Genetic, physiological and comparative genomic studies of hypertension and insulin resistance in the spontaneously hypertensive rat

Philip M Coan; Oliver Hummel; Ana Isabel Garcia Diaz; Marjorie Barrier; Neza Alfazema; Penny J Norsworthy; Michal Pravenec; Enrico Petretto; Norbert Huebner; Timothy J Aitman

doi:10.1242/dmm.026716

Genetic, physiological and comparative genomic studies of hypertension and insulin resistance in the spontaneously hypertensive rat

Philip M Coan, Oliver Hummel, Ana Isabel Garcia Diaz, Marjorie Barrier, Neza Alfazema, Penny J Norsworthy, Michal Pravenec, Enrico Petretto, Norbert Huebner, Timothy J Aitman

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Abstract

We previously mapped hypertension-related insulin resistance quantitative trait loci (QTL) to rat chromosomes 4, 12 and 16 using adipocytes from F2 crosses between spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats, and subsequently identified Cd36 as the gene underlying the chromosome 4 locus. The identity of the chromosome 12 and 16 genes remains unknown. To identify whole body phenotypes associated with the chromosome 12 and 16 linkage regions, we generated and characterised new congenic strains, with WKY donor segments introgressed onto an SHR genetic background, for the chromosome 12 and 16 linkage regions. We found a >50% increase in insulin sensitivity in both the chromosome 12 and 16 strains. Blood pressure and left ventricular weight were reduced in the two congenic strains consistent with the congenic segments harboring SHR genes for insulin resistance, hypertension and cardiac hypertrophy. Integrated genomic analysis, using physiological and whole genome sequence data across 42 rat strains, identified variants within the congenic regions in Upk3bl, RGD1565131 and AABR06087018.1 that were associated with blood pressure, cardiac mass and insulin sensitivity. Quantitative trait transcript analysis across 29 recombinant inbred strains showed correlation between expression of Hspb1, Zkscan5 and Pdgfrl respectively with adipocyte volume, systolic blood pressure and cardiac mass. Comparative genome analysis showed marked enrichment of orthologues for human GWAS-associated genes for insulin resistance within the syntenic regions of both the chromosome 12 and 16 congenic intervals. Our study defines whole body phenotypes associated with the SHR chromosome 12 and 16 insulin resistance QTLs, identifies candidate genes for these SHR QTLs and finds human orthologues of rat genes in these regions that associate with related human traits. Further study of these genes in the congenic strains will lead to robust identification of the underlying genes and cellular mechanisms.

Original language	English
Journal	Disease Models and Mechanisms
Volume	10
Issue number	3
Early online date	26 Jan 2017
DOIs	https://doi.org/10.1242/dmm.026716
Publication status	E-pub ahead of print - 26 Jan 2017

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Coan, P. M., Hummel, O., Diaz, A. I. G., Barrier, M., Alfazema, N., Norsworthy, P. J., Pravenec, M., Petretto, E., Huebner, N., & Aitman, T. J. (2017). Genetic, physiological and comparative genomic studies of hypertension and insulin resistance in the spontaneously hypertensive rat. Disease Models and Mechanisms, 10(3). Advance online publication. https://doi.org/10.1242/dmm.026716

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title = "Genetic, physiological and comparative genomic studies of hypertension and insulin resistance in the spontaneously hypertensive rat",

abstract = "We previously mapped hypertension-related insulin resistance quantitative trait loci (QTL) to rat chromosomes 4, 12 and 16 using adipocytes from F2 crosses between spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats, and subsequently identified Cd36 as the gene underlying the chromosome 4 locus. The identity of the chromosome 12 and 16 genes remains unknown. To identify whole body phenotypes associated with the chromosome 12 and 16 linkage regions, we generated and characterised new congenic strains, with WKY donor segments introgressed onto an SHR genetic background, for the chromosome 12 and 16 linkage regions. We found a >50% increase in insulin sensitivity in both the chromosome 12 and 16 strains. Blood pressure and left ventricular weight were reduced in the two congenic strains consistent with the congenic segments harboring SHR genes for insulin resistance, hypertension and cardiac hypertrophy. Integrated genomic analysis, using physiological and whole genome sequence data across 42 rat strains, identified variants within the congenic regions in Upk3bl, RGD1565131 and AABR06087018.1 that were associated with blood pressure, cardiac mass and insulin sensitivity. Quantitative trait transcript analysis across 29 recombinant inbred strains showed correlation between expression of Hspb1, Zkscan5 and Pdgfrl respectively with adipocyte volume, systolic blood pressure and cardiac mass. Comparative genome analysis showed marked enrichment of orthologues for human GWAS-associated genes for insulin resistance within the syntenic regions of both the chromosome 12 and 16 congenic intervals. Our study defines whole body phenotypes associated with the SHR chromosome 12 and 16 insulin resistance QTLs, identifies candidate genes for these SHR QTLs and finds human orthologues of rat genes in these regions that associate with related human traits. Further study of these genes in the congenic strains will lead to robust identification of the underlying genes and cellular mechanisms.",

author = "Coan, {Philip M} and Oliver Hummel and Diaz, {Ana Isabel Garcia} and Marjorie Barrier and Neza Alfazema and Norsworthy, {Penny J} and Michal Pravenec and Enrico Petretto and Norbert Huebner and Aitman, {Timothy J}",

