title: Refined mapping of blood pressure quantitative trait loci using congenic strains developed from two genetically hypertensive rat models.
abstract: Previously linkage and substitution mapping were conducted between the Dahl Salt-sensitive (S) rat and the Spontaneously Hypertensive Rat (SHR) to address the hypothesis that genetic contributions to blood pressure (BP) in two genetically hypertensive rat strains are different. Among the BP quantitative trait loci (QTLs) detected, two are located on chromosome 9 within large genomic segments. The goal of the current study was to develop new iterations of congenic substrains, to further resolve both of these BP QTLs on chromosome 9 as independent congenic segments. A total of 10 new congenic substrains were developed and characterized. The newly developed congenic substrains S.SHR(9)x8Ax11A and S.SHR(9)x10Ax1, with introgressed segments of 2.05 and 6.14 Mb, represented the shortest genomic segments. Both of these congenic substrains, S.SHR(9)x8Ax11A and S.SHR(9)x10Ax1 lowered BP of the S rat by 56 mm Hg (P<0.001) and 15 mm Hg (P<0.039), respectively. The BP measurements were corroborated by radiotelemetry. Urinary protein excretion was significantly lowered by SHR alleles within S.SHR(9)x10Ax1 but not by S.SHR(9)x8Ax11A. The shorter of the two congenic segments, 2.05 Mb was further characterized and found to contain a single differentially expressed protein-coding gene, Tomoregulin-2 (Tmeff2). The protein expression of Tmeff2 was higher in the S rat compared with S.SHR(9)x8Ax11A, which also had lower cardiac hypertrophy as measured by echocardiography. Tmeff2 is known to be upregulated in patients from multiple cohorts with cardiac hypertrophy. Taken together, Tmeff2 can be prioritized as a candidate gene for hypertension and associated cardiac hypertrophy in both rats and in humans.
authors.affiliation: Physiological Genomics Laboratory, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA.
authors.forename: Sivarajan
authors.initials: S
authors.lastname: Kumarasamy
authors.forename: Kathirvel
authors.initials: K
authors.lastname: Gopalakrishnan
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Toland
authors.forename: Shane
authors.initials: S
authors.lastname: Yerga-Woolwine
authors.forename: Phyllis
authors.initials: P
authors.lastname: Farms
authors.forename: Eric E
authors.initials: EE
authors.lastname: Morgan
authors.forename: Bina
authors.initials: B
authors.lastname: Joe
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D020296:Animals, Congenic; D001794:Blood Pressure / Q000235:genetics* / Q000502:physiology*; D015153:Blotting, Western; D001835:Body Weight / Q000235:genetics / Q000502:physiology; D002874:Chromosome Mapping; D004247:DNA / Q000235:genetics; D004452:Echocardiography; D056426:Genetic Loci / Q000235:genetics*; D006973:Hypertension / Q000235:genetics* / Q000503:physiopathology*; D008562:Membrane Glycoproteins / Q000235:genetics*; D018895:Microsatellite Repeats; D009929:Organ Size / Q000235:genetics / Q000502:physiology; D011507:Proteinuria / Q000235:genetics; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D051381:Rats; D020303:Rats, Inbred Dahl; D011918:Rats, Inbred SHR; D060888:Real-Time Polymerase Chain Reaction; D016019:Survival Analysis; D013686:Telemetry; D016277:Ventricular Function, Left
chemical_list: D008562:Membrane Glycoproteins; C571348:tomoregulin-2, rat; D012313:RNA; D004247:DNA