Genetic Discrimination between LADA and Type 1 Diabetes within the MHC

• Published in: Human heredity Vol. 83; no. 1; p. 47
• Main Authors: Mishra, R, Bradfield, JP, Cousminer, DL, Chesi, A, Hodge, KM, Hakonarson, H, Mauricio, D, Schloot, NC, Yderstræde, KB, Voight, B, Schwartz, S, Boehm, BO, Leslie, RDG, Grant, SFA
• Format: Journal Article
• Language: English
• Published: Basel S. Karger AG 01.06.2018
• Subjects: Autoimmune diseases; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Diabetes mellitus (non-insulin dependent); Drb1 protein; Etiology; Genome-wide association studies; Genomes; Histocompatibility antigen HLA; Major histocompatibility complex; Regression analysis
• ISSN: 0001-5652; 1423-0062

Studies on type 1 diabetes (T1D) and type 2 diabetes have revealed significant insights into novel biological mechanisms underlying diabetes, yet the genetic etiology of latent autoimmune diabetes in adults (LADA) remains largely unknown; furthermore, improved biomarkers of LADA are required to optimize diagnosis. Our genome-wide association study shows that the major histocompatibility complex (MHC) harbors the strongest association with LADA; however, the association is attenuated compared to observations in T1D cohorts. While T1D susceptibility has been known to be principally harbored within the MHC Class II genes HLA-DQB1 and HLA-DRB1, variation in the MHC class I genes HLA-A and HLA-B have been subsequently shown, through conditional analysis, to increase T1D risk further. We attempted recapitulation of findings in Nejentsev et al. using an imputation-based approach and performing forward stepwise conditional logistic regression of the MHC region in T1D cases (n = 1,990) and controls (n = 2,856) from the Wellcome Trust Case Control Consortium (WTCCC), and in a LADA cohort (n = 978) using populationbased controls (n = 1,057). We confirmed the strongest T1D associations at HLA-DRB1 and HLA-DQB1 (P = 6.10x10–175 and P = 2.90x10–219, respectively), as well as the independent effect of HLA-B (P = 1.67x10–14) and HLA-A (P = 5.25x10–8) to T1D. We then performed the conditional analysis in the LADA and population-based controls cohort, observing significant association at HLA-DRB1 and HLA-DQB1 (P = 5.93x10–22 and P = 4.68x10–13, respectively), however we did not observe significant independent effects in HLA-B or HLA-A for LADA, highlighting a potential use for MHC Class I markers in differentiating T1D from LADA.