgen, Gustafsson, Stefan, Hallmans, Göran, Hansen, Torben, Hingorani, Aroon, Holloway, John W, Hu, Frank B, Isomaa, Bo, Jameson, Karen A, Johansson, Ingegerd, Jonsson, Anna, Jørgensen, Torben, Kivimaki, Mika, Kovacs, Peter, Kumari, Meena, Kuusisto, Johanna, Laakso, Markku, Lecoeur, Cécile, Lévy-Marchal, Claire, Li, Guo, Loos, Ruth JF, Lyssenko, Valeri, Marmot, Michael, Marques-Vidal, Pedro, Morken, Mario A, Müller, Gabriele, North, Kari E, Pankow, James S, Payne, Felicity, Prokopenko, Inga, Psaty, Bruce M, Renström, Frida, Rice, Ken, Rotter, Jerome I, Rybin, Denis, Sandholt, Camilla H, Sayer, Avan A, Shrader, Peter, Schwarz, Peter EH, Siscovick, David S, Stančáková, Alena, Stumvoll, Michael, Teslovich, Tanya M, Waeber, Gérard, Williams, Gordon H, Witte, Daniel R, Wood, Andrew R, Xie, Weijia, Boehnke, Michael, Cooper, Cyrus, Ferrucci, Luigi, Froguel, Philippe, Groop, Leif, Kao, WH Linda, Vollenweider, Peter, Walker, Mark, Watanabe, Richard M, Pedersen, Oluf, and Meigs, James B

Subjects
Biomedical and Clinical Sciences, Clinical Research, Genetics, Diabetes, Prevention, Obesity, Nutrition, 2.1 Biological and endogenous factors, Aetiology, 2.3 Psychological, social and economic factors, Metabolic and endocrine, Blood Glucose, Body Mass Index, Epigenesis, Genetic, Gene Expression Regulation, Genotype, Humans, Life Style, Motor Activity, Polymorphism, Single Nucleotide, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences
Abstract

Gene-lifestyle interactions have been suggested to contribute to the development of type 2 diabetes. Glucose levels 2 h after a standard 75-g glucose challenge are used to diagnose diabetes and are associated with both genetic and lifestyle factors. However, whether these factors interact to determine 2-h glucose levels is unknown. We meta-analyzed single nucleotide polymorphism (SNP) × BMI and SNP × physical activity (PA) interaction regression models for five SNPs previously associated with 2-h glucose levels from up to 22 studies comprising 54,884 individuals without diabetes. PA levels were dichotomized, with individuals below the first quintile classified as inactive (20%) and the remainder as active (80%). BMI was considered a continuous trait. Inactive individuals had higher 2-h glucose levels than active individuals (β = 0.22 mmol/L [95% CI 0.13-0.31], P = 1.63 × 10(-6)). All SNPs were associated with 2-h glucose (β = 0.06-0.12 mmol/allele, P ≤ 1.53 × 10(-7)), but no significant interactions were found with PA (P > 0.18) or BMI (P ≥ 0.04). In this large study of gene-lifestyle interaction, we observed no interactions between genetic and lifestyle factors, both of which were associated with 2-h glucose. It is perhaps unlikely that top loci from genome-wide association studies will exhibit strong subgroup-specific effects, and may not, therefore, make the best candidates for the study of interactions.

Published
2012

11. Expression and functional assessment of candidate type 2 diabetes susceptibility genes identify four new genes contributing to human insulin secretion

Author

Ndiaye, Fatou K., Ortalli, Ana, Canouil, Mickaël, Huyvaert, Marlène, Salazar-Cardozo, Clara, Lecoeur, Cécile, Verbanck, Marie, Pawlowski, Valérie, Boutry, Raphaël, Durand, Emmanuelle, Rabearivelo, Iandry, Sand, Olivier, Marselli, Lorella, Kerr-Conte, Julie, Chandra, Vikash, Scharfmann, Raphaël, Poulain-Godefroy, Odile, Marchetti, Piero, Pattou, François, Abderrahmani, Amar, Froguel, Philippe, and Bonnefond, Amélie

Published
2017
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12. Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps

Author

Mahajan, Anubha, Taliun, Daniel, Thurner, Matthias, Robertson, Neil R., Torres, Jason M., Rayner, N. William, Payne, Anthony J., Steinthorsdottir, Valgerdur, Scott, Robert A., Grarup, Niels, Cook, James P., Schmidt, Ellen M., Wuttke, Matthias, Sarnowski, Chloé, Mägi, Reedik, Nano, Jana, Gieger, Christian, Trompet, Stella, Lecoeur, Cécile, Preuss, Michael H., Prins, Bram Peter, Guo, Xiuqing, Bielak, Lawrence F., Below, Jennifer E., Bowden, Donald W., Chambers, John Campbell, Kim, Young Jin, Ng, Maggie C. Y., Petty, Lauren E., Sim, Xueling, Zhang, Weihua, Bennett, Amanda J., Bork-Jensen, Jette, Brummett, Chad M., Canouil, Mickaël, Ec kardt, Kai-Uwe, Fischer, Krista, Kardia, Sharon L. R., Kronenberg, Florian, Läll, Kristi, Liu, Ching-Ti, Locke, Adam E., Luan, Jian’an, Ntalla, Ioanna, Nylander, Vibe, Schönherr, Sebastian, Schurmann, Claudia, Yengo, Loïc, Bottinger, Erwin P., Brandslund, Ivan, Christensen, Cramer, Dedoussis, George, Florez, Jose C., Ford, Ian, Franco, Oscar H., Frayling, Timothy M., Giedraitis, Vilmantas, Hackinger, Sophie, Hattersley, Andrew T., Herder, Christian, Ikram, M. Arfan, Ingelsson, Martin, Jørgensen, Marit E., Jørgensen, Torben, Kriebel, Jennifer, Kuusisto, Johanna, Ligthart, Symen, Lindgren, Cecilia M., Linneberg, Allan, Lyssenko, Valeriya, Mamakou, Vasiliki, Meitinger, Thomas, Mohlke, Karen L., Morris, Andrew D., Nadkarni, Girish, Pankow, James S., Peters, Annette, Sattar, Naveed, Stančáková, Alena, Strauch, Konstantin, Taylor, Kent D., Thorand, Barbara, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tuomilehto, Jaakko, Witte, Daniel R., Dupuis, Josée, Peyser, Patricia A., Zeggini, Eleftheria, Loos, Ruth J. F., Froguel, Philippe, Ingelsson, Erik, Lind, Lars, Groop, Leif, Laakso, Markku, Collins, Francis S., Jukema, J. Wouter, Palmer, Colin N. A., Grallert, Harald, Metspalu, Andres, Dehghan, Abbas, Köttgen, Anna, Abecasis, Goncalo R., Meigs, James B., Rotter, Jerome I., Marchini, Jonathan, Pedersen, Oluf, Hansen, Torben, Langenberg, Claudia, Wareham, Nicholas J., Stefansson, Kari, Gloyn, Anna L., Morris, Andrew P., Boehnke, Michael, and McCarthy, Mark I.

