Genetically hypertensive Brown Norway congenic rat strains suggest intermediate traits underlying genetic hypertension

Marijo Bilušić, Carol Moreno, Nadia E. Barreto, Michael R. Tschannen, Eugenie L. Harris, William K. Porteous, Caryn M. Thompson, Murray R. Grigor, Alan Weder, Eric Boerwinkle, Steven Hunt, J. David Curb, Howard J. Jacob, Anne E. Kwitek

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Aim: To determine the independent and combined effects of three quantitative trait loci (QTL) for blood pressure in the Genetically Hypertensive (GH/Omr) rat by generating and characterizing single and combined congenic strains that have QTL on rat chromosomes (RNO) 2, 6, and 18 from the GH rat introduced into a hypertension resistant Brown Norway (BN) background. Methods: Linkage analysis and QTL identification (genome wide QTL scan) were performed with MapMaker/EXP to build the genetic maps and MapMaker/QTL for linking the phenotypes to the genetic map. The congenic strains were derived using marker-assisted selection strategy from a single male F1 offspring of an intercross between the male GH/Omr and female BN/Elh, followed by 10 generations of selective backcrossing to the female BN progenitor strain. Single congenic strains generated were BN.GH-(D2Rat22-D2Mgh11)/Mcwi (BN.GH2); BN.GH-(D6Mit12-D6Rat15)/Mcwi (BN.GH6); and BN.GH-(D18Rat41-D18Mgh4)/Mcwi (BN.GH18). Blood pressure measurements were obtained either via a catheter placed in the femoral artery or by radiotelemetry in the single and combined congenics. Responses to angiotensin II (ANGII), norepinephrine (NE), and baroreceptor sensitivity were measured in the single congenics. Results: Transferring one or more QTL from the hypertensive GH into normotensive BN strain was not sufficient to cause hypertension in any of the developed congenic strains. There were no differences between the parental and congenic strains in their response to NE. However, BN.GH18 rats revealed significantly lower baroreceptor sensitivity (β = -1.25 ± 0.17), whereas BN.GH2 (β = 0.66 ± 0.09) and BN.GH18 (β = 0.71 ± 0.07) had significantly decreased responses to ANGII from those observed in the BN (β = 0.88 ± 0.08). Conclusion: The failure to alter blood pressure levels by introducing the hypertensive QTL from the GH into the hypertension resistant BN background suggests that the QTL effects are genome background-dependent in the GH rat. BN.GH2 and BN.GH18 rats reveal significant differences in response to ANGII and impaired baroreflex sensitivity, suggesting that we may have captured a locus responsible for the genetic control of baroreceptor sensitivity, which would be considered an intermediate phenotype of blood pressure.

Original languageEnglish
Pages (from-to)586-599
Number of pages14
JournalCroatian Medical Journal
Volume49
Issue number5
DOIs
Publication statusPublished - Oct 2008
Externally publishedYes

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Norway
Hypertension
Quantitative Trait Loci
Pressoreceptors
Angiotensin II
Blood Pressure
Norepinephrine
Genome
Phenotype
Genetic Loci
Chromosomes, Human, Pair 2
Inbreeding
Baroreflex
Femoral Artery

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Bilušić, M., Moreno, C., Barreto, N. E., Tschannen, M. R., Harris, E. L., Porteous, W. K., ... Kwitek, A. E. (2008). Genetically hypertensive Brown Norway congenic rat strains suggest intermediate traits underlying genetic hypertension. Croatian Medical Journal, 49(5), 586-599. https://doi.org/10.3325/cmj.2008.5.586

Genetically hypertensive Brown Norway congenic rat strains suggest intermediate traits underlying genetic hypertension. / Bilušić, Marijo; Moreno, Carol; Barreto, Nadia E.; Tschannen, Michael R.; Harris, Eugenie L.; Porteous, William K.; Thompson, Caryn M.; Grigor, Murray R.; Weder, Alan; Boerwinkle, Eric; Hunt, Steven; Curb, J. David; Jacob, Howard J.; Kwitek, Anne E.

In: Croatian Medical Journal, Vol. 49, No. 5, 10.2008, p. 586-599.