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AU - Coan, Philip M

AU - Hummel, Oliver

AU - Diaz, Ana Isabel Garcia

AU - Barrier, Marjorie

AU - Alfazema, Neza

AU - Norsworthy, Penny J

AU - Pravenec, Michal

AU - Petretto, Enrico

AU - Huebner, Norbert

AU - Aitman, Timothy J

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N2 - We previously mapped hypertension-related insulin resistance quantitative trait loci (QTL) to rat chromosomes 4, 12 and 16 using adipocytes from F2 crosses between spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats, and subsequently identified Cd36 as the gene underlying the chromosome 4 locus. The identity of the chromosome 12 and 16 genes remains unknown. To identify whole body phenotypes associated with the chromosome 12 and 16 linkage regions, we generated and characterised new congenic strains, with WKY donor segments introgressed onto an SHR genetic background, for the chromosome 12 and 16 linkage regions. We found a >50% increase in insulin sensitivity in both the chromosome 12 and 16 strains. Blood pressure and left ventricular weight were reduced in the two congenic strains consistent with the congenic segments harboring SHR genes for insulin resistance, hypertension and cardiac hypertrophy. Integrated genomic analysis, using physiological and whole genome sequence data across 42 rat strains, identified variants within the congenic regions in Upk3bl, RGD1565131 and AABR06087018.1 that were associated with blood pressure, cardiac mass and insulin sensitivity. Quantitative trait transcript analysis across 29 recombinant inbred strains showed correlation between expression of Hspb1, Zkscan5 and Pdgfrl respectively with adipocyte volume, systolic blood pressure and cardiac mass. Comparative genome analysis showed marked enrichment of orthologues for human GWAS-associated genes for insulin resistance within the syntenic regions of both the chromosome 12 and 16 congenic intervals. Our study defines whole body phenotypes associated with the SHR chromosome 12 and 16 insulin resistance QTLs, identifies candidate genes for these SHR QTLs and finds human orthologues of rat genes in these regions that associate with related human traits. Further study of these genes in the congenic strains will lead to robust identification of the underlying genes and cellular mechanisms.

AB - We previously mapped hypertension-related insulin resistance quantitative trait loci (QTL) to rat chromosomes 4, 12 and 16 using adipocytes from F2 crosses between spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats, and subsequently identified Cd36 as the gene underlying the chromosome 4 locus. The identity of the chromosome 12 and 16 genes remains unknown. To identify whole body phenotypes associated with the chromosome 12 and 16 linkage regions, we generated and characterised new congenic strains, with WKY donor segments introgressed onto an SHR genetic background, for the chromosome 12 and 16 linkage regions. We found a >50% increase in insulin sensitivity in both the chromosome 12 and 16 strains. Blood pressure and left ventricular weight were reduced in the two congenic strains consistent with the congenic segments harboring SHR genes for insulin resistance, hypertension and cardiac hypertrophy. Integrated genomic analysis, using physiological and whole genome sequence data across 42 rat strains, identified variants within the congenic regions in Upk3bl, RGD1565131 and AABR06087018.1 that were associated with blood pressure, cardiac mass and insulin sensitivity. Quantitative trait transcript analysis across 29 recombinant inbred strains showed correlation between expression of Hspb1, Zkscan5 and Pdgfrl respectively with adipocyte volume, systolic blood pressure and cardiac mass. Comparative genome analysis showed marked enrichment of orthologues for human GWAS-associated genes for insulin resistance within the syntenic regions of both the chromosome 12 and 16 congenic intervals. Our study defines whole body phenotypes associated with the SHR chromosome 12 and 16 insulin resistance QTLs, identifies candidate genes for these SHR QTLs and finds human orthologues of rat genes in these regions that associate with related human traits. Further study of these genes in the congenic strains will lead to robust identification of the underlying genes and cellular mechanisms.

U2 - 10.1242/dmm.026716

DO - 10.1242/dmm.026716

M3 - Article

C2 - 28130354

SN - 1754-8411

VL - 10

JO - Disease Models and Mechanisms

JF - Disease Models and Mechanisms

IS - 3

ER -

Genetic, physiological and comparative genomic studies of hypertension and insulin resistance in the spontaneously hypertensive rat

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