Genetic Insights into Latent Autoimmune Diabetes in Adults

‘Latent autoimmune diabetes in adults’ (LADA) is a controversial subtype of diabetes characterized by initial insulin independency and the presence of diabetes associated autoantibodies. As a result, LADA is often misclassified and can represent 5–10% of apparent type 2 diabetes (T2D) cases and is potentially more prevalent than childhood-onset type 1 diabetes (T1D). Despite LADA sharing features with the two better characterized classic diabetes subtypes, the genetic etiology of LADA remains largely unknown. Once there is a more accurate definition of LADA, there will be an improvement in diabetes classification and consequently better treatment and therapeutic interventions. The objective of this thesis is to understand the genetic basis of LADA in order to bring clarity to the current definition of LADA by being the first to leverage genome-wide genotype data from a LADA cohort and the subsequent application of statistical genetics approaches. These investigations can be divided into three parts: 1) the role of T1D and T2D loci in LADA 2) the first genome-wide association study (GWAS) of LADA, and 3) searching for genetic discrepancies between LADA and childhood-onset T1D in the human leukocyte antigen (HLA) region. Four out of the five strongest associations from the candidate locus study were known T1D loci (HLA, PTPN22, INS and SH2B3) and reached genome-wide significance in the GWAS meta-analysis. However, a novel independent signal at a known T1D locus was also observed to be genome-wide significant, near the PFKFB3 gene, which had not been implicated in previous T1D or T2D GWAS. Additionally, major T1D-susceptibility HLA haplotypes were observed to be less frequent in LADA. Furthermore, contrary to observations in childhood-onset T1D studies, HLA-B and HLA-A, were not significantly associated with LADA, independent of HLA-DQB1 and HLA-DRB1 haplotypes. Overall, the genetics of LADA point to a strong T1D component, but a positive genetic correlation between LADA and T2D is also evident, strongly suggesting LADA has both a T1D and T2D component. However, it remains unresolved whether LADA is at the genetic intersection of T1D and T2D or simply a mixture of relatively poorly phenotyped individuals who have either T1D or T2D