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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, ? [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 (? [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, ? [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.
SUBMITTER: Mishra R
PROVIDER: S-EPMC6971787 | biostudies-literature | 2020 Feb
REPOSITORIES: biostudies-literature
Mishra Rajashree R Åkerlund Mikael M Cousminer Diana L DL Ahlqvist Emma E Bradfield Jonathan P JP Chesi Alessandra A Hodge Kenyaita M KM Guy Vanessa C VC Brillon David J DJ Pratley Richard E RE Rickels Michael R MR Vella Adrian A Ovalle Fernando F Harris Ronald I RI Melander Olle O Varvel Stephen S Hakonarson Hakon H Froguel Phillippe P Lonsdale John T JT Mauricio Didac D Schloot Nanette C NC Khunti Kamlesh K Greenbaum Carla J CJ Yderstræde Knud B KB Tuomi Tiinamaija T Voight Benjamin F BF Schwartz Stanley S Boehm Bernhard O BO Groop Leif L Leslie Richard David RD Grant Struan F A SFA
Diabetes care 20191216 2
<h4>Objective</h4>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.<h4>Research design and me ...[more]