title: Fine-mapping diabetes-related traits, including insulin resistance, in heterogeneous stock rats.
abstract: 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 to 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 index. This region also encompasses 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.
authors.affiliation: Department of Pediatrics, Human and Molecular Genetics Center and Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. lsolberg@mcw.edu
authors.forename: Leah C
authors.initials: LC
authors.lastname: Solberg Woods
authors.forename: Katie L
authors.initials: KL
authors.lastname: Holl
authors.forename: Daniel
authors.initials: D
authors.lastname: Oreper
authors.forename: Yuying
authors.initials: Y
authors.lastname: Xie
authors.forename: Shirng-Wern
authors.initials: SW
authors.lastname: Tsaih
authors.forename: William
authors.initials: W
authors.lastname: Valdar
mesh_terms: D000818:Animals; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D004195:Disease Models, Animal; D005838:Genotype; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D010641:Phenotype; D040641:Quantitative Trait Loci; D051381:Rats; D011912:Rats, Inbred ACI; D011921:Rats, Inbred WKY
chemical_list: D007328:Insulin; D005947:Glucose