Abstract 617: The Consomic LH-17LN Rat Is A Single Chromosome Model Of Metabolic Syndrome
The Lyon Hypertensive (LH) rat is an inbred model of Metabolic Syndrome, exhibiting spontaneous hypertension, high body weight, high plasma lipids, altered insulin:glucose ratio. The Lyon Normotensive (LN) control strain, selectively bred for normal blood pressure from the same Sprague Dawley (SD) colony, is genetically quite similar to the LH, but displays no features of MetS. Genetic mapping in an LHxLN cross determined that all of the MetS phenotypes mapped to rat chromosome (RNO 17). In order to identify the gene(s) causing MetS on RNO17 we generated a consomic strain (LH-17LN) where the LH RNO17 was replaced with that of the LN strain. Substitution of the single chromosome was sufficient to significantly lower blood pressure lower systolic blood pressure (145 + 2 vs. 161 + 2 mmHg; p<0.05), body weight (408 + 6 vs 453 + 5 g; p<0.05), and plasma cholesterol (2.5 ± 0.1 vs 2.9 ± 0.08; p<0.05) compared to the LH parental strain. To identify putative causal genes for MetS, we fine-mapped RNO17 in silico utilizing the genome sequence of the LH and LN rat strains. The genomes of the LH and LN strains are highly similar, differing by <0.02% at the sequence level (in comparison, humans typically differ by about 1%). Moreover, we have shown that the variants cluster into <500 divergent haplotype blocks with an average length of 880 kb, which are presumed to contain the genetic variation causing the phenotypic variation between the LH and LN strains. On RNO17 there are just 14 divergent haplotypes, containing 11 genes with coding sequence differences in the LH. The combined in vivo and in silico approaches allowed for the identification of candidate causal variants for the phenotypes on RNO17 and will be studied further to determine their role(s) in MetS.
Author Disclosures: J. Ma: None. J.M. Pettus: None. J. Jakoubek: None. A.E. Kwitek: None.
- © 2014 by American Heart Association, Inc.