We previously mapped hypertension-related insulin resistance quantitative trait loci (QTLs) to rat chromosomes 4, 12 and 16 using adipocytes from F2 crosses between spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats, and subsequently identified Cd36 as the gene underlying the chromosome 4 locus. The identity of the chromosome 12 and 16 genes remains unknown. To identify whole-body phenotypes associated with the chromosome 12 and 16 linkage regions, we generated and characterised new congenic strains, with WKY donor segments introgressed onto an SHR genetic background, for the chromosome 12 and 16 linkage regions. We found a >50% increase in insulin sensitivity in both the chromosome 12 and 16 strains. Blood pressure and left ventricular mass were reduced in the two congenic strains consistent with the congenic segments harbouring SHR genes for insulin resistance, hypertension and cardiac hypertrophy. Integrated genomic analysis, using physiological and whole-genome sequence data across 42 rat strains, identified variants within the congenic regions in Upk3bl, RGD1565131 and AABR06087018.1 that were associated with blood pressure, cardiac mass and insulin sensitivity. Quantitative trait transcript analysis across 29 recombinant inbred strains showed correlation between expression of Hspb1, Zkscan5 and Pdgfrl with adipocyte volume, systolic blood pressure and cardiac mass, respectively. Comparative genome analysis showed a marked enrichment of orthologues for human GWAS-associated genes for insulin resistance within the syntenic regions of both the chromosome 12 and 16 congenic intervals. Our study defines whole-body phenotypes associated with the SHR chromosome 12 and 16 insulin-resistance QTLs, identifies candidate genes for these SHR QTLs and finds human orthologues of rat genes in these regions that associate with related human traits. Further study of these genes in the congenic strains will lead to robust identification of the underlying genes and cellular mechanisms.

• MeSH
• Genome-Wide Association Study MeSH
• Energy Metabolism genetics   MeSH
• Genomics * MeSH
• Homeostasis MeSH
• Hypertension genetics   physiopathology   MeSH
• Insulin pharmacology   MeSH
• Insulin Resistance genetics   MeSH
• Liver drug effects   metabolism   MeSH
• Polymorphism, Single Nucleotide genetics   MeSH
• Calorimetry MeSH
• Cardiomegaly genetics   physiopathology   MeSH
• Muscle, Skeletal drug effects   metabolism   MeSH
• Blood Pressure drug effects   MeSH
• Humans MeSH
• Quantitative Trait Loci genetics   MeSH
• Rats, Inbred SHR MeSH
• Gene Expression Regulation drug effects   MeSH
• Chromosomes, Mammalian genetics   MeSH
• Heart Ventricles drug effects   pathology   MeSH
• Feeding Behavior drug effects   MeSH
• Body Weight drug effects   MeSH
• Triglycerides metabolism   MeSH
• Organ Size drug effects   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH