title: Dissecting the genetic components of a quantitative trait locus for blood pressure and renal pathology on rat chromosome 3.
abstract: We have previously confirmed the importance of rat chromosome 3 (RNO3) genetic loci on blood pressure elevation, pulse pressure (PP) variability and renal pathology during salt challenge in the stroke-prone spontaneously hypertensive (SHRSP) rat. The aims of this study were to generate a panel of RNO3 congenic sub-strains to genetically dissect the implicated loci and identify positional candidate genes by microarray expression profiling and analysis of next-generation sequencing data.
  
  
  
  A panel of congenic sub-strains were generated containing Wistar-Kyoto (WKY)-introgressed segments of varying size on the SHRSP genetic background, focused within the first 50 Mbp of RNO3. Haemodynamic profiling during salt challenge demonstrated significantly reduced systolic blood pressure, diastolic blood pressure and PP variability in SP.WKYGla3a, SP.WKYGla3c, SP.WKYGla3d and SP.WKYGla3e sub-strains. Only SBP and DBP were significantly reduced during salt challenge in SP.WKYGla3b and SP.WKYGla3f sub-strains, whereas SP.WKYGla3g rats did not differ in haemodynamic response to SHRSP. Those sub-strains demonstrating significantly reduced PP variability during salt challenge also demonstrated significantly reduced renal pathology and proteinuria. Microarray expression profiling prioritized two candidate genes for blood pressure regulation (Dnm1, Tor1b), localized within the common congenic interval shared by SP.WKYGla3d and SP.WKYGla3f strains, and one candidate gene for salt-induced PP variability and renal pathology (Rabgap1), located within the region unique to the SP.WKYGla3d strain. Comparison of next-generation sequencing data identified variants within additional positional genes that are likely to affect protein function.
  
  
  
  This study has identified distinct intervals on RNO3-containing genes that may be important for blood pressure regulation and renal pathology during salt challenge.
authors.affiliation: aInstitute of Cardiovascular & Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK bDepartment of Anatomical Pathology, Pathology North (Hunter), John Hunter Hospital, New Lambton, New South Wales, Australia.
authors.forename: H H Caline
authors.initials: HH
authors.lastname: Koh-Tan
authors.forename: Mohammed
authors.initials: M
authors.lastname: Dashti
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.forename: Wendy
authors.initials: W
authors.lastname: Beattie
authors.forename: John
authors.initials: J
authors.lastname: Mcclure
authors.forename: Barbara
authors.initials: B
authors.lastname: Young
authors.forename: Anna F
authors.initials: AF
authors.lastname: Dominiczak
authors.forename: Martin W
authors.initials: MW
authors.lastname: McBride
authors.forename: Delyth
authors.initials: D
authors.lastname: Graham
mesh_terms: D000818:Animals; D020296:Animals, Congenic; D001794:Blood Pressure / Q000235:genetics*; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian; D034284:Dynamin I / Q000235:genetics*; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006973:Hypertension / Q000235:genetics* / Q000473:pathology; D007668:Kidney / Q000378:metabolism; D008297:Male; D018832:Molecular Chaperones / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D040641:Quantitative Trait Loci; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017422:Sequence Analysis, DNA; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage; D020521:Stroke / Q000473:pathology
chemical_list: D018832:Molecular Chaperones; D017673:Sodium Chloride, Dietary; C000622666:Tor1b protein, rat; D034284:Dynamin I