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

Autor: Penny J. Norsworthy, Marjorie Barrier, Enrico Petretto, Ana Garcia Diaz, Michal Pravenec, Timothy J. Aitman, Neza Alfazema, P. M. Coan, Norbert Huebner, Oliver Hummel
Jazyk: angličtina
Rok vydání: 2017
Předmět:
0301 basic medicine
Candidate gene
Medicine (miscellaneous)
lcsh:Medicine
Blood Pressure
030204 cardiovascular system & hematology
600 Technik
Medizin
angewandte Wissenschaften::610 Medizin und Gesundheit
0302 clinical medicine
Congenic
Immunology and Microbiology (miscellaneous)
Inbred strain
Rats
Inbred SHR
Homeostasis
Insulin
Genetics
Genomics
Organ Size
Liver
Hypertension
lcsh:RB1-214
Research Article
Heart Ventricles
Quantitative Trait Loci
Neuroscience (miscellaneous)
Locus (genetics)
Cardiomegaly
Quantitative trait locus
Biology
Calorimetry
Polymorphism
Single Nucleotide
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
Spontaneously hypertensive rat
lcsh:Pathology
Animals
Humans
Muscle
Skeletal
Chromosome 12
Triglycerides
lcsh:R
Body Weight
Insulin resistance
Feeding Behavior
Chromosomes
Mammalian
030104 developmental biology
Chromosome 4
Gene Expression Regulation
Cardiovascular and Metabolic Diseases
Genomic
Rat
Energy Metabolism
Genome-Wide Association Study
Zdroj: Disease Models & Mechanisms
Coan, P M, Hummel, O, Diaz, A I G, Barrier, M, Alfazema, N, Norsworthy, P J, Pravenec, M, Petretto, E, Huebner, N & Aitman, T J 2017, ' Genetic, physiological and comparative genomic studies of hypertension and insulin resistance in the spontaneously hypertensive rat ', Disease Models and Mechanisms, vol. 10, no. 3 . https://doi.org/10.1242/dmm.026716
Disease Models & Mechanisms, Vol 10, Iss 3, Pp 297-306 (2017)
DOI: 10.1242/dmm.026716
Popis: 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.
Summary: Comparative genome analyses identify candidate genes for hypertension and insulin resistance on rat chromosomes 12 and 16, and marked enrichment of insulin resistance genes in the syntenic regions of the human genome.
Databáze: OpenAIRE
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