A set of circulating microRNAs belonging to the 14q32 chromosomic locus identifies two clinically and phenotypically different subgroups of individuals with recent onset Stage 3 type 1 diabetes

Abstract

SUMMARYPrevious research has indicated that circulating microRNAs are linked to the onset and progression of type 1 diabetes mellitus (T1DM), making them potential biomarkers for the disease. In this study, we employed a multiplatform sequencing approach to analyze circulating microRNAs in an extended cohort of individuals recently diagnosed with T1DM from the European INNODIA consortium. Our findings revealed that a specific set of microRNAs located within the T1DM susceptibility chromosomal locus 14q32 distinguishes two distinct subgroups of T1DM individuals. To validate our results, we conducted additional analyses on a second cohort of T1DM individuals, independently confirming the identification of these two subgroups, which we have named Cluster A and Cluster B. Remarkably, Cluster B T1DM individuals, who exhibited increased expression of 14q32 miRNAs, displayed a different peripheral blood immunomics profile, possessed a lower T1DM risk HLA genotype, and showed better glycaemic control during follow-up visits compared to Cluster A individuals. Taken together, our findings suggest that this specific set of circulating microRNAs located in the 14q32 locus can effectively identify T1DM subgroups with distinct characteristics and different clinical outcomes during follow-up.GRAPHICAL ABSTRACTHIGHLIGHTSCirculating miRNA profiles in individuals with newly diagnosed Type 1 Diabetes Mellitus (T1DM) can distinguish two subgroups: Cluster A and Cluster B.miR-409-3p, miR-127-3p, and miR-382-5p are increased in the plasma of individuals in Cluster B.Individuals in Cluster B showed lower IAA titers, a reduced prevalence of HLA risk genotype, and an improved glycaemic profile during the follow-up period.Immunomic profiling revealed a reduced frequency of pro-inflammatory immune cells and a higher frequency of exhausted T lymphocytes among individuals in Cluster B.