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Genetic, physiological and comparative genomic studies of hypertension and insulin resistance in the spontaneously hypertensive rat

PM. Coan, O. Hummel, A. Garcia Diaz, M. Barrier, N. Alfazema, PJ. Norsworthy, M. Pravenec, E. Petretto, N. Hübner, TJ. Aitman,

. 2017 ; 10 (3) : 297-306. [pub] 20170126

Language English Country Great Britain

Document type Comparative Study, Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc18016786

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.

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$a 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.
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$a Hummel, Oliver $u Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC), 13125 Berlin, Germany.
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$a Garcia Diaz, Ana $u Department of Medicine, Imperial College London, London SW7 2AZ, UK.
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$a Barrier, Marjorie $u Centre for Genomic and Experimental Medicine & Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH4 2XU, UK.
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$a Alfazema, Neza $u Centre for Genomic and Experimental Medicine & Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH4 2XU, UK.
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$a Norsworthy, Penny J $u MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, UK.
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$a Pravenec, Michal $u Department of Model Diseases, Institute of Physiology, Czech Academy of Sciences, 142 20 Prague, Czech Republic.
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$a Petretto, Enrico $u MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, UK. Duke-NUS Medical School, Singapore 169857, Republic of Singapore.
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$a Hübner, Norbert $u Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC), 13125 Berlin, Germany. DZHK (German Centre for Cardiovascular Research), partner site, 13316 Berlin, Germany. Charité-Universitätsmedizin, 10117 Berlin, Germany.
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$a Aitman, Timothy J $u Centre for Genomic and Experimental Medicine & Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH4 2XU, UK. Department of Medicine, Imperial College London, London SW7 2AZ, UK.
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