Citations 1
Genetic Discrimination Between LADA and Childhood-Onset Type 1 Diabetes Within the MHC
Mishra, Rajashree, Åkerlund, Mikael, Cousminer, Diana L. , Ahlqvist, Emma , Bradfield, Jonathan P., Chesi, Alessandra , Hodge, Kenyaita M., Guy, Vanessa C., Brillon, David J., Harris, Ronald I., Melander, Olle , Varvel, Stephen A. , Håkonarson, Håkon , Froguel, Philippe , Lonsdale, John T., Mauricio, Dı́dac , Schloot, Nanette C. , Khunti, Kamlesh , Greenbaum, Carla J. , Yderstræde, Knud Bonnet , Tuomi, Tiinamaija , Voight, Benjamin F. , Schwartz, Stanley S. , Boehm, Bernhard O. , Groop, Leif , Leslie, Richard David , Grant, Struan F.A. , Vella, Adrian , Hakonarson, Hakon , Froguel, Phillippe , Mauricio, Didac , Schloot, Nanette C , Khunti, Kamlesh , Greenbaum, Carla J , Tuomi, Tiinamaija , Leslie, R David , Grant, Struan F A , Ahlqvist, Emma , Bradfield, Jonathan P., Pratley, Richard E. , Rickels, Michael R. , Vella, Adrian , Ovalle, Fernando , Lonsdale, John T.
Diabetes Care | December 16, 2019 | Volume: 43 | Issue: 2 | Pages: 418-425
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.