Statistical and Functional Characterization of Genetic Loci Associated with Metabolic Syndrome for Therapeutic Development 35 views

MetSyn is a cluster of five conditions strongly influenced by genetic and lifestyle factors: hypertension, elevated abdominal obesity, insulin resistance, elevated blood triglyceride levels, and low high-density lipoprotein cholesterol (HDL-C) levels. MetSyn is a major risk factor for type 2 diabetes (T2D). Both T2D and MetSyn have a heritable component to disease risk; therefore, genomic loci associated with these traits can be identified with genome-wide association studies (GWAS). Moving from association to functional annotation of a GWAS signal is not trivial; GWAS signals often lie in non-coding regions of the genome with tissue-specific and cellular-specific regulatory function. Understanding the genetic basis of complex disorders like MetSyn is critical for the prevention and development of novel treatment approaches for T2D. In this dissertation, we investigate the mechanisms of action at genetic loci associated with MetSyn traits. Chapter 1 summarizes the role of various adipose tissue depots, sexual dimorphism, models of adipose tissue function, and the genetics of MetSyn traits. In Chapter 2, we use statistical genetic approaches to identify genetic loci that contain significant associations for increased abdominal obesity but protection from type 2 diabetes. We predict candidate effector genes that mediate these genetic associations, and compile evidence of tissue-specific contributions and physiological correlates of gene expression. In Chapter 3, we study the potential of adipose-specific overexpression of transcription factor Krüppel-like factor 14 (KLF14) for MetSyn. We employ a transgenic mouse model to investigate the protective effects of KLF14 adipose-specific overexpression on weight, body composition, insulin and glucose resistance, whole-body metabolism, and serum lipid levels. We investigate potential molecular mediators of these phenotypes. In Chapter 4, we nominate an adipocyte-specific gene as a target for adipocyte-specific drug delivery. We use publicly available data to prioritize a commonly expressed adipocyte marker and use flow cytometry to validate its protein presence on the surface of adipocytes. In Chapter 5, we put our results in the context of the larger body of work surrounding MetSyn genetics. We discuss potential strategies for KLF14-based therapeutics, mediators of metabolically healthy obesity, and the future of the field.

PHD (Doctor of Philosophy)

metabolism; functional genomics; biomedical engineering; drug delivery; adipose tissue; sex differences

English

2025-07-21