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 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

doi:10.2337/dc18-1032

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

Population Health and Genomics

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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 language	English
Pages (from-to)	2396-2403
Number of pages	7
Journal	Diabetes Care
Early online date	22 Oct 2018
DOIs	https://doi.org/10.2337/dc18-1032
Publication status	Published - 1 Nov 2018

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, 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., ... Grant, S. F. A. (2018). First Genome Wide Association Study of Latent Autoimmune Diabetes in Adults Reveals Novel Insights Linking Immune and Metabolic Diabetes. Diabetes Care, 2396-2403. https://doi.org/10.2337/dc18-1032

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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 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.",

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 {\AA}kerlund 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 Witte, {Daniel R.} 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 Hakonarson, {Hakon H.} 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 Ewan Pearson and Stanley Schwartz and Voight, {Benjamin F.} and Torben Hansen and Tiinamaija Tuomi and Boehm, {Bernhard O.} and Groop, {Leif C.} and Leslie, {R. David} and Grant, {Struan F. A.}",

year = "2018",

month = nov,

day = "1",

doi = "10.2337/dc18-1032",

language = "English",

pages = "2396--2403",

journal = "Diabetes Care",

issn = "0149-5992",

publisher = "American Diabetes Association Inc.",

}

Cousminer, DL, Ahlqvist, E, Mishra, R, Andersen , MK, Chesi, A, Hawa, MI, Davis, A, Hodge, KM, Bradfield, JP, Zhou, K, Guy, VC, Åkerlund, M, Wod, M, Fritsche, LG, Vestergaard, H, Snyder, J, Højlund, K, Linneberg, A, Käräjämäki, A, Brandslund, I, Kim, CE, Witte, DR, Sørgjerd, EP, Brillon, DJ, Pedersen, O, Beck-Nielsen, H, Grarup, N, Pratley, RE, Rickels, MR, Vella, A, Ovalle, F, Melander, O, Harris, RI, Varvel, S, Grill, VER, Hakonarson, HH, Froguel, P, Lonsdale, JT, Mauricio, D, Schloot, NC, Khunti, K, Greenbaum, CJ, Asvold, BO, Yderstræde, KB, Pearson, E, Schwartz, S, Voight, BF, Hansen, T, Tuomi, T, Boehm, BO, Groop, LC & Leslie, RD & Grant, SFA 2018, 'First Genome Wide Association Study of Latent Autoimmune Diabetes in Adults Reveals Novel Insights Linking Immune and Metabolic Diabetes', Diabetes Care, pp. 2396-2403. https://doi.org/10.2337/dc18-1032

TY - JOUR

T1 - First Genome Wide Association Study of Latent Autoimmune Diabetes in Adults Reveals Novel Insights Linking Immune and Metabolic Diabetes

AU - Cousminer, Diana L.

AU - Ahlqvist, Emma

AU - Mishra, Rajashree

AU - Andersen , Mette K.

AU - Chesi, Alessandra

AU - Hawa, Mohammad I.

AU - Davis, Asa

AU - Hodge, Kenyaita M.

AU - Bradfield, Jonathan P.

AU - Zhou, Kaixin

AU - Guy, Vanessa C.

AU - Åkerlund, Mikael

AU - Wod, Mette

AU - Fritsche, Lars G.

AU - Vestergaard, Henrik

AU - Snyder, James

AU - Højlund, Kurt

AU - Linneberg, Allan

AU - Käräjämäki, Annemari

AU - Brandslund, Ivan

AU - Kim, Cecilia E.

AU - Witte, Daniel R.

AU - Sørgjerd, Elin Pettersen

AU - Brillon, David J.

AU - Pedersen, Oluf

AU - Beck-Nielsen, Henning

AU - Grarup, Niels

AU - Pratley, Richard E.

AU - Rickels, Michael R.

AU - Vella, Adrian

AU - Ovalle, Fernando

AU - Melander, Olle

AU - Harris, Ronald I.

AU - Varvel, Stephen

AU - Grill, Valdemar E.R.

AU - Hakonarson, Hakon H.

AU - Froguel, Philippe

AU - Lonsdale, John T.

AU - Mauricio, Didac

AU - Schloot, Nanette C.

AU - Khunti, Kamlesh

AU - Greenbaum, Carla J.

AU - Asvold, Bjørn Olav

AU - Yderstræde, Knud B.

AU - Pearson, Ewan

AU - Schwartz, Stanley

AU - Voight, Benjamin F.

AU - Hansen, Torben

AU - Tuomi, Tiinamaija

AU - Boehm, Bernhard O.

AU - Groop, Leif C.

AU - Leslie, R. David

AU - Grant, Struan F. A.

PY - 2018/11/1

Y1 - 2018/11/1

N2 - 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.

AB - 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.

U2 - 10.2337/dc18-1032

DO - 10.2337/dc18-1032

M3 - Article

C2 - 30254083

SN - 0149-5992

SP - 2396

EP - 2403

JO - Diabetes Care

JF - Diabetes Care

ER -

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

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