First Genome Wide Association Study of Latent Autoimmune Diabetes in Adults Reveals Novel Insights Linking Immune and Metabolic Diabetes

, Diana L. Cousminer, Emma Ahlqvist, Rajashree Mishra, Mette K. Andersen , Alessandra Chesi, Mohammad I. Hawa, Asa Davis, Kenyaita M. Hodge, Jonathan P. Bradfield, Kaixin Zhou, Vanessa C. Guy, Mikael Åkerlund, Mette Wod, Lars G. Fritsche, Henrik Vestergaard, James Snyder, Kurt Højlund, Allan Linneberg, Annemari KäräjämäkiIvan Brandslund, Cecilia E. Kim, Daniel R. Witte, Elin Pettersen Sørgjerd, David J. Brillon, Oluf Pedersen, Henning Beck-Nielsen, Niels Grarup, Richard E. Pratley, Michael R. Rickels, Adrian Vella, Fernando Ovalle, Olle Melander, Ronald I. Harris, Stephen Varvel, Valdemar E.R. Grill, Hakon H. Hakonarson, Philippe Froguel, John T. Lonsdale, Didac Mauricio, Nanette C. Schloot, Kamlesh Khunti, Carla J. Greenbaum, Bjørn Olav Asvold, Knud B. Yderstræde, Ewan Pearson, Stanley Schwartz, Benjamin F. Voight, Torben Hansen, Tiinamaija Tuomi, Bernhard O. Boehm, Leif C. Groop, R. David Leslie, Struan F. A. Grant

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Abstract

Objective: Latent 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 in to appropriate classification of this diabetes subtype.

Research Design and Methods: We performed the first genome-wide association study of LADA in cases of European ancestry versus population controls (n = 2,634 vs. 5,947), cases with type 1 diabetes (n = 2,454 vs. 968) and type 2 diabetes (n = 2,779 vs. 10, 396).

Results: The 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.

Conclusion: Our results support the need for further investigations of the genetic factors that distinguish forms of autoimmune diabetes, as well as more precise classification strategies.
Original languageEnglish
Pages (from-to)2396-2403
Number of pages7
JournalDiabetes Care
Early online date22 Oct 2018
DOIs
Publication statusPublished - 1 Nov 2018

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