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Olle Melander

Principal investigator

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Genetic Discrimination Between LADA and Childhood-Onset Type 1 Diabetes Within the MHC

Author

  • Rajashree Mishra
  • Mikael Åkerlund
  • Diana L. Cousminer
  • Emma Ahlqvist
  • Jonathan P. Bradfield
  • Alessandra Chesi
  • Kenyaita M. Hodge
  • Vanessa C. Guy
  • David J. Brillon
  • Richard E. Pratley
  • Michael R. Rickels
  • Adrian Vella
  • Fernando Ovalle
  • Ronald I. Harris
  • Olle Melander
  • Stephen Varvel
  • Hakon Hakonarson
  • Phillippe Froguel
  • John T. Lonsdale
  • Didac Mauricio
  • Nanette C. Schloot
  • Kamlesh Khunti
  • Carla J. Greenbaum
  • Knud B. Yderstræde
  • Tiinamaija Tuomi
  • Benjamin F. Voight
  • Stanley Schwartz
  • Bernhard O. Boehm
  • Leif Groop
  • Richard David Leslie
  • Struan F.A. Grant

Summary, in English

OBJECTIVE: The MHC region harbors the strongest loci for latent autoimmune diabetes in adults (LADA); however, the strength of association is likely attenuated compared with that for childhood-onset type 1 diabetes. In this study, we recapitulate independent effects in the MHC class I region in a population with type 1 diabetes and then determine whether such conditioning in LADA yields potential genetic discriminators between the two subtypes within this region. RESEARCH DESIGN AND METHODS: Chromosome 6 was imputed using SNP2HLA, with conditional analysis performed in type 1 diabetes case subjects (n = 1,985) and control subjects (n = 2,219). The same approach was applied to a LADA cohort (n = 1,428) using population-based control subjects (n = 2,850) and in a separate replication cohort (656 type 1 diabetes case, 823 LADA case, and 3,218 control subjects). RESULTS: The strongest associations in the MHC class II region (rs3957146, β [SE] = 1.44 [0.05]), as well as the independent effect of MHC class I genes, on type 1 diabetes risk, particularly HLA-B*39 (β [SE] = 1.36 [0.17]), were confirmed. The conditional analysis in LADA versus control subjects showed significant association in the MHC class II region (rs3957146, β [SE] = 1.14 [0.06]); however, we did not observe significant independent effects of MHC class I alleles in LADA. CONCLUSIONS: In LADA, the independent effects of MHC class I observed in type 1 diabetes were not observed after conditioning on the leading MHC class II associations, suggesting that the MHC class I association may be a genetic discriminator between LADA and childhood-onset type 1 diabetes.

Department/s

  • Diabetic Complications
  • EXODIAB: Excellence in Diabetes Research in Sweden
  • Genomics, Diabetes and Endocrinology
  • EpiHealth: Epidemiology for Health
  • Cardiovascular Research - Hypertension

Publishing year

2020

Language

English

Pages

418-425

Publication/Series

Diabetes Care

Volume

43

Issue

2

Document type

Journal article

Publisher

American Diabetes Association

Topic

  • Endocrinology and Diabetes
  • Medical Genetics

Status

Published

Research group

  • Diabetic Complications
  • Genomics, Diabetes and Endocrinology
  • Cardiovascular Research - Hypertension

ISBN/ISSN/Other

  • ISSN: 1935-5548