Published
2018
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13. An Arginine-Rich Motif in the ORF2 capsid protein regulates the hepatitis E virus lifecycle and interactions with the host cell

Author

Hervouet, Kévin, primary, Ferrié, Martin, additional, Ankavay, Maliki, additional, Montpellier, Claire, additional, Camuzet, Charline, additional, Alexandre, Virginie, additional, Dembélé, Aïcha, additional, Lecoeur, Cécile, additional, Foe, Arnold Thomas, additional, Bouquet, Peggy, additional, Hot, David, additional, Vausselin, Thibaut, additional, Saliou, Jean-Michel, additional, Salomé-Desnoulez, Sophie, additional, Vandeputte, Alexandre, additional, Marsollier, Laurent, additional, Brodin, Priscille, additional, Dreux, Marlène, additional, Rouillé, Yves, additional, Dubuisson, Jean, additional, Aliouat-Denis, Cécile-Marie, additional, and Cocquerel, Laurence, additional

Published
2022
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14. Processing and Subcellular Localization of the Hepatitis E Virus Replicase: Identification of Candidate Viral Factories

Author

Metzger, Karoline, primary, Bentaleb, Cyrine, additional, Hervouet, Kévin, additional, Alexandre, Virginie, additional, Montpellier, Claire, additional, Saliou, Jean-Michel, additional, Ferrié, Martin, additional, Camuzet, Charline, additional, Rouillé, Yves, additional, Lecoeur, Cécile, additional, Dubuisson, Jean, additional, Cocquerel, Laurence, additional, and Aliouat-Denis, Cécile-Marie, additional

Published
2022
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15. Characterization of the hepatitis E virus replicase

Author

Metzger, Karoline, primary, Bentaleb, Cyrine, additional, Hervouet, Kévin, additional, Alexandre, Virginie, additional, Montpellier, Claire, additional, Saliou, Jean-Michel, additional, Ferrié, Martin, additional, Camuzet, Charline, additional, Rouillé, Yves, additional, Lecoeur, Cécile, additional, Dubuisson, Jean, additional, Cocquerel, Laurence, additional, and Aliouat-Denis, Cécile-Marie, additional

Published
2021
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17. The fate of Hepatitis E virus capsid protein is regulated by an Arginine-Rich Motif

Author

Hervouet, Kévin, Ferrié, Martin, Ankavay, Maliki, Montpellier, Claire, Camuzet, Charline, Alexandre, Virginie, Dembélé, Aïcha, Lecoeur, Cécile, Foe, Arnold Thomas, Bouquet, Peggy, Hot, David, Vausselin, Thibaut, Saliou, Jean-Michel, Salomé-Desnoulez, Sophie, Vandeputte, Alexandre, Marsollier, Laurent, Brodin, Priscille, Dreux, Marlène, Rouillé, Yves, Dubuisson, Jean, Aliouat-Denis, Cécile-Marie, Cocquerel, Laurence, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Plateformes Lilloises en Biologie et Santé - UMS 2014 - US 41 (PLBS), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work was supported by a grant from the Frenchagency ANRS-Maladies infectieuses émergentes. This work was also supported by the Pasteur Institute of Lille, Région Haut-de-France and Inserm-transfert. K.H., M.A. and T.V. were supported by a fellowship from the ANRS. M.F. was supported by a fellowship from the Pasteur Institute of Lille and Région Hauts-de-France. The PLBS platform used in this work was supported by the ANR (ANR-10-EQPX-04-01) and Feder (12001407 [D-AL] EquipEx ImagInEx BioMed)., ANR-10-EQPX-0004,Imaginex BioMed,Plateau de microscopie de criblage à haut débit et d'analyse à très haute résolution(2010), Plateformes Lilloises en Biologie et Santé - UAR 2014 - US 41 (PLBS), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cocquerel, Laurence, and Equipements d'excellence - Plateau de microscopie de criblage à haut débit et d'analyse à très haute résolution - - Imaginex BioMed2010 - ANR-10-EQPX-0004 - EQPX - VALID

Subjects
[SDV] Life Sciences [q-bio], animal diseases, viruses, [SDV]Life Sciences [q-bio], virus diseases
Abstract

Posté sur bioRxiv le 2021-05-26; Producing multifunctional proteins is one of the major strategies developed by viruses to condense their genetic information. Here, we investigated the molecular determinants of the multifunctionality of hepatitis E virus (HEV) ORF2 capsid protein. We previously identified 3 isoforms of ORF2 which are partitioned in different subcellular compartments to perform distinct functions. Notably, the infectious ORF2 (ORF2i) protein is the structural component of the virion, whereas the genome-free secreted and glycosylated ORF2 proteins likely act as a humoral immune decoy. We identified a 5 amino acid Arginine-Rich Motif (ARM) located in the ORF2 N-terminal region as a central regulator of the subcellular localizations and functions of ORF2 isoforms. We showed that the ARM controls ORF2 nuclear translocation, promoting regulation of host antiviral responses. This motif also regulates the dual topology and functionality of ORF2 signal peptide, leading to the production of either cytosolic infectious ORF2i or reticular non-infectious glycosylated ORF2 forms. Furthermore, the ARM likely serves as a cleavage site of the glycosylated ORF2 protein. Finally, it promotes ORF2 membrane association that is likely essential for particle assembly. In conclusion, our observations highlight ORF2 ARM as a unique central regulator of ORF2 addressing that finely controls the HEV lifecycle.

