Date of Completion
Massively Parallel Reporter Assay (MPRA), human pancreatic islets, MIN6 beta cells, chromatin accessibility, ATAC-seq, chromatin accessibility quantitative trait locus (caQTLs), genome-wide association study (GWAS), single nucleotide polymorphism (SNP), Type 2 diabetes (T2D), endoplasmic reticulum (ER) stress, short interspersed nuclear elements (SINEs), Alu elements.
Field of Study
Doctor of Philosophy
Type 2 diabetes (T2D) results when pancreatic beta cells are unable to secrete adequate amounts of insulin in response to elevated blood glucose levels. Genome-wide association studies (GWAS) have linked single nucleotide polymorphisms (SNPs) in >250 regions of the human genome to a higher risk for developing T2D. These T2D-associated GWAS SNPs are predominantly non-coding (~90%) and enriched at islet regulatory elements, implicating altered transcriptional regulation in islets as a molecular mechanism underlying T2D risk. However, the sharp rise in T2D incidence over the past few decades cannot be attributed to changes in the human genome, but our environment, such as rising overnutrition and pollution levels. Therefore, T2D is a multifactorial disorder with both genetic and environmental components risk factors. In order to elucidate the mechanistic link between non-coding SNPs and a complex trait like T2D, we first identified functional SNPs among the 10s-100s that are in linkage disequilibrium (LD) at any given T2D-associated GWAS signal. We then show that endoplasmic reticulum (ER) stress in beta cells is an important environmental context for the genetic risk of T2D. ER folding capacity, therefore, may be a major factor determining how much insulin can be released by beta cells before stress ensues. SNPs at regulatory elements modulating the expression of genes relevant to meet higher demands for insulin synthesis may impair or improve ER capacity, ultimately determining the threshold at which ER stress ensues, leading to beta cell failure and T2D.
Khetan, Shubham, "Deciphering Type 2 Diabetes-associated SNP Effects on Islet Chromatin Accessibility and Beta Cell Expression Levels Using Functional Genomics" (2020). Doctoral Dissertations. 2608.