Dissecting the genetic components of a quantitative trait locus for blood pressure and renal pathology on rat chromosome 3

Koh-Tan, H.H. C., Dashti, M., Wang, T., Beattie, W., Mcclure, J. , Young, B., Dominiczak, A. F. , McBride, M. W. and Graham, D. (2017) Dissecting the genetic components of a quantitative trait locus for blood pressure and renal pathology on rat chromosome 3. Journal of Hypertension, 35(2), pp. 319-329. (doi:10.1097/HJH.0000000000001155) (PMID:27755386) (PMCID:PMC5214373)

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Abstract

Background: 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. Method and results: 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. Conclusion: This study has identified distinct intervals on RNO3-containing genes that may be important for blood pressure regulation and renal pathology during salt challenge.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Young, Dr Barbara and Graham, Dr Delyth and McBride, Dr Martin and Dominiczak, Professor Anna and Beattie, Mrs Wendy and Koh-Tan, Dr Han Hui and McClure, Dr John
Authors: Koh-Tan, H.H. C., Dashti, M., Wang, T., Beattie, W., Mcclure, J., Young, B., Dominiczak, A. F., McBride, M. W., and Graham, D.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Journal of Hypertension
Publisher:Lippincott Williams & Wilkins
ISSN:0263-6352
ISSN (Online):1473-5598
Published Online:17 October 2016
Copyright Holders:Copyright © 2017 Wolters Kluwer Health, Inc.
First Published:First published in Journal of Hypertension 35(2): 319-329
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
464051Genomics and proteomics of hypertension and its vascular complications: the pathwayomic strategies.Anna DominiczakBritish Heart Foundation (BHF)RG/07/005/23633RI CARDIOVASCULAR & MEDICAL SCIENCES
302341Cardiovascular Functional genomics - Translating experimental work to human diseaseAnna DominiczakWellcome Trust (WELLCOME)066780/Z/01/ZRI CARDIOVASCULAR & MEDICAL SCIENCES
515251EuratransAnna DominiczakEuropean Commission (EC)241504RI CARDIOVASCULAR & MEDICAL SCIENCES