243-LB: Characterization and Genetic Validation of Gene Expression Changes across Diabetes Development

Abstract

Type 2 diabetes is a complex and heritable disease. Gene expression is influenced by a number of factors, including genetic and environmental factors as well as disease progression. Yet, the changes in genome-wide transcriptome profiles during diabetic development have not yet been studied. We recruited 58 subjects from Cameron County, Texas, whose fasting glucose was less than 126 mg/dl (mean 106.74 mg/dl). During the follow-up period, 24 subjects' fasting glucose elevated to the diabetes diagnostic level (≥126 mg/dl), and the other 34 subjects’ maintained healthy level (<126 mg/dl). To explore the effect of gene expression, we applied RNA-sequencing to profile the peripheral blood transcriptome at both baseline and follow-up visit for all individuals. We then performed an unsupervised network approach, weighted gene co-expression network analysis, to cluster genes into modules with correlated changes in expression pattern over time. Among 17 identified modules, one showed significant differences in gene expression pattern over time between convert and control groups. This module contains 822 genes, including WDFY3, which accounted for the most variance, and STX3, which exhibited the highest connectivity. In addition, change pattern over time of MIR3605, ASB9P1, NUDT16, and MKNK1-AS1 had the highest correlation with transition status. To validate the function of genes in this interesting module, we examined the association between these 822 genes and diabetes and related metabolism disease via genetically regulated expression in a large electronic health record linked biobank at Vanderbilt University. We found that the genes in this module were significantly enriched with significant association to diabetes mellitus, disorders of pancreatic internal secretion, and disorders of mineral metabolism. In sum, we present a set of genes expression change correlated with diabetes progression, and validated their function on diabetes related disorders in a large biobank. Disclosure H. Chen: None. L.E. Petty: None. J. Mccormick: None. S.P. McCormick: None. E. Gamazon: None. J.E. Below: None.