@article{91fe99cb9b234dc0977e18d2e1662fb6,
title = "First genome-wide association study of latent autoimmune diabetes in adults reveals novel insights linking immune and metabolic diabetes",
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.",
author = "Cousminer, {Diana L.} and Emma Ahlqvist and Rajashree Mishra and Andersen, {Mette K.} and Alessandra Chesi and Hawa, {Mohammad I.} and Asa Davis and Hodge, {Kenyaita M.} and Bradfield, {Jonathan P.} and Kaixin Zhou and Guy, {Vanessa C.} and Mikael Akerlund and Mette Wod and Fritsche, {Lars G.} and Henrik Vestergaard and James Snyder and Kurt H{\o}jlund and Allan Linneberg and Annemari K{\"a}r{\"a}j{\"a}m{\"a}ki and Ivan Brandslund and Kim, {Cecilia E.} and Daniel Witte and S{\o}rgjerd, {Elin Pettersen} and Brillon, {David J.} and Oluf Pedersen and Henning Beck-Nielsen and Niels Grarup and Pratley, {Richard E.} and Rickels, {Michael R.} and Adrian Vella and Fernando Ovalle and Olle Melander and Harris, {Ronald I.} and Stephen Varvel and Grill, {Valdemar E.R.} and Hakon Hakonarson and Philippe Froguel and Lonsdale, {John T.} and Didac Mauricio and Schloot, {Nanette C.} and Kamlesh Khunti and Greenbaum, {Carla J.} and Asvold, {Bj{\o}rn Olav} and Yderstr{\ae}de, {Knud B.} and Pearson, {Ewan R.} and Stanley Schwartz and Voight, {Benjamin F.} and Torben Hansen and Tiinamaija Tuomi and Boehm, {Bernhard O.} and Leif Groop and {David Leslie}, R. and Grant, {Struan F.A.}",
note = "Funding Information: Acknowledgments. For cohort-specific ac knowledgments, please see the Supplementary Data. M.I.H. is deceased. Funding. D.L.C. is supported by American Diabetes Association grant 1-17-PDF-077. D.M. is supported by CIBERDEM, Instituto de Salud Carlos III (Spain). B.O.B. is supported by the German Research Council (SFB 518, A1), the state of Baden-W{\"u}erttemberg, and a Ministry of Education, Singapore startup grant. S.F.A.G. is supported by the National Institutes of Health (R01-DK-085212) and the Children{\textquoteright}s Hospital of Philadelphia Daniel B. Burke Endowed Chair for Diabetes Research. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. D.L.C., E.A., R.M., M.K.A., A.C., S.S., T.H., T.T., B.O.B., L.G., R.D.L., and S.F.A.G. were responsible for study concept and design. D.L.C., E.A., R.M., M.K.A., A.C., J.P.B., K.Z., B.F.V., T.H., T.T., B.O.B., L.G., R.D.L., and S.F.A.G. were responsible for analysis and interpretation of data. D.L.C., E.A., R.M., M.K.A., A.C., J.P.B., V.E.R.G., N.C.S., B.O.{\AA}., B.F.V., T.H., T.T., B.O.B., L.G., R.D.L., and S.F.A.G. were responsible for drafting and critical revision of the manuscript. S.S., T.H., B.O.B., R.D.L., and S.F.A.G. obtained funding. M.I.H., A.D., K.M.H., V.C.G., M.{\AA}., M.W., L.G.F., H.V., J.S., K.H., A.L., A.K., I.B., C.E.K., D.W., E.P.S., D.J.B., O.P., H.B.-N., N.G., R.E.P., M.R.R., A.V., F.O., R.I.H., S.V., V.E.R.G., H.H., P.F., J.T.L., D.M., N.C.S., K.K., C.J.G., B.O.{\AA}., K.B.Y., E.R.P., T.H., T.T., B.O.B., L.G., R.D.L., and S.F.A.G. were responsibleforresources.D.L.C.,E.A.,R.M.,M.K.A., A.C., M.I.H., A.D., K.M.H., J.P.B., K.Z., V.C.G., M.{\AA}., M.W., L.G.F., H.V., J.S., K.H., A.L., A.K., I.B., C.E.K., D.W., E.P.S., D.J.B., O.P., H.B.-N., N.G., R.E.P., M.R.R., A.V., F.O., O.M., R.I.H., S.V., V.E.R.G., H.H., P.F., J.T.L., D.M., N.C.S., K.K., C.J.G., B.O.{\AA}., K.B.Y., E.R.P., S.S., T.H., T.T., B.O.B., L.G., R.D.L., and S.F.A.G. contributed to the final version of the manuscript. D.L.C. and S.F.A.G. are the guarantors of this work and, as such, had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented in oral form at the 77th Scientific Sessions of the American Diabetes Association, San Diego, CA, 9–13 June 2017. Publisher Copyright: {\textcopyright} 2018 by the American Diabetes Association.",
year = "2018",
month = nov,
day = "1",
doi = "10.2337/dc18-1032",
language = "English (US)",
volume = "41",
pages = "2396--2403",
journal = "Diabetes Care",
issn = "1935-5548",
publisher = "American Diabetes Association Inc.",
number = "11",
}