Genetic discrimination between LADA and childhood-onset type 1 diabetes within the MHC

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 MauricioNanette 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

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Abstract

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-B39 (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 werenot 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.

Original languageEnglish (US)
Pages (from-to)418-425
Number of pages8
JournalDiabetes care
Volume43
Issue number2
DOIs
StatePublished - Feb 1 2020

ASJC Scopus subject areas

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

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    Mishra, R., Åkerlund, M., Cousminer, D. L., Ahlqvist, E., Bradfield, J. P., Chesi, A., Hodge, K. M., Guy, V. C., Brillon, D. J., Pratley, R. E., Rickels, M. R., Vella, A., Ovalle, F., Harris, R. I., Melander, O., Varvel, S., Hakonarson, H., Froguel, P., Lonsdale, J. T., ... Grant, S. F. A. (2020). Genetic discrimination between LADA and childhood-onset type 1 diabetes within the MHC. Diabetes care, 43(2), 418-425. https://doi.org/10.2337/dc19-0986