title: Genetic, physiological and comparative genomic studies of hypertension and insulin resistance in the spontaneously hypertensive rat.
abstract: 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 identifiedCd36as 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 inUpk3bl,RGD1565131andAABR06087018.1that were associated with blood pressure, cardiac mass and insulin sensitivity. Quantitative trait transcript analysis across 29 recombinant inbred strains showed correlation between expression ofHspb1,Zkscan5andPdgfrlwith 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.
authors.affiliation: Centre for Genomic and Experimental Medicine & Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH4 2XU, UK p.m.coan.02@cantab.net.
authors.forename: Philip M
authors.identifier: 0000-0001-6158-380X
authors.initials: PM
authors.lastname: Coan
authors.affiliation: Cardiovascular and Metabolic Sciences, Max-Delbrück-Center for Molecular Medicine (MDC), 13125 Berlin, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Hummel
authors.affiliation: Department of Medicine, Imperial College London, London SW7 2AZ, UK.
authors.forename: Ana
authors.initials: A
authors.lastname: Garcia Diaz
authors.affiliation: Centre for Genomic and Experimental Medicine & Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Barrier
authors.affiliation: Centre for Genomic and Experimental Medicine & Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Neza
authors.initials: N
authors.lastname: Alfazema
authors.affiliation: MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, UK.
authors.forename: Penny J
authors.initials: PJ
authors.lastname: Norsworthy
authors.affiliation: Department of Model Diseases, Institute of Physiology, Czech Academy of Sciences, 142 20 Prague, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Pravenec
authors.affiliation: MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, UK.|Duke-NUS Medical School, Singapore 169857, Republic of Singapore.
authors.forename: Enrico
authors.initials: E
authors.lastname: Petretto
authors.affiliation: 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.
authors.forename: Norbert
authors.initials: N
authors.lastname: Hübner
authors.affiliation: 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.
authors.forename: Timothy J
authors.identifier: 0000-0002-7875-4502
authors.initials: TJ
authors.lastname: Aitman
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002151:Calorimetry; D006332:Cardiomegaly / Q000235:genetics / Q000503:physiopathology; D033481:Chromosomes, Mammalian / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics; D005247:Feeding Behavior / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D055106:Genome-Wide Association Study; D023281:Genomics; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D006706:Homeostasis; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000503:physiopathology*; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D011918:Rats, Inbred SHR; D014280:Triglycerides / Q000378:metabolism
chemical_list: D007328:Insulin; D014280:Triglycerides
keywords: Congenic; Genomic; Hypertension; Insulin resistance; Rat