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. 2018 Nov;41(11):2396-2403.
doi: 10.2337/dc18-1032. Epub 2018 Sep 25.

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 Käräjämäki, Ivan Brandslund, Cecilia E Kim, Daniel 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; Bone Mineral Density in Childhood Study; Hakon Hakonarson, Philippe Froguel, John T Lonsdale, Didac Mauricio, Nanette C Schloot, Kamlesh Khunti, Carla J Greenbaum, Bjørn Olav Åsvold, Knud B Yderstræde, Ewan R Pearson, Stanley Schwartz, Benjamin F Voight, Torben Hansen, Tiinamaija Tuomi, Bernhard O Boehm, Leif Groop, R David Leslie, Struan F A Grant
Collaborators

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

Diana L Cousminer et al. Diabetes Care. 2018 Nov.

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 into appropriate classification of this diabetes subtype.

Research design and methods: We 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).

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.

Conclusions: 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.

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Figures

Figure 1
Figure 1
LocusZoom plots for the PFKFB3 locus. A: In LADA vs. population control subjects with the addition of replication samples, rs1983890 reached borderline genome-wide significance. B: This signal lies in between two type 1 diabetes–associated loci at 10p15.1 (21). C: When we conditioned on the two known type 1 diabetes loci, the signal in LADA remained. LocusZoom plots were constructed to show the association data of SNPs 400 kb upstream and downstream of the lead LADA-associated signal at rs1983890. chr10, chromosome 10.
See this image and copyright information in PMC

Comment in

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