Published
2021

18. An Arginine-Rich Motif in the ORF2 Capsid Protein Regulates the Hepatitis E Virus Lifecycle and Interactions with the Host Cell

Author

Hervouet, Kévin, primary, Ferrié, Martin, additional, Ankavay, Maliki, additional, Montpellier, Claire, additional, Camuzet, Charline, additional, Alexandre, Virginie, additional, Dembélé, Aïcha, additional, Lecoeur, Cécile, additional, Foe, Arnold Thomas, additional, Bouquet, Peggy, additional, Hot, David, additional, Vausselin, Thibaut, additional, Saliou, Jean-Michel, additional, Salomé-Desnoulez, Sophie, additional, Vandeputte, Alexandre, additional, Marsollier, Laurent, additional, Brodin, Priscille, additional, Dreux, Marlène, additional, Rouillé, Yves, additional, Dubuisson, Jean, additional, Aliouat-Denis, Cécile-Marie, additional, and Cocquerel, Laurence, additional

Published
2021
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19. Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human

Author

Ichimura, Atsuhiko, Hirasawa, Akira, Poulain-Godefroy, Odile, Bonnefond, Amélie, Hara, Takafumi, Yengo, Loïc, Kimura, Ikuo, Leloire, Audrey, Liu, Ning, Iida, Keiko, Choquet, Hélène, Besnard, Philippe, Lecoeur, Cécile, Vivequin, Sidonie, Ayukawa, Kumiko, Takeuchi, Masato, Ozawa, Kentaro, Tauber, Maithé, Maffeis, Claudio, Morandi, Anita, Buzzetti, Raffaella, Elliott, Paul, Pouta, Anneli, Jarvelin, Marjo-Riitta, Körner, Antje, Kiess, Wieland, Pigeyre, Marie, Caiazzo, Roberto, Van Hul, Wim, Van Gaal, Luc, Horber, Fritz, Balkau, Beverley, Lévy-Marchal, Claire, Rouskas, Konstantinos, Kouvatsi, Anastasia, Hebebrand, Johannes, Hinney, Anke, Scherag, Andre, Pattou, François, Meyre, David, Koshimizu, Taka-aki, Wolowczuk, Isabelle, Tsujimoto, Gozoh, and Froguel, Philippe

Published
2012
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20. Obesity status modifies the association between rs7556897T>C in the intergenic region SLC19A3-CCL20 and blood pressure in French children

Author

El Shamieh, Said, primary, Stathopoulou, Maria G., additional, Bonnefond, Amélie, additional, Ndiaye, Ndeye Coumba, additional, Lecoeur, Cécile, additional, Meyre, David, additional, Dadé, Sébastien, additional, Chedid, Pia, additional, Salami, Ali, additional, Shahabi, Payman, additional, Dedoussis, George V., additional, Froguel, Philippe, additional, and Visvikis-Siest, Sophie, additional

Published
2020
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21. Genetic Variant in HK1 Is Associated With a Proanemic State and A1C but Not Other Glycemic Control–Related Traits

Author

Bonnefond, Amélie, Vaxillaire, Martine, Labrune, Yann, Lecoeur, Cécile, Chèvre, Jean-Claude, Bouatia-Naji, Nabila, Cauchi, Stéphane, Balkau, Beverley, Marre, Michel, Tichet, Jean, Riveline, Jean-Pierre, Hadjadj, Samy, Gallois, Yves, Czernichow, Sébastien, Hercberg, Serge, Kaakinen, Marika, Wiesner, Susanne, Charpentier, Guillaume, Lévy-Marchal, Claire, Elliott, Paul, Jarvelin, Marjo-Riitta, Horber, Fritz, Dina, Christian, Pedersen, Oluf, Sladek, Robert, Meyre, David, and Froguel, Philippe

Published
2009

22. The T-381C SNP in BNP gene may be modestly associated with type 2 diabetes: an updated meta-analysis in 49 279 subjects

Author

Choquet, Hélène, Cavalcanti-Proença, Christine, Lecoeur, Cécile, Dina, Christian, Cauchi, Stéphane, Vaxillaire, Martine, Hadjadj, Samy, Horber, Fritz, Potoczna, Natasha, Charpentier, Guillaume, Ruiz, Juan, Hercberg, Serge, Maimaitiming, Suliya, Roussel, Ronan, Boenhnke, Michael, Jackson, Anne U., Patsch, Wolfgang, Krempler, Franz, Voight, Benjamin F., Altshuler, David, Groop, Leif, Thorleifsson, Gudmar, Steinthorsdottir, Valgerdur, Stefansson, Kari, Balkau, Beverley, Froguel, Philippe, and Meyre, David

Published
2009

28. Association of Birth Weight With Type 2 Diabetes and Glycemic Traits:A Mendelian Randomization Study

Author

Huang, Tao, Wang, Tiange, Zheng, Yan, Ellervik, Christina, Li, Xiang, Gao, Meng, Fang, Zhe, Chai, Jin-Fang, Ahluwalia, Tarun Veer S, Wang, Yujie, Voortman, Trudy, Noordam, Raymond, Frazier-Wood, Alexis, Scholz, Markus, Sonestedt, Emily, Akiyama, Masato, Dorajoo, Rajkumar, Zhou, Ang, Kilpeläinen, Tuomas O, Kleber, Marcus E, Crozier, Sarah R, Godfrey, Keith M, Lemaitre, Rozenn, Felix, Janine F, Shi, Yuan, Gupta, Preeti, Khor, Chiea-Chuen, Lehtimäki, Terho, Wang, Carol A, Tiesler, Carla M T, Thiering, Elisabeth, Standl, Marie, Rzehak, Peter, Marouli, Eirini, He, Meian, Lecoeur, Cécile, Corella, Dolores, Lai, Chao-Qiang, Moreno, Luis A, Pitkänen, Niina, Boreham, Colin A, Zhang, Tao, Hansen, Torben, Sørensen, Thorkild I A, Tjønneland, Anne, Overvad, Kim, Bisgaard, Hans, Pedersen, Oluf, Bønnelykke, Klaus, Rossing, Peter, Huang, Tao, Wang, Tiange, Zheng, Yan, Ellervik, Christina, Li, Xiang, Gao, Meng, Fang, Zhe, Chai, Jin-Fang, Ahluwalia, Tarun Veer S, Wang, Yujie, Voortman, Trudy, Noordam, Raymond, Frazier-Wood, Alexis, Scholz, Markus, Sonestedt, Emily, Akiyama, Masato, Dorajoo, Rajkumar, Zhou, Ang, Kilpeläinen, Tuomas O, Kleber, Marcus E, Crozier, Sarah R, Godfrey, Keith M, Lemaitre, Rozenn, Felix, Janine F, Shi, Yuan, Gupta, Preeti, Khor, Chiea-Chuen, Lehtimäki, Terho, Wang, Carol A, Tiesler, Carla M T, Thiering, Elisabeth, Standl, Marie, Rzehak, Peter, Marouli, Eirini, He, Meian, Lecoeur, Cécile, Corella, Dolores, Lai, Chao-Qiang, Moreno, Luis A, Pitkänen, Niina, Boreham, Colin A, Zhang, Tao, Hansen, Torben, Sørensen, Thorkild I A, Tjønneland, Anne, Overvad, Kim, Bisgaard, Hans, Pedersen, Oluf, Bønnelykke, Klaus, and Rossing, Peter

