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.

• Klíčová slova
• Congenic, Genomic, Hypertension, Insulin resistance, Rat,
• MeSH
• celogenomová asociační studie MeSH
• energetický metabolismus genetika   MeSH
• genomika * MeSH
• homeostáza MeSH
• hypertenze genetika   patofyziologie   MeSH
• inzulin farmakologie   MeSH
• inzulinová rezistence genetika   MeSH
• játra účinky léků   metabolismus   MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• kalorimetrie MeSH
• kardiomegalie genetika   patofyziologie   MeSH
• kosterní svaly účinky léků   metabolismus   MeSH
• krevní tlak účinky léků   MeSH
• lidé MeSH
• lokus kvantitativního znaku genetika   MeSH
• potkani inbrední SHR MeSH
• regulace genové exprese účinky léků   MeSH
• savčí chromozomy genetika   MeSH
• srdeční komory účinky léků   patologie   MeSH
• stravovací zvyklosti účinky léků   MeSH
• tělesná hmotnost účinky léků   MeSH
• triglyceridy metabolismus   MeSH
• velikost orgánu účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• inzulin MeSH
• triglyceridy MeSH