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

Leif C Groop, R. David Leslie, Struan F.A. Grant, Bone Mineral Density in Childhood Study

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.

OriginalsprogEngelsk
TidsskriftDiabetes Care
Vol/bind41
Udgave nummer11
Sider (fra-til)2396-2403
ISSN0149-5992
DOI
StatusUdgivet - nov. 2018

Fingeraftryk

Genome-Wide Association Study
Type 2 Diabetes Mellitus
Population Control
Latent Autoimmune Diabetes in Adults
Glycolysis
Haplotypes
Insulin

Citer dette

Groop, Leif C ; Leslie, R. David ; Grant, Struan F.A. ; Bone Mineral Density in Childhood Study. / First Genome-Wide Association Study of Latent Autoimmune Diabetes in Adults Reveals Novel Insights Linking Immune and Metabolic Diabetes. I: Diabetes Care. 2018 ; Bind 41, Nr. 11. s. 2396-2403.
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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 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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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 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 {\AA}svold, {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 Groop, {Leif C} and Leslie, {R. David} and Grant, {Struan F.A.} and {Bone Mineral Density in Childhood Study}",
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First Genome-Wide Association Study of Latent Autoimmune Diabetes in Adults Reveals Novel Insights Linking Immune and Metabolic Diabetes. / Groop, Leif C; Leslie, R. David ; Grant, Struan F.A. ; Bone Mineral Density in Childhood Study.

I: Diabetes Care, Bind 41, Nr. 11, 11.2018, s. 2396-2403.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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

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

AU - Froguel, Philippe

AU - Lonsdale, John T

AU - Mauricio, Didac

AU - Schloot, Nanette C

AU - Khunti, Kamlesh

AU - Greenbaum, Carla J

AU - Åsvold, Bjørn Olav

AU - Yderstræde, Knud B

AU - Pearson, Ewan R

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.

AU - Bone Mineral Density in Childhood Study

N1 - © 2018 by the American Diabetes Association.

PY - 2018/11

Y1 - 2018/11

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 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.

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 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.

KW - Adult

KW - Aged

KW - Case-Control Studies

KW - Diabetes Mellitus, Type 1/genetics

KW - Diabetes Mellitus, Type 2/genetics

KW - Female

KW - Genome-Wide Association Study

KW - Glucose Intolerance/genetics

KW - Haplotypes

KW - Humans

KW - Immune System Phenomena/genetics

KW - Insulin/metabolism

KW - Latent Autoimmune Diabetes in Adults/genetics

KW - Male

KW - Middle Aged

KW - Young Adult

U2 - 10.2337/dc18-1032

DO - 10.2337/dc18-1032

M3 - Journal article

VL - 41

SP - 2396

EP - 2403

JO - Diabetes Care

JF - Diabetes Care

SN - 0149-5992

IS - 11

ER -