Abstract

Importance: Observational studies have shown associations of birth weight with type 2 diabetes (T2D) and glycemic traits, but it remains unclear whether these associations represent causal associations.Objective: To test the association of birth weight with T2D and glycemic traits using a mendelian randomization analysis.Design, Setting, and Participants: This mendelian randomization study used a genetic risk score for birth weight that was constructed with 7 genome-wide significant single-nucleotide polymorphisms. The associations of this score with birth weight and T2D were tested in a mendelian randomization analysis using study-level data. The association of birth weight with T2D was tested using both study-level data (7 single-nucleotide polymorphisms were used as an instrumental variable) and summary-level data from the consortia (43 single-nucleotide polymorphisms were used as an instrumental variable). Data from 180 056 participants from 49 studies were included.Main Outcomes and Measures: Type 2 diabetes and glycemic traits.Results: This mendelian randomization analysis included 49 studies with 41 155 patients with T2D and 80 008 control participants from study-level data and 34 840 patients with T2D and 114 981 control participants from summary-level data. Study-level data showed that a 1-SD decrease in birth weight due to the genetic risk score was associated with higher risk of T2D among all participants (odds ratio [OR], 2.10; 95% CI, 1.69-2.61; P = 4.03 × 10-5), among European participants (OR, 1.96; 95% CI, 1.42-2.71; P = .04), and among East Asian participants (OR, 1.39; 95% CI, 1.18-1.62; P = .04). Similar results were observed from summary-level analyses. In addition, each 1-SD lower birth weight was associated with 0.189 SD higher fasting glucose concentration (β = 0.189; SE = 0.060; P = .002), but not with fasting insulin, 2-hour glucose, or hemoglobin A1c concentration.Conclusions and Relevance: In this stud

Published
2019

31. A Genome-Wide Scan in Families With Maturity-Onset Diabetes of the Young: Evidence for Further Genetic Heterogeneity

Author

Frayling, Timothy M., Lindgren, Cecilia M., Chevre, Jean Claude, Menzel, Stephan, Wishart, Marie, Benmezroua, Yamina, Brown, Alison, Evans, Julie C., Rao, Pamidghantam Subba, Dina, Christian, Lecoeur, Cécile, Kanninen, Timo, Almgren, Peter, Bulman, Michael P., Wang, Youxiang, Mills, James, Wright-Pascoe, Rosemarie, Mahtani, Melanie M., Prisco, Francesco, Costa, Angels, Cognet, Ignacio, Hansen, Torben, Pedersen, Oluf, Ellard, Sian, Tuomi, Tiinamaija, Groop, Leif C., Froguel, Philippe, Hattersley, Andrew T., and Vaxillaire, Martine

Published
2003

34. Fine-mapping of an expanded set of type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps

Author

Mahajan, Anubha, Taliun, Daniel, Thurner, Matthias, Robertson, Neil R, Torres, Jason M, Rayner, N William, Payne, Anthony J, Steinthorsdottir, Valgerdur, Scott, Robert A, Grarup, Niels, Cook, James P, Schmidt, Ellen M, Wuttke, Matthias, Sarnowski, Chloé, Mägi, Reedik, Nano, Jana, Gieger, Christian, Trompet, Stella, Lecoeur, Cécile, Preuss, Michael H, Prins, Bram Peter, Guo, Xiuqing, Bielak, Lawrence F, Below, Jennifer E, Bowden, Donald W, Chambers, John Campbell, Kim, Young Jin, Ng, Maggie C Y, Petty, Lauren E, Sim, Xueling, Zhang, Weihua, Bennett, Amanda J, Bork-Jensen, Jette, Brummett, Chad M, Canouil, Mickaël, Ec Kardt, Kai-Uwe, Fischer, Krista, Kardia, Sharon L R, Kronenberg, Florian, Läll, Kristi, Liu, Ching-Ti, Locke, Adam E, Luan, Jian'an, Ntalla, Ioanna, Nylander, Vibe, Schönherr, Sebastian, Schurmann, Claudia, Yengo, Loïc, Bottinger, Erwin P, Brandslund, Ivan, Christensen, Cramer, Dedoussis, George, Florez, Jose C, Ford, Ian, Franco, Oscar H, Frayling, Timothy M, Giedraitis, Vilmantas, Hackinger, Sophie, Hattersley, Andrew T, Herder, Christian, Ikram, M Arfan, Ingelsson, Martin, Jørgensen, Marit E, Jørgensen, Torben, Kriebel, Jennifer, Kuusisto, Johanna, Ligthart, Symen, Lindgren, Cecilia M, Linneberg, Allan, Lyssenko, Valeriya, Mamakou, Vasiliki, Meitinger, Thomas, Mohlke, Karen L, Morris, Andrew D, Nadkarni, Girish, Pankow, James S, Peters, Annette, Sattar, Naveed, Stančáková, Alena, Strauch, Konstantin, Taylor, Kent D, Thorand, Barbara, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Tuomilehto, Jaakko, Witte, Daniel R, Dupuis, Josée, Peyser, Patricia A, Zeggini, Eleftheria, Loos, Ruth J F, Froguel, Philippe, Ingelsson, Erik, Lind, Lars, Groop, Leif, Laakso, Markku, Collins, Francis S, Jukema, J Wouter, Palmer, Colin N A, Grallert, Harald, Metspalu, Andres, Dehghan, Abbas, Köttgen, Anna, Abecasis, Goncalo R, Meigs, James B, Rotter, Jerome I, Marchini, Jonathan, Pedersen, Oluf, Hansen, Torben, Langenberg, Claudia, Wareham, Nicholas J, Stefansson, Kari, Gloyn, Anna L, Morris, Andrew P, Boehnke, Michael, and McCarthy, Mark I

Subjects
endocrine system diseases
Abstract

We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency 2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).

