Genetic analysis of metabolic defects in the spontaneously hypertensive rat |
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Authors: | Michal Pravenec Václav Zídek Alena Musilová Miroslava Simáková Vlastimil Kostka Petr Mlejnek Vladimír Kren Drahomíra Krenova Vlasta Bílá Blanka Míková Marie Jáchymová Karel Horký Ludmila Kazdová Elizabeth St Lezin Theodore W Kurtz |
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Institution: | (1) Institute of Physiology, Czech Academy of Science, Vídenska 1083, 14220 Prague, Czech Republic, CS;(2) Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, 12800 Prague, Czech Republic, CS;(3) General Faculty Hospital, 1st Medical Faculty, Charles University, 12000 Prague, Czech Republic, CS;(4) Institute of Clinical and Experimental Medicine, 14000 Prague, Czech Republic, CS;(5) Department of Laboratory Medicine, University of California and Department of Veterans Affairs Medical Center, San Francisco, California 94143, USA, US |
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Abstract: | Abnormalities in carbohydrate and lipid metabolism are common in patients with essential hypertension and in the spontaneously
hypertensive rat (SHR). To identify chromosome regions contributing to this clustering of cardiovascular risk factors in the
SHR, we searched for quantitative trait loci (QTL) associated with insulin resistance, glucose intolerance, and dyslipidemia
by using the HXB/BXH recombinant inbred (RI) strains. Analysis of variance in RI strains suggested significant effects of
genetic factors. A genome screening of the RI strains with more than 700 markers revealed QTL significantly associated with
insulin resistance on Chromosomes (Chrs) 3 and 19. The Chr 19 QTL was confirmed by testing a previously derived SHR-19 congenic
strain: transfer of a Chr 19 segment delineated by markers D19Rat57 and D19Mit7 from the Brown Norway (BN/Cr) strain onto the genetic background of the SHR/Ola was associated with decreased insulin and
glucose concentrations and ameliorated insulin resistance at the tissue level. These findings suggest that closely linked
genes on Chr 19, or perhaps even a single gene with pleiotropic effects, influence the clustering of metabolic disturbances
in the SHR-BN model. |
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