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

First Genome-Wide Association Study of Latent Autoimmune Diabetes in Adults Reveals Novel Insights Linking Immune and Metabolic Diabetes. Cousminer, D. L., Ahlqvist, E., Mishra, R., Andersen, M. K., Chesi, A., Hawa, M. I., Davis, A., Hodge, K. M., Bradfield, J. P., Zhou, K., Guy, V. C., Åkerlund, M., Wod, M., Fritsche, L. G., Vestergaard, H., Snyder, J., Højlund, K., Linneberg, A., Käräjämäki, A., Brandslund, I., Kim, C. E., Witte, D., Sørgjerd, E. P., Brillon, D. J., Pedersen, O., Beck-Nielsen, H., Grarup, N., Pratley, R. E., Rickels, M. R., Vella, A., Ovalle, F., Melander, O., Harris, R. I., Varvel, S., Grill, V. E. R., Bone Mineral Density in Childhood Study, Hakonarson, H., Froguel, P., Lonsdale, J. T., Mauricio, D., Schloot, N. C., Khunti, K., Greenbaum, C. J., Åsvold, B. O., Yderstræde, K. B., Pearson, E. R., Schwartz, S., Voight, B. F., Hansen, T., Tuomi, T., Boehm, B. O., Groop, L., Leslie, R. D., & Grant, S. F. A. Diabetes Care, 41(11):2396–2403, 2018.
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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.

@article{cousminer_first_2018,
	title = {First {Genome}-{Wide} {Association} {Study} of {Latent} {Autoimmune} {Diabetes} in {Adults} {Reveals} {Novel} {Insights} {Linking} {Immune} and {Metabolic} {Diabetes}},
	volume = {41},
	issn = {1935-5548},
	doi = {10.2337/dc18-1032},
	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.},
	language = {eng},
	number = {11},
	journal = {Diabetes Care},
	author = {Cousminer, Diana L. and Ahlqvist, Emma and Mishra, Rajashree and Andersen, Mette K. and Chesi, Alessandra and Hawa, Mohammad I. and Davis, Asa and Hodge, Kenyaita M. and Bradfield, Jonathan P. and Zhou, Kaixin and Guy, Vanessa C. and Åkerlund, Mikael and Wod, Mette and Fritsche, Lars G. and Vestergaard, Henrik and Snyder, James and Højlund, Kurt and Linneberg, Allan and Käräjämäki, Annemari and Brandslund, Ivan and Kim, Cecilia E. and Witte, Daniel and Sørgjerd, Elin Pettersen and Brillon, David J. and Pedersen, Oluf and Beck-Nielsen, Henning and Grarup, Niels and Pratley, Richard E. and Rickels, Michael R. and Vella, Adrian and Ovalle, Fernando and Melander, Olle and Harris, Ronald I. and Varvel, Stephen and Grill, Valdemar E. R. and {Bone Mineral Density in Childhood Study} and Hakonarson, Hakon and Froguel, Philippe and Lonsdale, John T. and Mauricio, Didac and Schloot, Nanette C. and Khunti, Kamlesh and Greenbaum, Carla J. and Åsvold, Bjørn Olav and Yderstræde, Knud B. and Pearson, Ewan R. and Schwartz, Stanley and Voight, Benjamin F. and Hansen, Torben and Tuomi, Tiinamaija and Boehm, Bernhard O. and Groop, Leif and Leslie, R. David and Grant, Struan F. A.},
	year = {2018},
	pmid = {30254083},
	pmcid = {PMC6196829},
	keywords = {Adult, Aged, Case-Control Studies, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Female, Genome-Wide Association Study, Glucose Intolerance, Haplotypes, Humans, Immune System Phenomena, Insulin, Latent Autoimmune Diabetes in Adults, Male, Middle Aged, Young Adult},
	pages = {2396--2403}
}

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