2012-LB: Type 2 Diabetes GWAS Signal C2CD4A/B Insulin Resistance Mechanisms in Skeletal Muscle

Mechanisms of insulin action differ between fasting and postprandial states across tissues, with postprandial disturbance in insulin action being crucial in the development of type 2 diabetes (T2D). We generated single nucleus (sn-) chromatin accessibility and transcriptome profiles of 287 skeletal muscle biopsies from the FUSION Tissue Biopsy Study. These data found chromatin accessibility quantitative trait loci (caQTL) in muscle fibers colocalized with a T2D GWAS signal and a recently identified C2CD4A/B GWAS signal for insulin fold change (IFC) (coloc PP H4 = 0.969). This chromatin accessibility peak had previously been identified in an islet stretch enhancer and implicated C2CD4A/B in islet dysfunction. However, there has been no formal colocalization with any current islet QTL signals. In our skeletal muscle data, chromatin looping models nominated VPS13C as a candidate target gene. VPS13C encodes a lipid transfer protein. A previous study showed that VPS13C knockdown in an adipocyte cell model decreased insulin-induced translocation and cell-surface abundance of the glucose transporter, GLUT4, thereby implicating this candidate target gene in insulin resistance (IR) mechanisms. We hypothesize that VPS13C modulates IR and T2D risk in skeletal muscle in a cell-type and cell-state-specific manner. We are evaluating the allele-specific activity of the caQTL regulatory element with luciferase reporter assays in the LHCN-M2 human skeletal myoblast cell line. The chromatin looping models predict low contact with the VPS13C transcription start site for the risk allele. Reporter assay results that support this model would suggest a role for VPS13C in glucose uptake mechanisms in skeletal muscle fibers. Moreover, we are generating gene co-expression networks of the sn-transcriptome profiles to identify the network relationships of VPS13C. Collectively, these results will help illuminate the context-specific risk mechanisms at the C2CD4A/B T2D and IR GWAS locus.