Citations 2
First Genome-Wide Association Study of Latent Autoimmune Diabetes in Adults Reveals Novel Insights Linking Immune and Metabolic Diabetes
Cousminer, Diana L. , Ahlqvist, Emma , Mishra, Rajashree, Andersen, Mette K. , Chesi, Alessandra , Hawa, M. I., Davis, Asa K., Hodge, Kenyaita M., Bradfield, Jonathan P., Zhou, Kaixin , Guy, Vanessa C., Åkerlund, Mikael, Wod, Mette , Fritsche, Lars G. , Vestergaard, Henrik , Snyder, James W. , Højlund, Kurt , Linneberg, Allan , Käräjämäki, Annemari , Brandslund, Ivan , Kim, Cecilia E, Witte, Daniel R. , Sørgjerd, Elin Pettersen , Brillon, David J., Pedersen, Oluf , Beck‐Nielsen, Henning , Grarup, Niels , Rickels, Michael R. , Melander, Olle , Harris, Ronald I., Varvel, Stephen A. , Grill, Valdemar , Håkonarson, Håkon , Froguel, Philippe , Lonsdale, John T., Mauricio, Dı́dac , Schloot, Nanette C. , Khunti, Kamlesh , Greenbaum, Carla J. , Åsvold, Bjørn Olav , Yderstræde, Knud Bonnet , Pearson, Ewan R. , Schwartz, Stanley S. , Voight, Benjamin F. , Hansen, Torben , Tuomi, Tiinamaija , Boehm, Bernhard O. , Groop, Leif , Leslie, Richard David , Grant, Struan F.A. , Study, Bone Mineral Density in Childhood, Mitchell, Jonathan A. , Lappe, Joan M. , Gilsanz, Vicente , Rickels, Michael R , Vella, Adrian , Hakonarson, Hakon , Mauricio, Didac , Schloot, Nanette C , Khunti, Kamlesh , Greenbaum, Carla J , Hansen, Torben , Tuomi, Tiinamaija , Leslie, R David , Froguel, Phillippe , Grant, Struan F A , Ahlqvist, Emma , Snyder, James, Pratley, Richard E. , Vella, Adrian , Ovalle, Fernando , Lonsdale, John T., Study, Bone Mineral Density in Childhood, McCormack, Shana Erin , Kelly, Andrea True , Kalkwarf, Heidi J. , Shepherd, John , Oberfield, Sharon E. , Zemel, Babette S.
Diabetes Care | September 25, 2018 | Volume: 41 | Issue: 11 | Pages: 2396-2403
OBJECTIVELatent autoimmune diabetes in adults (LADA) shares clinical features with both type 1 and type 2 diabetes; however, there is ongoing debate regarding the precise definition of LADA. Understanding its genetic basis is one potential strategy to gain insight into appropriate classification of this diabetes subtype.RESEARCH DESIGN AND METHODSWe performed the first genome-wide association study of LADA in case subjects of European ancestry versus population control subjects (n = 2,634 vs. 5,947) and compared against both case subjects with type 1 diabetes (n = 2,454 vs. 968) and type 2 diabetes (n = 2,779 vs. 10,396).RESULTSThe leading genetic signals were principally shared with type 1 diabetes, although we observed positive genetic correlations genome-wide with both type 1 and type 2 diabetes. Additionally, we observed a novel independent signal at the known type 1 diabetes locus harboring PFKFB3, encoding a regulator of glycolysis and insulin signaling in type 2 diabetes and inflammation and autophagy in autoimmune disease, as well as an attenuation of key type 1–associated HLA haplotype frequencies in LADA, suggesting that these are factors that distinguish childhood-onset type 1 diabetes from adult autoimmune diabetes.CONCLUSIONSOur results support the need for further investigations of the genetic factors that distinguish forms of autoimmune diabetes as well as more precise classification strategies.
Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function
Neve, Bernadette , Fernández-Zapico, Martín E. , Ashkenazi-Katalan, Vered, Dina, Christian , Hamid, Yasmin H., Joly, Érik, Vaillant, Emmanuel, Benmezroua, Yamina, Durand, Emmanuelle , Bakaher, Nicolas, Delannoy, Valérie, Vaxillaire, Martine , Cook, Tiffany , Dallinga‐Thie, Geesje M. , Jansen, Hans, Charles, Marie‐Aline , Clément, Karine, Helbecque, Nicole, Charpentier, G. , Prentki, Marc , Hansen, Torben , Pedersen, Oluf , Melloul, Danielle , Froguel, Philippe , Galán, Pilar , Herçberg, Serge , Urrutia, Raúl , Hansen, Torben , Froguel, Phillippe , Dina, Christian
Proceedings of the National Academy of Sciences | March 17, 2005 | Volume: 102 | Issue: 13 | Pages: 4807-4812
KLF11 (TIEG2) is a pancreas-enriched transcription factor that has elicited significant attention because of its role as negative regulator of exocrine cell growth in vitro and in vivo . However, its functional role in the endocrine pancreas remains to be established. Here, we report, for the first time, to our knowledge, the characterization of KLF11 as a glucose-inducible regulator of the insulin gene. A combination of random oligonucleotide binding, EMSA, luciferase reporter, and chromatin immunoprecipitation assays shows that KLF11 binds to the insulin promoter and regulates its activity in beta cells. Genetic analysis of the KLF11 gene revealed two rare variants (Ala347Ser and Thr220Met) that segregate with diabetes in families with early-onset type 2 diabetes, and significantly impair its transcriptional activity. In addition, analysis of 1,696 type 2 diabetes mellitus and 1,776 normoglycemic subjects show a frequent polymorphic Gln62Arg variant that significantly associates with type 2 diabetes mellitus in North European populations (OR = 1.29, P = 0.00033). Moreover, this variant alters the corepressor mSin3A-binding activity of KLF11, impairs the activation of the insulin promoter and shows lower levels of insulin expression in pancreatic beta cells. In addition, subjects carrying the Gln62Arg allele show decreased plasma insulin after an oral glucose challenge. Interestingly, all three nonsynonymous KLF11 variants show increased repression of the catalase 1 promoter, suggesting a role in free radical clearance that may render beta cells more sensitive to oxidative stress. Thus, both functional and genetic analyses reveal that KLF11 plays a role in the regulation of pancreatic beta cell physiology, and its variants may contribute to the development of diabetes.