Published
2018

35. The expression of genes in top obesity-associated loci is enriched in insula and substantia nigra brain regions involved in addiction and reward

Author

Ndiaye, Fatou K., primary, Huyvaert, Marlène, additional, Ortalli, Ana, additional, Canouil, Mickaël, additional, Lecoeur, Cécile, additional, Verbanck, Marie, additional, Lobbens, Stéphane, additional, Khamis, Amna, additional, Marselli, Lorella, additional, Marchetti, Piero, additional, Kerr-Conte, Julie, additional, Pattou, François, additional, Marre, Michel, additional, Roussel, Ronan, additional, Balkau, Beverley, additional, Froguel, Philippe, additional, and Bonnefond, Amélie, additional

Published
2019
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36. The association of CD81 with tetraspanin-enriched microdomains is not essential for Hepatitis C virus entry

Author

Rubinstein Eric, Lecoeur Cécile, Potel Julie, Pillez André, Canton Jonathan, Delgrange David, Lavie Muriel, Rocha-Perugini Vera, Dubuisson Jean, Wychowski Czeslaw, and Cocquerel Laurence

Subjects
Microbiology, QR1-502
Abstract

Abstract Background Three percent of the world's population is chronically infected with hepatitis C virus (HCV) and thus at risk of developing liver cancer. Although precise mechanisms regulating HCV entry into hepatic cells are still unknown, several cell surface proteins have been identified as entry factors for this virus. Among these molecules, the tetraspanin CD81 is essential for HCV entry. Interestingly, CD81 is also required for Plasmodium infection. A major characteristic of tetraspanins is their ability to interact with each other and other transmembrane proteins to build tetraspanin-enriched microdomains (TEM). Results In our study, we describe a human hepatoma Huh-7 cell clone (Huh-7w7) which has lost CD81 expression and can be infected by HCV when human CD81 (hCD81) or mouse CD81 (mCD81) is ectopically expressed. We took advantage of these permissive cells expressing mCD81 and the previously described MT81/MT81w mAbs to analyze the role of TEM-associated CD81 in HCV infection. Importantly, MT81w antibody, which only recognizes TEM-associated mCD81, did not strongly affect HCV infection. Furthermore, cholesterol depletion, which inhibits HCV infection and reduces total cell surface expression of CD81, did not affect TEM-associated CD81 levels. In addition, sphingomyelinase treatment, which also reduces HCV infection and cell surface expression of total CD81, raised TEM-associated CD81 levels. Conclusion In contrast to Plasmodium infection, our data show that association of CD81 with TEM is not essential for the early steps of HCV life cycle, indicating that these two pathogens, while using the same molecules, invade their host by different mechanisms.

Published
2009
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37. Secretory granule neuroendocrine protein 1 (SGNE1) genetic variation and glucose intolerance in severe childhood and adult obesity

Author

Charpentier Guillaume, Tichet Jean, Jouret Béatrice, Veslot Jacques, Proença Christine, Heude Barbara, Lecoeur Cécile, Vatin Vincent, Bouatia-Naji Nabila, Marre Michel, Balkau Beverley, Froguel Philippe, and Meyre David

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

Abstract Background 7B2 is a regulator/activator of the prohormone convertase 2 which is involved in the processing of numerous neuropeptides, including insulin, glucagon and pro-opiomelanocortin. We have previously described a suggestive genetic linkage peak with childhood obesity on chr15q12-q14, where the 7B2 encoding gene, SGNE1 is located. The aim of this study is to analyze associations of SGNE1 genetic variation with obesity and metabolism related quantitative traits. Methods We screened SGNE1 for genetic variants in obese children and genotyped 12 frequent single nucleotide polymorphisms (SNPs). Case control analyses were performed in 1,229 obese (534 children and 695 adults), 1,535 individuals with type 2 diabetes and 1,363 controls, all French Caucasians. We also studied 4,922 participants from the D.E.S.I.R prospective population-based cohort. Results We did not find any association between SGNE1 SNPs and childhood or adult obesity. However, the 5' region SNP -1,701A>G associated with higher area under glucose curve after oral glucose tolerance test (p = 0.0005), higher HOMA-IR (p = 0.005) and lower insulinogenic index (p = 0.0003) in obese children. Similar trends were found in obese adults. SNP -1,701A>G did not associate with risk of T2D but tends to associate with incidence of type 2 diabetes (HR = 0.75 95%CI [0.55–1.01]; p = 0.06) in the prospective cohort. Conclusion SGNE1 genetic variation does not contribute to obesity and common forms of T2D but may worsen glucose intolerance and insulin resistance, especially in the background of severe and early onset obesity. Further molecular studies are required to understand the molecular bases involved in this process.

Published
2007
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38. TCF7L2 rs7903146 variant does not associate with smallness for gestational age in the French population

Author

Gaget Stefan, Durand Emmanuelle, Deghmoun Samia, Choquet Hélène, Meyre David, Cauchi Stéphane, Lecoeur Cécile, Froguel Philippe, and Levy-Marchal Claire

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

Abstract Background In adults, the TCF7L2 rs7903146 T allele, commonly associated with type 2 diabetes (T2D), has been also associated with a lower body mass index (BMI) in T2D individuals and with a smaller waist circumference in subjects with impaired glucose tolerance. Methods The present association study aimed at analyzing the contribution of the rs7903146 SNP to smallness for gestational age (SGA) and metabolic profiles in subjects with SGA or appropriate for gestational age birth weight (AGA). Two groups of French Caucasian subjects were selected on birth data: SGA (birth weight < 10th percentile; n = 764), and AGA (25th < birth weight < 75th percentile; n = 627). Family-based association tests were also performed in 3,012 subjects from 628 SGA and AGA pedigrees. Results The rs7903146 genotypic distributions between AGA (30.7%) and SGA (29.0%) were not statistically different (allelic OR = 0.92 [0.78–1.09], p = 0.34). Family association-based studies did not show a distortion of T allele transmission in SGA subjects (p = 0.52). No significant effect of the T allele was detected on any of the metabolic parameters in the SGA group. However, in the AGA group, trends towards a lower insulin secretion (p = 0.03) and a higher fasting glycaemia (p = 0.002) were detected in carriers of the T allele. Conclusion The TCF7L2 rs7903146 variant neither increases the risk for SGA nor modulates birth weight and young adulthood glucose homeostasis in French Caucasian subjects born with SGA.

