Fine-mapping diabetes-related traits, including insulin resistance, in heterogeneous stock rats.

Authors: Solberg Woods, LC  Holl, KL  Oreper, D  Xie, Y  Tsaih, SW  Valdar, W 
Citation: Solberg Woods LC, etal., Physiol Genomics. 2012 Sep 4.
Pubmed: (View Article at PubMed) PMID:22947656
DOI: Full-text: DOI:10.1152/physiolgenomics.00040.2012

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 measures of insulin resistance and insulin secretion in 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). A separate <3 Mb QTL was identified for body weight. Using a novel penalized regression method we then estimated effects of alternative haplotype pairings under each locus. These studies highlight the utility of HS rats for fine-mapping genetic loci involved in the underlying causes of T2D.

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RGD ID: 6893578
Created: 2012-09-10
Species: All species
Last Modified: 2012-09-10
Status: ACTIVE