RGD Reference Report - Fine-mapping diabetes-related traits, including insulin resistance, in heterogeneous stock rats. - Rat Genome Database

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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.
RGD ID: 6893578
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.

Annotation

Disease Annotations    

Phenotype Annotations    
Objects Annotated

QTLs
Bw97  (Body weight QTL 97)
Gluco64  (Glucose level QTL 64)
Insul17  (Insulin level QTL 17)
Insul18  (Insulin level QTL 18)
Insul19  (Insulin level QTL 19)

Strains
ACI/Eur  (August x Copenhagen Irish)
BN/SsNHsd  (NA)
BUF/NHsd  (NA)
M520/N  (NA)
NMcwi:HS  (Heterogeneous stock)
WKY/NHsd  (NA)

Objects referenced in this article
Strain ACI/N A X C 9935, Irish Rattus norvegicus
Strain BUF/N null Rattus norvegicus
Strain WKY/N null Rattus norvegicus

Additional Information