Published
2007
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39. Analysis of common PTPN1 gene variants in type 2 diabetes, obesity and associated phenotypes in the French population

Author

Marre Michel, Balkau Beverley, Charpentier Guillaume, Bibi Amina, Dechaume Aurélie, Lecoeur Cécile, Cheyssac Claire, Froguel Philippe, Gibson Fernando, and Vaxillaire Martine

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

Abstract Background The protein tyrosine phosphatase-1B, a negative regulator for insulin and leptin signalling, potentially modulates glucose and energy homeostasis. PTP1B is encoded by the PTPN1 gene located on chromosome 20q13 showing linkage with type 2 diabetes (T2D) in several populations. PTPN1 gene variants have been inconsistently associated with T2D, and the aim of our study was to investigate the effect of PTPN1 genetic variations on the risk of T2D, obesity and on the variability of metabolic phenotypes in the French population. Methods Fourteen single nucleotide polymorphisms (SNPs) spanning the PTPN1 locus were selected from previous association reports and from HapMap linkage disequilibrium data. SNPs were evaluated for association with T2D in two case-control groups with 1227 cases and 1047 controls. Association with moderate and severe obesity was also tested in a case-control study design. Association with metabolic traits was evaluated in 736 normoglycaemic, non-obese subjects from a general population. Five SNPs showing a trend towards association with T2D, obesity or metabolic parameters were investigated for familial association. Results From 14 SNPs investigated, only SNP rs914458, located 10 kb downstream of the PTPN1 gene significantly associated with T2D (p = 0.02 under a dominant model; OR = 1.43 [1.06–1.94]) in the combined sample set. SNP rs914458 also showed association with moderate obesity (allelic p = 0.04; OR = 1.2 [1.01–1.43]). When testing for association with metabolic traits, two strongly correlated SNPs, rs941798 and rs2426159, present multiple consistent associations. SNP rs2426159 exhibited evidence of association under a dominant model with glucose homeostasis related traits (p = 0.04 for fasting insulin and HOMA-B) and with lipid markers (0.02 = p = 0.04). Moreover, risk allele homozygotes for this SNP had an increased systolic blood pressure (p = 0.03). No preferential transmission of alleles was observed for the SNPs tested in the family sample. Conclusion In our study, PTPN1 variants showed moderate association with T2D and obesity. However, consistent associations with metabolic variables reflecting insulin resistance and dyslipidemia are found for two intronic SNPs as previously reported. Thus, our data indicate that PTPN1 variants may modulate the lipid profile, thereby influencing susceptibility to metabolic disease.

Published
2006
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40. Mutations exomiques rares transmises au sein de familles de type MODY : analyse de corrélation avec la variabilité phénotypique et les défauts métaboliques précoces

Author

Vaxillaire, Martine, primary, Vaxillaire, Martine, additional, Lecoeur, Cécile, additional, Durand, Emmanuelle, additional, Vaillant, Emmanuel, additional, Toussaint, Bénédicte, additional, Leloire, Audrey, additional, De Graeve, Franck, additional, Rabearivelo, Iandry, additional, Sand, Olivier, additional, Bonnefond, Amélie, additional, and Froguel, Philippe, additional

Published
2017
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41. Impact of Type 2 Diabetes Susceptibility Variants on Quantitative Glycemic Traits Reveals Mechanistic Heterogeneity

Author

Erdos, Michael R., Barroso, Inês, Benazzo, Andrea, Rybin, Denis, Payne, Felicity, Grarup, Niels, Fischer-Rosinsky, Antje, Bumpstead, Suzannah, Assimes, Themistocles L., Narisu, Narisu, Lecoeur, Cécile, Dimas, Antigone S., Jackson, Anne U., Böttcher, Yvonne, Stringham, Heather M., Barker, Adam, Morken, Mario A., Hao, Ke, Kovacs, Peter, Yang, Xia, Mägi, Reedik, Bonnycastle, Lori L., Stancakova, Alena, Boesgaard, Trine Welløv, Knowles, Joshua W., Lagou, Vasiliki, Hivert, Marie-France, Graessler, Jurgen, Swift, Amy J., Chines, Peter S., Song, Ci, and Abbasi, Fahim A.

Abstract

Patients with established type 2 diabetes display both β-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci, and indices of proinsulin processing, insulin secretion, and insulin sensitivity. We included data from up to 58,614 nondiabetic subjects with basal measures and 17,327 with dynamic measures. We used additive genetic models with adjustment for sex, age, and BMI, followed by fixed-effects, inverse-variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second cluster (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without a detectable change in fasting glucose levels. The final group contained 20 risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.

Published
2014
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42. 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

43. 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

44. Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge

Author

Vollenweider, Peter, Lyssenko, Valeriya, Couper, David J, Luan, Jian'an, Glazer, Nicole L, Li, Man, Bouatia-Naji, Nabila, Song, Kijoung, Le Bacquer, Olivier, Hivert, Marie-France, Tanaka, Toshiko, O'Connell, Jeffrey, Prokopenko, Inga, Lecoeur, Cécile, Manning, Alisa K, Andreasen, Camilla H, Dina, Christian, Rice, Kenneth, Pattou, François, Grarup, Niels, Pankow, James S, Saxena, Richa, Jackson, Anne U, Köttgen, Anna, Ingelsson, Erik, Stringham, Heather M, Langenberg, Claudia, Johnson, Toby, Boesgaard, Trine W, Kao, W H Linda, Dupuis, Josée, and Shrader, Peter

Abstract

Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958–30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, β (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 × 10−15). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 × 10−17; ratio of insulin to glucose area under the curve, P = 1.3 × 10−16) and diminished incretin effect (n = 804; P = 4.3 × 10−4). We also identified variants at ADCY5 (rs2877716, P = 4.2 × 10−16), VPS13C (rs17271305, P = 4.1 × 10−8), GCKR (rs1260326, P = 7.1 × 10−11) and TCF7L2 (rs7903146, P = 4.2 × 10−10) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09–1.15, P = 4.8 × 10−18).

Published
2010
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46. Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity

