New genetic characteristics of latent autoimmune diabetes in adults (LADA)

Latent autoimmune diabetes in adults (LADA) is assigned to a subtype of immune-mediated type 1 diabetes (T1DM) according to the typing method for diabetes of WHO in 1999 which shares clinical features of T1DM and type 2 diabetes (T2DM). The association of LADA with T1DM and T2DM still remains unclear and the precise definition of LADA has always been controversial (1,2). There have been some genetic studies on LADA that are directed at a limited number of candidate genes that support the role of risk loci in the pathogenesis of T1DM and T2DM (1,3-5). The study entitled “First Genome-Wide Association Study of Latent Autoimmune Diabetes in Adults Reveals Novel Insights Linking Immune and Metabolic Diabetes” published online in Diabetes Care of September 25, 2018 is the first genome-wide association study (GWAS) for LADA, making the genetic characteristics of LADA more clear (6). The study included multiple cohorts of European descent from Denmark, Sweden and so on. The inclusion and exclusion criteria for LADA, T1DM, T2DM and population control subjects varied by cohort. In general, LADA was defined by an age older than 20, 30, or 35 years, while some cohorts setting the upper age limit to 70 years; the existence of diabetes associated autoimmune auto antibodies, especially GAD autoantibody (GADA) positivity; and the lack of insulin requirement for half of a year or one year after diagnosis. In some cohorts, C-peptide level was also applied as a filter. A variety of efficient and reliable analysis methods were adopted in this research including meta-analysis, signal path enrichment analysis, condition analysis, stratified analysis, regression analysis and HLA interpolation analysis. A meta-analysis was first performed in LADA patients versus healthy subjects (n=2,634 vs. 5,947) and it was found that four signals reached genome-wide significance (P<5×10？8), all of which at the identified T1DM risk loci (HLA, PTPN22, INS and SH2B3). Signal pathway analysis supported the important role of immunity in the pathogenesis of LADA (P<10？5). Further gene enrichment analysis revealed that physiological abnormalities were associated with cytotoxic T cells (P=6.39×10？7), mTOR regulatory network (P=6.03×10？5), cell cycle (P=1.67×10？5), natural killer cells and T lymphocytes (P=0.0079 and 0.0082, respectively)