Research output: Contribution to journalArticle

Bilušić, M, Moreno, C, Barreto, NE, Tschannen, MR, Harris, EL, Porteous, WK, Thompson, CM, Grigor, MR, Weder, A, Boerwinkle, E, Hunt, S, Curb, JD, Jacob, HJ & Kwitek, AE 2008, 'Genetically hypertensive Brown Norway congenic rat strains suggest intermediate traits underlying genetic hypertension', Croatian Medical Journal, vol. 49, no. 5, pp. 586-599. https://doi.org/10.3325/cmj.2008.5.586
Bilušić, Marijo ; Moreno, Carol ; Barreto, Nadia E. ; Tschannen, Michael R. ; Harris, Eugenie L. ; Porteous, William K. ; Thompson, Caryn M. ; Grigor, Murray R. ; Weder, Alan ; Boerwinkle, Eric ; Hunt, Steven ; Curb, J. David ; Jacob, Howard J. ; Kwitek, Anne E. / Genetically hypertensive Brown Norway congenic rat strains suggest intermediate traits underlying genetic hypertension. In: Croatian Medical Journal. 2008 ; Vol. 49, No. 5. pp. 586-599.
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abstract = "Aim: To determine the independent and combined effects of three quantitative trait loci (QTL) for blood pressure in the Genetically Hypertensive (GH/Omr) rat by generating and characterizing single and combined congenic strains that have QTL on rat chromosomes (RNO) 2, 6, and 18 from the GH rat introduced into a hypertension resistant Brown Norway (BN) background. Methods: Linkage analysis and QTL identification (genome wide QTL scan) were performed with MapMaker/EXP to build the genetic maps and MapMaker/QTL for linking the phenotypes to the genetic map. The congenic strains were derived using marker-assisted selection strategy from a single male F1 offspring of an intercross between the male GH/Omr and female BN/Elh, followed by 10 generations of selective backcrossing to the female BN progenitor strain. Single congenic strains generated were BN.GH-(D2Rat22-D2Mgh11)/Mcwi (BN.GH2); BN.GH-(D6Mit12-D6Rat15)/Mcwi (BN.GH6); and BN.GH-(D18Rat41-D18Mgh4)/Mcwi (BN.GH18). Blood pressure measurements were obtained either via a catheter placed in the femoral artery or by radiotelemetry in the single and combined congenics. Responses to angiotensin II (ANGII), norepinephrine (NE), and baroreceptor sensitivity were measured in the single congenics. Results: Transferring one or more QTL from the hypertensive GH into normotensive BN strain was not sufficient to cause hypertension in any of the developed congenic strains. There were no differences between the parental and congenic strains in their response to NE. However, BN.GH18 rats revealed significantly lower baroreceptor sensitivity (β = -1.25 ± 0.17), whereas BN.GH2 (β = 0.66 ± 0.09) and BN.GH18 (β = 0.71 ± 0.07) had significantly decreased responses to ANGII from those observed in the BN (β = 0.88 ± 0.08). Conclusion: The failure to alter blood pressure levels by introducing the hypertensive QTL from the GH into the hypertension resistant BN background suggests that the QTL effects are genome background-dependent in the GH rat. BN.GH2 and BN.GH18 rats reveal significant differences in response to ANGII and impaired baroreflex sensitivity, suggesting that we may have captured a locus responsible for the genetic control of baroreceptor sensitivity, which would be considered an intermediate phenotype of blood pressure.",
author = "Marijo Bilušić and Carol Moreno and Barreto, {Nadia E.} and Tschannen, {Michael R.} and Harris, {Eugenie L.} and Porteous, {William K.} and Thompson, {Caryn M.} and Grigor, {Murray R.} and Alan Weder and Eric Boerwinkle and Steven Hunt and Curb, {J. David} and Jacob, {Howard J.} and Kwitek, {Anne E.}",
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T1 - Genetically hypertensive Brown Norway congenic rat strains suggest intermediate traits underlying genetic hypertension

AU - Bilušić, Marijo

AU - Moreno, Carol

AU - Barreto, Nadia E.

AU - Tschannen, Michael R.

AU - Harris, Eugenie L.

AU - Porteous, William K.

AU - Thompson, Caryn M.

AU - Grigor, Murray R.

AU - Weder, Alan

AU - Boerwinkle, Eric

AU - Hunt, Steven

AU - Curb, J. David

AU - Jacob, Howard J.

AU - Kwitek, Anne E.

