Abstract 478: Biological Pathways Mediating the Effect of a 1.37 Mbp Genomic Region on Salt-Induced Hypertension in the SS Rat

Abstract

Previous analysis of 13 overlapping subcongenic strains led to the identification of a 1.37 Mbp region on chromosome 13 (positions 80.92 to 82.29 Mbp in the Rn5 genome assembly) that influenced the mean arterial blood pressure of the Dahl salt-sensitive (SS) rat on a high-salt diet by more than 20 mmHg. The goal of the present study was to identify biological pathways that could mediate the blood pressure effect of this genomic region. RNA-seq analysis was performed for the renal outer medulla tissue in five selected subcongenic strains, the SS, and a congenic strain from which the subcongenic strains were derived. Rats were fed a 0.4% salt diet or switched to a high-salt diet for 7 days. Affymetrix GeneChip data for SS and three additional congenic or consomic strains were obtained from a previous study. The RNA-seq and microarray data were merged using a cross-platform normalization method to generate a transcriptome dataset containing 90 observations for each gene. A Bayesian model analysis was performed for 243 biological pathways to assess their likelihood to discriminate blood pressure levels across experimental groups. Seven pathways showed posterior probabilities greater than 0.4. These pathways involved neuroactive ligand-receptor interaction, phenylalanine, tyrosine and tryptophan biosynthesis, and protein degradation. A Bayesian approach was used to estimate undirected graphical models among the three known genes located in the 1.37 Mbp region (Astn1, Fam5b, and Rfwd2) and genes in each of the 7 pathways identified above and 11 additional pathways known to be involved in blood pressure regulation. The analysis identified several previously unknown relationships between the three candidate genes and genes in pathways that could regulate blood pressure. The study demonstrated a new, unbiased approach for identifying biological pathways mediating the effect of a candidate genomic region on hypertension.