Independent and Pleiotropic Gene Effects on Hypertension and Metabolic Syndrome in Lyon Hypertensive Rats

Abstract

The Lyon Hypertensive (LH) rat is an inbred selection model of spontaneous hypertension. However through the selection and inbreeding of the LH strain for high blood pressure, genes causing salt‐sensitivity and several features of the Metabolic Syndrome (MetS) including obesity and dyslipidemia were also fixed; thus the LH rat is a genetic model of MetS associated hypertension. Conversely, the Lyon Normotensive (LN) control strain is normotensive, salt‐resistant and displays no features of MetS. Both strains were selectively bred from the same outbred Sprague Dawley founders, based on divergent blood pressures, yet their genomes are >99.98% identical. Our overall goal is to identify novel genes and pathways linking disparate phenotypes in MetS. We performed comprehensive systems genetic studies in LH rats and determined that rat chromosome (RNO) 17 contributes not only hypertension but also obesity and dyslipidemia. Genetic mapping studies identified overlapping quantitative trait loci (QTL) for blood pressure, body weight, and plasma lipids on RNO17 in the LH rat. Whole genome sequencing of LH and LN strains revealed large blocks of RNO17 are of shared ancestry; haplotype fine‐mapping refined a list of 26 candidate causal genes. Consomic and congenic studies determined that the whole chromosome substitution of LH RNO17 with that of the LN was sufficient to reduce blood pressure, lipid levels, and body weight. Interestingly, a congenic strain substituting only the distal end of LH RNO17 with the LN allele reduces blood pressure and serum lipids independent of body weight, suggesting both independent and pleiotropic gene effects in LH hypertension. We used RNA‐seq to identify transcriptome differences between LH and LN strains, and to map genetic regulation of gene expression (eQTL). Proximal RNO17 was found to regulate the expression of over 60 genes located elsewhere in the genome (a trans‐eQTL hotspot). A single candidate gene in this locus (RGD1562963), is cis‐regulated, has sequence variation between LH and LN rats, is differentially expressed in multiple tissues between LH and LN, and controls the expression of downstream genes mapping to the trans‐eQTL hotspot that are associated with hypertension and MetS. Our integrative studies suggest that genetic variation in LH RNO17 has independent and pleiotropic effects on hypertension and features of MetS.Support or Funding InformationThis work is supported by NIH grants R01HL089895 and R21DK089417, AHA grant 14GRNT20410043, and the Fraternal Order of Eagles Diabetes Research Center at the University of Iowa.