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

• Published in: Diabetes care Vol. 43; no. 2; pp. 418 - 425
• Main Authors: Mishra, Rajashree, Åkerlund, Mikael, Cousminer, Diana L., Ahlqvist, Emma, Bradfield, Jonathan P., Chesi, Alessandra, Hodge, Kenyaita M., Guy, Vanessa C., Brillon, David J., Pratley, Richard E., Rickels, Michael R., Vella, Adrian, Ovalle, Fernando, Harris, Ronald I., Melander, Olle, Varvel, Stephen, Hakonarson, Hakon, Froguel, Phillippe, Lonsdale, John T., Mauricio, Didac, Schloot, Nanette C., Khunti, Kamlesh, Greenbaum, Carla J., Yderstræde, Knud B., Tuomi, Tiinamaija, Voight, Benjamin F., Schwartz, Stanley, Boehm, Bernhard O., Groop, Leif, Leslie, Richard David, Grant, Struan F.A.
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.02.2020
• Subjects: Adolescent; Adult; Age of Onset; Alleles; ANDIS; Associations; Autoimmune diseases; Basic Medicine; Case-Control Studies; Child; Child, Preschool; Childhood; Children; Chromosome 6; Chromosomes; Chromosomes, Human, Pair 6 - genetics; Clinical Medicine; Cohort Studies; Conditioning; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - classification; Diabetes Mellitus, Type 1 - diagnosis; Diabetes Mellitus, Type 1 - epidemiology; Diabetes Mellitus, Type 1 - genetics; Diabetics; Diagnosis, Differential; Discriminators; Endocrinology and Diabetes; Endokrinologi och diabetes; Female; Genes, MHC Class I - genetics; Genes, MHC Class II - genetics; Genetic Association Studies; Genetic Testing - methods; Genetics; Health risks; Humans; Klinisk medicin; Latent Autoimmune Diabetes in Adults - classification; Latent Autoimmune Diabetes in Adults - diagnosis; Latent Autoimmune Diabetes in Adults - genetics; Life Sciences; Major histocompatibility complex; Male; Medical and Health Sciences; Medical Genetics; Medical Genetics and Genomics (including Gene Therapy); Medicin och hälsovetenskap; Medicinsk genetik; Medicinsk genetik och genomik (Här ingår: Genterapi); Medicinska och farmaceutiska grundvetenskaper; Pathophysiology/Complications; Polymorphism, Single Nucleotide; Research design; Young Adult
• ISSN: 0149-5992; 1935-5548; 1935-5548; 0149-5992
• DOI: 10.2337/dc19-0986

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. Chromosome 6 was imputed using SNP2HLA, with conditional analysis performed in type 1 diabetes case subjects ( = 1,985) and control subjects ( = 2,219). The same approach was applied to a LADA cohort ( = 1,428) using population-based control subjects ( = 2,850) and in a separate replication cohort (656 type 1 diabetes case, 823 LADA case, and 3,218 control subjects). 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 (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. 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.