Author

Dimas, Antigone S, Lagou, Vasiliki, Barker, Adam, Knowles, Joshua W, Mägi, Reedik, Hivert, Marie-France, Benazzo, Andrea, Rybin, Denis, Jackson, Anne U, Stringham, Heather M, Song, Ci, Fischer-Rosinsky, Antje, Boesgaard, Trine Welløv, Grarup, Niels, Abbasi, Fahim A, Assimes, Themistocles L, Hao, Ke, Yang, Xia, Lecoeur, Cécile, Barroso, Inês, Bonnycastle, Lori L, Böttcher, Yvonne, Bumpstead, Suzannah, Chines, Peter S, Erdos, Michael R, Graessler, Jurgen, Kovacs, Peter, Morken, Mario A, Narisu, Narisu, Payne, Felicity, Stancakova, Alena, Swift, Amy J, Tönjes, Anke, Bornstein, Stefan R, Cauchi, Stéphane, Froguel, Philippe, Meyre, David, Schwarz, Peter E H, Häring, Hans-Ulrich, Smith, Ulf, Boehnke, Michael, Bergman, Richard N, Collins, Francis S, Mohlke, Karen L, Tuomilehto, Jaakko, Quertemous, Thomas, Lind, Lars, Hansen, Torben, Pedersen, Oluf, Walker, Mark, Dimas, Antigone S, Lagou, Vasiliki, Barker, Adam, Knowles, Joshua W, Mägi, Reedik, Hivert, Marie-France, Benazzo, Andrea, Rybin, Denis, Jackson, Anne U, Stringham, Heather M, Song, Ci, Fischer-Rosinsky, Antje, Boesgaard, Trine Welløv, Grarup, Niels, Abbasi, Fahim A, Assimes, Themistocles L, Hao, Ke, Yang, Xia, Lecoeur, Cécile, Barroso, Inês, Bonnycastle, Lori L, Böttcher, Yvonne, Bumpstead, Suzannah, Chines, Peter S, Erdos, Michael R, Graessler, Jurgen, Kovacs, Peter, Morken, Mario A, Narisu, Narisu, Payne, Felicity, Stancakova, Alena, Swift, Amy J, Tönjes, Anke, Bornstein, Stefan R, Cauchi, Stéphane, Froguel, Philippe, Meyre, David, Schwarz, Peter E H, Häring, Hans-Ulrich, Smith, Ulf, Boehnke, Michael, Bergman, Richard N, Collins, Francis S, Mohlke, Karen L, Tuomilehto, Jaakko, Quertemous, Thomas, Lind, Lars, Hansen, Torben, Pedersen, Oluf, and Walker, Mark

Abstract

Patients with established type 2 diabetes display both beta-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci and indices of proinsulin processing, insulin secretion and insulin sensitivity. We included data from up to 58,614 non-diabetic subjects with basal measures, and 17,327 with dynamic measures. We employed additive genetic models with adjustment for sex, age and BMI, followed by fixed-effects inverse variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (including TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without detectable change in fasting glucose. The final group contained twenty risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.

Published
2013

47. Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge

Author

Saxena, Richa, Hivert, Marie-France, Langenberg, Claudia, Tanaka, Toshiko, Pankow, James S, Vollenweider, Peter, Lyssenko, Valeriya, Bouatia-Naji, Nabila, Dupuis, Josée, Jackson, Anne U, Kao, W H Linda, Li, Man, Glazer, Nicole L, Manning, Alisa K, Luan, Jian'an, Stringham, Heather M, Prokopenko, Inga, Johnson, Toby, Grarup, Niels, Boesgaard, Trine W, Lecoeur, Cécile, Shrader, Peter, O'Connell, Jeffrey, Ingelsson, Erik, Couper, David J, Rice, Kenneth, Song, Kijoung, Andreasen, Camilla H, Dina, Christian, Köttgen, Anna, Le Bacquer, Olivier, Pattou, François, Taneera, Jalal, Steinthorsdottir, Valgerdur, Rybin, Denis, Ardlie, Kristin, Sampson, Michael, Qi, Lu, van Hoek, Mandy, Weedon, Michael N, Aulchenko, Yurii S, Voight, Benjamin F, Grallert, Harald, Balkau, Beverley, Bergman, Richard N, Bielinski, Suzette J, Bonnefond, Amelie, Bonnycastle, Lori L, Borch-Johnsen, Knut, Böttcher, Yvonne, Brunner, Eric, Buchanan, Thomas A, Bumpstead, Suzannah J, Cavalcanti-Proença, Christine, Charpentier, Guillaume, Chen, Yii-Der Ida, Chines, Peter S, Collins, Francis S, Cornelis, Marilyn, J Crawford, Gabriel, Delplanque, Jerome, Doney, Alex, Egan, Josephine M, Erdos, Michael R, Firmann, Mathieu, Forouhi, Nita G, Fox, Caroline S, Goodarzi, Mark O, Graessler, Jürgen, Hingorani, Aroon, Isomaa, Bo, Jørgensen, Torben, Kivimaki, Mika, Kovacs, Peter, Krohn, Knut, Kumari, Meena, Lauritzen, Torsten, Lévy-Marchal, Claire, Mayor, Vladimir, McAteer, Jarred B, Meyre, David, Mitchell, Braxton D, Mohlke, Karen L, Morken, Mario A, Narisu, Narisu, Palmer, Colin N A, Pakyz, Ruth, Pascoe, Laura, Payne, Felicity, Pearson, Daniel, Rathmann, Wolfgang, Sandbaek, Annelli, Sayer, Avan Aihie, Scott, Laura J, Sharp, Stephen J, Sijbrands, Eric, Singleton, Andrew, Siscovick, David S, Smith, Nicholas L, Sparsø, Thomas, Swift, Amy J, Syddall, Holly, Thorleifsson, Gudmar, Tönjes, Anke, Tuomi, Tiinamaija, Tuomilehto, Jaakko, Valle, Timo T, Waeber, Gérard, Walley, Andrew, Waterworth, Dawn M, Zeggini, Eleftheria, Zhao, Jing Hua, Illig, Thomas, Wichmann, H Erich, Wilson, James F, van Duijn, Cornelia, Hu, Frank B, Morris, Andrew D, Frayling, Timothy M, Hattersley, Andrew T, Thorsteinsdottir, Unnur, Stefansson, Kari, Nilsson, Peter, Syvänen, Ann-Christine, Shuldiner, Alan R, Walker, Mark, Bornstein, Stefan R, Schwarz, Peter, Williams, Gordon H, Nathan, David M, Kuusisto, Johanna, Laakso, Markku, Cooper, Cyrus, Marmot, Michael, Ferrucci, Luigi, Mooser, Vincent, Stumvoll, Michael, Loos, Ruth J F, Altshuler, David, Psaty, Bruce M, Rotter, Jerome I, Boerwinkle, Eric, Hansen, Torben, Pedersen, Oluf, Florez, Jose C, McCarthy, Mark I, Boehnke, Michael, Barroso, Inês, Sladek, Robert, Froguel, Philippe, Meigs, James B, Groop, Leif, Wareham, Nicholas J, Watanabe, Richard M, Saxena, Richa, Hivert, Marie-France, Langenberg, Claudia, Tanaka, Toshiko, Pankow, James S, Vollenweider, Peter, Lyssenko, Valeriya, Bouatia-Naji, Nabila, Dupuis, Josée, Jackson, Anne U, Kao, W H Linda, Li, Man, Glazer, Nicole L, Manning, Alisa K, Luan, Jian'an, Stringham, Heather M, Prokopenko, Inga, Johnson, Toby, Grarup, Niels, Boesgaard, Trine W, Lecoeur, Cécile, Shrader, Peter, O'Connell, Jeffrey, Ingelsson, Erik, Couper, David J, Rice, Kenneth, Song, Kijoung, Andreasen, Camilla H, Dina, Christian, Köttgen, Anna, Le Bacquer, Olivier, Pattou, François, Taneera, Jalal, Steinthorsdottir, Valgerdur, Rybin, Denis, Ardlie, Kristin, Sampson, Michael, Qi, Lu, van Hoek, Mandy, Weedon, Michael N, Aulchenko, Yurii S, Voight, Benjamin F, Grallert, Harald, Balkau, Beverley, Bergman, Richard N, Bielinski, Suzette J, Bonnefond, Amelie, Bonnycastle, Lori L, Borch-Johnsen, Knut, Böttcher, Yvonne, Brunner, Eric, Buchanan, Thomas A, Bumpstead, Suzannah J, Cavalcanti-Proença, Christine, Charpentier, Guillaume, Chen, Yii-Der Ida, Chines, Peter S, Collins, Francis S, Cornelis, Marilyn, J Crawford, Gabriel, Delplanque, Jerome, Doney, Alex, Egan, Josephine M, Erdos, Michael R, Firmann, Mathieu, Forouhi, Nita G, Fox, Caroline S, Goodarzi, Mark O, Graessler, Jürgen, Hingorani, Aroon, Isomaa, Bo, Jørgensen, Torben, Kivimaki, Mika, Kovacs, Peter, Krohn, Knut, Kumari, Meena, Lauritzen, Torsten, Lévy-Marchal, Claire, Mayor, Vladimir, McAteer, Jarred B, Meyre, David, Mitchell, Braxton D, Mohlke, Karen L, Morken, Mario A, Narisu, Narisu, Palmer, Colin N A, Pakyz, Ruth, Pascoe, Laura, Payne, Felicity, Pearson, Daniel, Rathmann, Wolfgang, Sandbaek, Annelli, Sayer, Avan Aihie, Scott, Laura J, Sharp, Stephen J, Sijbrands, Eric, Singleton, Andrew, Siscovick, David S, Smith, Nicholas L, Sparsø, Thomas, Swift, Amy J, Syddall, Holly, Thorleifsson, Gudmar, Tönjes, Anke, Tuomi, Tiinamaija, Tuomilehto, Jaakko, Valle, Timo T, Waeber, Gérard, Walley, Andrew, Waterworth, Dawn M, Zeggini, Eleftheria, Zhao, Jing Hua, Illig, Thomas, Wichmann, H Erich, Wilson, James F, van Duijn, Cornelia, Hu, Frank B, Morris, Andrew D, Frayling, Timothy M, Hattersley, Andrew T, Thorsteinsdottir, Unnur, Stefansson, Kari, Nilsson, Peter, Syvänen, Ann-Christine, Shuldiner, Alan R, Walker, Mark, Bornstein, Stefan R, Schwarz, Peter, Williams, Gordon H, Nathan, David M, Kuusisto, Johanna, Laakso, Markku, Cooper, Cyrus, Marmot, Michael, Ferrucci, Luigi, Mooser, Vincent, Stumvoll, Michael, Loos, Ruth J F, Altshuler, David, Psaty, Bruce M, Rotter, Jerome I, Boerwinkle, Eric, Hansen, Torben, Pedersen, Oluf, Florez, Jose C, McCarthy, Mark I, Boehnke, Michael, Barroso, Inês, Sladek, Robert, Froguel, Philippe, Meigs, James B, Groop, Leif, Wareham, Nicholas J, and Watanabe, Richard M

