Poster 29
Presenter: Leah Solberg Woods
Wednesday, 3:00 – 5:00pm
Leah C Solberg Woods1, Katie L Holl1, Daniel Oreper2, Yuying Xie2, Shirng-Wern Tsaih1, and William Valdar2 1Medical College of Wisconsin, 2University of North Carolina at Chapel Hill
Type 2 diabetes (T2D) is a disease of relative insulin deficiency resulting from both insulin resistance and beta cell failure. We have previously used heterogeneous stock (HS) rats to fine-map a locus for glucose tolerance. We show here that glucose intolerance in the founder strains of the HS colony is mediated by different mechanisms: insulin resistance in WKY and an insulin secretion defect in ACI, and we demonstrate a high degree of variability for these measures in the HS rats. As such, our goal was to use HS rats to fine-map several diabetes-related traits within a region on rat chromosome 1. We measured blood glucose and plasma insulin levels after a glucose tolerance test in 782 male HS rats. Using 97 SSLP markers, we genotyped a 68 Mb region on rat chromosome 1 previously implicated in glucose and insulin regulation. We used linkage disequilibrium mapping by mixed model regression with inferred descent to identify a region from 198.85 – 205.9 that contains one or more quantitative trait loci (QTL) for fasting insulin and a measure of insulin resistance, the quantitative insulin sensitivity check (QUICKI). This region also encompasses smaller loci identified for fasting glucose and Insulin_AUC (Area Under the Curve). Using a novel penalized regression method we then estimated effects of alternative haplotype pairings under each locus. Preliminary results using expression analysis and founder sequence indicate a potential candidate gene within this region. These studies highlight the utility of HS rats for fine-mapping genetic loci involved in the underlying causes of T2D.