Genetic analysis of metabolic defects in the spontaneously hypertensive rat

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.

Aryl hydrocarbon receptor nuclear translocator-like (BMAL1) is associated with susceptibility to hypertension and type 2 diabetes

“…It is equally possible that Bmal1 variants have been selected in SHR for their roles on the regulation of a broad range of biological processes, including blood pressure (19), and therefore directly underlie hypertension QTL effects. This hypothesis is supported by the fact that the SHR, which is primarily a model of essential hypertension caused by selected naturally occurring variants, is widely accepted as a model of genetically determined metabolic syndrome (29). The relationship between alteration of components of the circadian clock and pathophysiological components of the metabolic syndrome has been clearly established in mice (17,19).…”

“…To test the relevance of BMAL1 polymorphisms to human hypertension and extend the study to the broad context of insulin resistance, which accounts for the spectrum of SHR pathophysiology (29) and the biological function of the gene (17,19), we carried out extensive sequence and SNP analyses in British families ascertained through a T2D proband (30). The National Center for Biotechnology Information dbSNP database, the International HapMap Project SNP database, and our original sequencing data in 96 individuals provided us with 19 SNPs for the initial phase of SNP genotyping.…”

Isolation of a Chromosome 1 Region Affecting Blood Pressure and Vascular Disease Traits in the Stroke-Prone Rat Model

“…In the case of our congenic rats derived from SHRSP/Izm and WKY/Izm, because hypertension and impaired glucose tolerance are attributed to the alternate progenitor alleles, it is plausible that different genes rather than identical genes with pleiotropic effects underlie each of the metabolic traits. Thus far, several QTLs have been reported for metabolic traits and insulin resistance-associated phenotypes in SHR(SR) of NIH-derived colonies, 21,22 whereas a few of them have not been replicated in SHRSR/Izm. 23 The discrepancies may result from potential interstrain diversity that is assumed to exist between SHRSR and SHRSP and/or between SHRSR of different colonies.…”

Novel Integrative Approaches to the Identification of Candidate Genes in Hypertension

“…22 The investigation was facilitated by the availability of the reference BN genome sequence, 4 of tens of thousands of rat SNPs, 23,24 of a dense genetic map, 25,26 and of the previous mapping of more than 70 physiological and pathophysiological phenotypes in this RI panel. 27 The next step in the investigation was to use expression levels in the RI strains as "expression" phenotypes, the transcripts being expression traits. The investigators proceeded with linkage analysis to link these expression phenotypes to QTL, in this case expression QTL (eQTL), which embed transcripts or genes that control the expression of known genes.…”