Isolation of a Genomic Region Affecting Most Components of Metabolic Syndrome in a Chromosome-16 Congenic Rat Model

Abstract

Metabolic syndrome is a highly prevalent human disease with substantial genomic and environmental components. Previous studies indicate the presence of significant genetic determinants of several features of metabolic syndrome on rat chromosome 16 (RNO16) and the syntenic regions of human genome. We derived the SHR.BN16 congenic strain by introgression of a limited RNO16 region from the Brown Norway congenic strain (BN-Lx) into the genomic background of the spontaneously hypertensive rat (SHR) strain. We compared the morphometric, metabolic, and hemodynamic profiles of adult male SHR and SHR.BN16 rats. We also compared in silico the DNA sequences for the differential segment in the BN-Lx and SHR parental strains. SHR.BN16 congenic rats had significantly lower weight, decreased concentrations of total triglycerides and cholesterol, and improved glucose tolerance compared with SHR rats. The concentrations of insulin, free fatty acids, and adiponectin were comparable between the two strains. SHR.BN16 rats had significantly lower systolic (18–28 mmHg difference) and diastolic (10–15 mmHg difference) blood pressure throughout the experiment (repeated-measures ANOVA, P < 0.001). The differential segment spans approximately 22 Mb of the telomeric part of the short arm of RNO16. The in silico analyses revealed over 1200 DNA variants between the BN-Lx and SHR genomes in the SHR.BN16 differential segment, 44 of which lead to missense mutations, and only eight of which (in Asb14, Il17rd, Itih1, Syt15, Ercc6, RGD1564958, Tmem161a, and Gatad2a genes) are predicted to be damaging to the protein product. Furthermore, a number of genes within the RNO16 differential segment associated with metabolic syndrome components in human studies showed polymorphisms between SHR and BN-Lx (including Lpl, Nrg3, Pbx4, Cilp2, and Stab1). Our novel congenic rat model demonstrates that a limited genomic region on RNO16 in the SHR significantly affects many of the features of metabolic syndrome.

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

“…Our study provides a complementary view to a recently published study by Sedova et al (2016) , which carried out blood pressure and metabolic testing and an appraisal of SNVs on a single SHR congenic strain for chromosome 16. Although these two studies highlight some genes in common (such as the plausible candidates Lpl and Gatad2a ), our study, of congenic strains on chromosomes 12 and 16, was carried out in linkage regions to adipocyte insulin resistance that we had defined previously.…”

Single-Gene Congenic Strain Reveals the Effect of Zbtb16 on Dexamethasone-Induced Insulin Resistance

“…1641851) strains were maintained at the Institute of Medical Biology and Genetics, Charles University in Prague. To derive SHR- Lx .PD5 PD- Zbtb16 and SHR- Lx .PD5 SHR- Zbtb16 congenic strains, a marker-assisted backcross breeding approach was used, as described previously ( 12 , 22 , 23 ). In short, SHR rats were crossed with SHR- Lx .PD5 rats, and the subsequent F1 hybrids were repeatedly backcrossed to SHR.…”

Spontaneously Hypertensive Rat Chromosome 2 with Mutant Connexin 50 Triggers Divergent Effects on Metabolic Syndrome Components

“…2293729) strains are maintained at the Institute of Medical Biology and Genetics, Charles University in Prague. In order to derive the BN-Dca congenic strain and the BN-Lx.Dca double-congenic strain, we employed the marker-assisted backcross breeding approach as described previously (Seda et al, 2002;Šedová et al, 2012;Sedova et al, 2016). In short, the SHR-Dca rats were crossed with the other progenitor strain, i.e., BN/Cub or BN-Lx, for derivation of BN-Dca and BN-Lx.Dca, respectively.…”