Abstract

Glucose levels 2 h after an oral glucose challenge are a clinical measure of glucose tolerance used in the diagnosis of type 2 diabetes. We report a meta-analysis of nine genome-wide association studies (n = 15,234 nondiabetic individuals) and a follow-up of 29 independent loci (n = 6,958–30,620). We identify variants at the GIPR locus associated with 2-h glucose level (rs10423928, β (s.e.m.) = 0.09 (0.01) mmol/l per A allele, P = 2.0 × 10−15). The GIPR A-allele carriers also showed decreased insulin secretion (n = 22,492; insulinogenic index, P = 1.0 × 10−17; ratio of insulin to glucose area under the curve, P = 1.3 × 10−16) and diminished incretin effect (n = 804; P = 4.3 × 10−4). We also identified variants at ADCY5 (rs2877716, P = 4.2 × 10−16), VPS13C (rs17271305, P = 4.1 × 10−8), GCKR (rs1260326, P = 7.1 × 10−11) and TCF7L2 (rs7903146, P = 4.2 × 10−10) associated with 2-h glucose. Of the three newly implicated loci (GIPR, ADCY5 and VPS13C), only ADCY5 was found to be associated with type 2 diabetes in collaborating studies (n = 35,869 cases, 89,798 controls, OR = 1.12, 95% CI 1.09–1.15, P = 4.8 × 10−18).

Published
2010
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48. 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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49. Whole-Exome Sequencing and High Throughput Genotyping Identified KCNJ11 as the Thirteenth MODY Gene

Author

Bonnefond, Amélie, primary, Philippe, Julien, additional, Durand, Emmanuelle, additional, Dechaume, Aurélie, additional, Huyvaert, Marlène, additional, Montagne, Louise, additional, Marre, Michel, additional, Balkau, Beverley, additional, Fajardy, Isabelle, additional, Vambergue, Anne, additional, Vatin, Vincent, additional, Delplanque, Jérôme, additional, Le Guilcher, David, additional, De Graeve, Franck, additional, Lecoeur, Cécile, additional, Sand, Olivier, additional, Vaxillaire, Martine, additional, and Froguel, Philippe, additional

Published
2012
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50. Glucose-Dependent Regulation of NR2F2 Promoter and Influence of SNP-rs3743462 on Whole Body Insulin Sensitivity

Author

Boutant, Marie, primary, Ramos, Oscar Henrique Pereira, additional, Lecoeur, Cécile, additional, Vaillant, Emmanuel, additional, Philippe, Julien, additional, Zhang, Pili, additional, Perilhou, Anaïs, additional, Valcarcel, Beatriz, additional, Sebert, Sylvain, additional, Jarvelin, Mario-Ritta, additional, Balkau, Beverley, additional, Scott, Donald, additional, Froguel, Philippe, additional, Vaxillaire, Martine, additional, and Vasseur-Cognet, Mireille, additional

Published
2012
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