Session 9: Big Data

As immunoassays for C-peptide have become more sensitive it has become more apparent that many people with Type 1 diabetes have some degree of residual beta cell function. However the true extent of this across the full range of age of onset and duration of Type 1 diabetes is unclear. Neither is it clear how the genetic determinants of Type 1 diabetes or other clinical features of diabetes relate to this residual function. Whether residual beta cell function alters the clinical course of Type 1 diabetes and the incidence of acute or chronic complications is also unclear. The Scottish Diabetes Research Network Type 1 Bioresource (SDRNT1BIO) is a large (n=6127) collection of biosamples and retrospective and prospective data from a representative sample of people with Type 1 diabetes in Scotland. Participants had a clinical diagnosis of Type 1 diabetes with confirmation of insulin use within a year of onset but with no constraint on age at diagnosis. The cohort has been genotyped and random serum C-peptide (Roche ultrasensitive immunoassay) measured at recruitment. Overall 39% had detectable C-peptide (≥5 pmol/L) with prevalence being highest with older age of onset (p=6.9x10-05) and shorter duration (p=1.8x10-10). Heritability was 0.31 for age at onset and 0.26 for C-peptide adjusted for sex and age at onset. This presentation will summarise the distribution of C-peptide levels by age at onset and duration, will explore genetic associations with C-peptide levels and will summarise the relationship of C-peptide levels to complications in this cohort.

A healthy immune system requires immune cells that adapt rapidly to environmental challenges. This phenotypic plasticity can be mediated by transcriptional and epigenetic variability.
First, I report findings from an epigenome-wide association study in 52 monozygotic twin pairs discordant for type 1 diabetes (T1D) across CD4+ T cells, CD19+ B cells and CD14+CD16− monocytes. We observe a substantial enrichment of differentially variable CpG sites in T1D twins when compared with their healthy co-twins and when compared with healthy, unrelated individuals. Integration with cell type-specific gene regulatory circuits highlight pathways involved in immune cell metabolism and the cell cycle, including mTOR signalling. Evidence from cord blood of newborns who progress to overt T1D suggests that the epigenetic changes likely emerge after birth.
Second, I present results from a genome-wide analysis of transcriptional and epigenetic variability across CD14+CD16− monocytes, CD66b+CD16+ neutrophils and CD4+CD45RA+ naïve T cells from the same 125 healthy individuals. We find increased variability in neutrophils compared to monocytes and T cells. In neutrophils, genes with hypervariable expression are found to be implicated in key immune pathways and are associated with cellular properties and environmental exposure. We also observe increased sex-specific gene expression differences in neutrophils.
Taken together, these large-scale, multi-omics data reveal insights into the cell type-specific molecular events that underpin the risk for immune diseases.