First Genome-Wide Association Study of Latent Autoimmune Diabetes in Adults Reveals Novel Insights Linking Immune and Metabolic Diabetes-Reference-Cited by-同舟云学术

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

Published:2018-10-15 Issue:11 Volume:41 Page:2396-2403
ISSN:0149-5992
Container-title:Diabetes Care
language:en
Short-container-title:

Author:

Cousminer Diana L.¹²^ORCID,Ahlqvist Emma³,Mishra Rajashree¹⁴,Andersen Mette K.⁵,Chesi Alessandra¹,Hawa Mohammad I.⁶,Davis Asa⁷,Hodge Kenyaita M.¹,Bradfield Jonathan P.⁸,Zhou Kaixin⁹,Guy Vanessa C.¹,Åkerlund Mikael³,Wod Mette¹⁰,Fritsche Lars G.¹¹,Vestergaard Henrik⁵,Snyder James⁸,Højlund Kurt¹⁰,Linneberg Allan⁵,Käräjämäki Annemari¹²,Brandslund Ivan¹⁰,Kim Cecilia E.⁸,Witte Daniel¹⁰¹³,Sørgjerd Elin Pettersen¹⁴,Brillon David J.¹⁵,Pedersen Oluf⁵,Beck-Nielsen Henning¹⁰,Grarup Niels⁵^ORCID,Pratley Richard E.¹⁶,Rickels Michael R.¹⁷^ORCID,Vella Adrian¹⁸^ORCID,Ovalle Fernando¹⁹,Melander Olle³,Harris Ronald I.²⁰,Varvel Stephen²¹,Grill Valdemar E.R.²²²³,Hakonarson Hakon⁸²⁴^ORCID,Froguel Philippe²⁵²⁶,Lonsdale John T.²⁷,Mauricio Didac²⁸^ORCID,Schloot Nanette C.²⁹^ORCID,Khunti Kamlesh³⁰^ORCID,Greenbaum Carla J.⁷^ORCID,Åsvold Bjørn Olav¹¹²²,Yderstræde Knud B.¹⁰,Pearson Ewan R.⁹,Schwartz Stanley³¹,Voight Benjamin F.²¹⁷³²³³,Hansen Torben⁵^ORCID,Tuomi Tiinamaija³⁴³⁵³⁶^ORCID,Boehm Bernhard O.³⁷³⁸,Groop Leif³³⁶,Leslie R. David⁶^ORCID,Grant Struan F.A.¹²⁸¹⁷²⁴,McCormack Shana E.,Mitchell Jonathan A.,Kelly Andrea,Kalkwarf Heidi J.,Lappe Joan M.,Shepherd John A.,Oberfield Sharon E.,Gilsanz Vicente,Zemel Babette S.,

Affiliation:

1. Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA

2. Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

3. Department of Clinical Sciences Malmö, Lund University Diabetes Centre, Lund University, Skåne University Hospital, Malmö, Sweden

4. Graduate Group in Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

5. The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

6. Department of Immunobiology, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, U.K.

7. Benaroya Research Institute, Seattle, WA

8. Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA

9. Division of Molecular and Clinical Medicine, Medical Research Institute, University of Dundee, Dundee, U.K.

10. Odense University Hospital, Odense, Denmark

11. Department of Public Health and Nursing, K.G. Jebsen Center for Genetic Epidemiology, Norwegian University of Science and Technology, Trondheim, Norway

12. Vaasa Health Care Center and Department of Primary Health Care, Vaasa Central Hospital, Vaasa, Finland

13. Department of Public Health, Aarhus University, Aarhus, Denmark

14. Department of Public Health and Nursing, HUNT Research Centre, Norwegian University of Science and Technology, Levanger, Norway

15. Weill Cornell Medical College, New York, NY

16. Florida Hospital Translational Research Institute for Metabolism and Diabetes, Orlando, FL

17. Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

18. Mayo Clinic, Rochester, MN

19. University of Alabama, Birmingham, AL

20. Geisinger Health System, Danville, PA

21. Health Diagnostic Laboratory Inc., Richmond, VA

22. Department of Endocrinology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway

23. Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway

24. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

25. CNRS 8199, Université Lille Nord de France, Pasteur Institute, Lille, France

26. Department of Genomics of Common Disease, Imperial College London, London, U.K.

27. National Disease Research Interchange, Philadelphia, PA

28. Hospital Universitari Germans Trias i Pujol, Barcelona, Spain

29. German Diabetes Center, Düsseldorf, Germany

30. Diabetes Research Centre, University of Leicester, Leicester, U.K.

31. Main Line Health System, Wynnewood, PA

32. Department of Systems, Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

33. Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

34. Department of Endocrinology, Helsinki University Hospital, Helsinki, Finland

35. Research Programs Unit, Diabetes and Obesity, Folkhälsan Research Centre, University of Helsinki, Helsinki, Finland

36. Finnish Institute for Molecular Medicine, Helsinki, Finland

37. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore and Imperial College, London, U.K.

38. Department of Internal Medicine I, Ulm University Medical Centre, Ulm, Germany

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.

Funder

American Diabetes Association

CIBERDEM, Instituto de Salud Carlos III

German Research Council

National Institutes of Health

Children’s Hospital of Philadelphia

Publisher

American Diabetes Association

Subject

Advanced and Specialized Nursing,Endocrinology, Diabetes and Metabolism,Internal Medicine

Link

https://diabetesjournals.org/care/article-pdf/41/11/2396/526959/dc181032.pdf