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N2 - Aim: To determine the independent and combined effects of three quantitative trait loci (QTL) for blood pressure in the Genetically Hypertensive (GH/Omr) rat by generating and characterizing single and combined congenic strains that have QTL on rat chromosomes (RNO) 2, 6, and 18 from the GH rat introduced into a hypertension resistant Brown Norway (BN) background. Methods: Linkage analysis and QTL identification (genome wide QTL scan) were performed with MapMaker/EXP to build the genetic maps and MapMaker/QTL for linking the phenotypes to the genetic map. The congenic strains were derived using marker-assisted selection strategy from a single male F1 offspring of an intercross between the male GH/Omr and female BN/Elh, followed by 10 generations of selective backcrossing to the female BN progenitor strain. Single congenic strains generated were BN.GH-(D2Rat22-D2Mgh11)/Mcwi (BN.GH2); BN.GH-(D6Mit12-D6Rat15)/Mcwi (BN.GH6); and BN.GH-(D18Rat41-D18Mgh4)/Mcwi (BN.GH18). Blood pressure measurements were obtained either via a catheter placed in the femoral artery or by radiotelemetry in the single and combined congenics. Responses to angiotensin II (ANGII), norepinephrine (NE), and baroreceptor sensitivity were measured in the single congenics. Results: Transferring one or more QTL from the hypertensive GH into normotensive BN strain was not sufficient to cause hypertension in any of the developed congenic strains. There were no differences between the parental and congenic strains in their response to NE. However, BN.GH18 rats revealed significantly lower baroreceptor sensitivity (β = -1.25 ± 0.17), whereas BN.GH2 (β = 0.66 ± 0.09) and BN.GH18 (β = 0.71 ± 0.07) had significantly decreased responses to ANGII from those observed in the BN (β = 0.88 ± 0.08). Conclusion: The failure to alter blood pressure levels by introducing the hypertensive QTL from the GH into the hypertension resistant BN background suggests that the QTL effects are genome background-dependent in the GH rat. BN.GH2 and BN.GH18 rats reveal significant differences in response to ANGII and impaired baroreflex sensitivity, suggesting that we may have captured a locus responsible for the genetic control of baroreceptor sensitivity, which would be considered an intermediate phenotype of blood pressure.

AB - Aim: To determine the independent and combined effects of three quantitative trait loci (QTL) for blood pressure in the Genetically Hypertensive (GH/Omr) rat by generating and characterizing single and combined congenic strains that have QTL on rat chromosomes (RNO) 2, 6, and 18 from the GH rat introduced into a hypertension resistant Brown Norway (BN) background. Methods: Linkage analysis and QTL identification (genome wide QTL scan) were performed with MapMaker/EXP to build the genetic maps and MapMaker/QTL for linking the phenotypes to the genetic map. The congenic strains were derived using marker-assisted selection strategy from a single male F1 offspring of an intercross between the male GH/Omr and female BN/Elh, followed by 10 generations of selective backcrossing to the female BN progenitor strain. Single congenic strains generated were BN.GH-(D2Rat22-D2Mgh11)/Mcwi (BN.GH2); BN.GH-(D6Mit12-D6Rat15)/Mcwi (BN.GH6); and BN.GH-(D18Rat41-D18Mgh4)/Mcwi (BN.GH18). Blood pressure measurements were obtained either via a catheter placed in the femoral artery or by radiotelemetry in the single and combined congenics. Responses to angiotensin II (ANGII), norepinephrine (NE), and baroreceptor sensitivity were measured in the single congenics. Results: Transferring one or more QTL from the hypertensive GH into normotensive BN strain was not sufficient to cause hypertension in any of the developed congenic strains. There were no differences between the parental and congenic strains in their response to NE. However, BN.GH18 rats revealed significantly lower baroreceptor sensitivity (β = -1.25 ± 0.17), whereas BN.GH2 (β = 0.66 ± 0.09) and BN.GH18 (β = 0.71 ± 0.07) had significantly decreased responses to ANGII from those observed in the BN (β = 0.88 ± 0.08). Conclusion: The failure to alter blood pressure levels by introducing the hypertensive QTL from the GH into the hypertension resistant BN background suggests that the QTL effects are genome background-dependent in the GH rat. BN.GH2 and BN.GH18 rats reveal significant differences in response to ANGII and impaired baroreflex sensitivity, suggesting that we may have captured a locus responsible for the genetic control of baroreceptor sensitivity, which would be considered an intermediate phenotype of blood pressure.

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