New target regions for human hypertension via comparative genomics

Abstract

Models of human disease have long been used to understand the basic pathophysiology of disease and to facilitate the discovery of new therapeutics. However, as long as models have been used there have been debates about the utility of these models and their ability to mimic clinical disease at the phenotypic level. The application of genetic studies to both humans and model systems allows for a new paradigm, whereby a novel comparative genomics strategy combined with phenotypic correlates can be used to bridge between clinical relevance and model utility. This study presents a comparative genomic map for "candidate hypertension loci in humans" based on translating QTLs between rat and human, predicting 26 chromosomal regions in the human genome that are very likely to harbor hypertension genes. The predictive power appears robust, as several of these regions have also been implicated in mouse, suggesting that these regions represent primary targets for the development of SNPs for linkage disequilibrium testing in humans and/or provide a means to select specific models for additional functional studies and the development of new therapeutics.

Figure 1

Demonstration of QTL clustering. The dark-shaded area of the QTL profile represents the 99% C.I. of each QTL. The dark vertical lines indicate the boundary of the QTL cluster, which is defined by the nearest two markers flanking the combined 99% C.I, in this example D1Mgh9 and D1Mgh5.

Figure 2

Flow chart showing the algorithm for constructing framework comparative maps between rat, mouse, and human genomes based on publicly available databases.

Figure 3

Human chromosomal regions implicated in hypertension based on rat–human comparative maps for 67 QTLs identified in seven different progenies from genetically hypertensive rats. Distribution of the 26 predicted genomic regions in the human genome located on 16 different autosomes based on cytogenetics. Human chromosomes 6, 12, 14, 20, 21, and 22 do not contain positional candidate loci predicted by the rat studies, and the sex chromosomes were not evaluated in this study. Regions of the genome in which multiple blood pressure-related phenotypes cluster from more than one cross are designated first priority regions. There are 20 of 26 regions that fall into this category (boxed regions). We predict six “second priority regions” based on QTLs identified in a single rat cross that may represent either areas of interest for a distinct subtype of hypertension or areas harboring modifier genes for blood pressure (nonboxed regions). Confidence level for placement of syntenic regions designated by vertical bars: (Red) Highest, (blue) high, (black) moderate. Numbers: (Black) SHR × BN, (purple) SS/MCW × BN, (blue) SHR × WKY, (red) SHR × DRY, (dark green) ACI × FHH, (light green) GH × BN, (magenta) LH × LN. Mouse syntenic QTLs are represented by the vertical bars to the left of the human idiograms. (Star) Genomic region reported with significant or suggestive linkage in genome scans for hypertension in humans.

Figure 3

Human chromosomal regions implicated in hypertension based on rat–human comparative maps for 67 QTLs identified in seven different progenies from genetically hypertensive rats. Distribution of the 26 predicted genomic regions in the human genome located on 16 different autosomes based on cytogenetics. Human chromosomes 6, 12, 14, 20, 21, and 22 do not contain positional candidate loci predicted by the rat studies, and the sex chromosomes were not evaluated in this study. Regions of the genome in which multiple blood pressure-related phenotypes cluster from more than one cross are designated first priority regions. There are 20 of 26 regions that fall into this category (boxed regions). We predict six “second priority regions” based on QTLs identified in a single rat cross that may represent either areas of interest for a distinct subtype of hypertension or areas harboring modifier genes for blood pressure (nonboxed regions). Confidence level for placement of syntenic regions designated by vertical bars: (Red) Highest, (blue) high, (black) moderate. Numbers: (Black) SHR × BN, (purple) SS/MCW × BN, (blue) SHR × WKY, (red) SHR × DRY, (dark green) ACI × FHH, (light green) GH × BN, (magenta) LH × LN. Mouse syntenic QTLs are represented by the vertical bars to the left of the human idiograms. (Star) Genomic region reported with significant or suggestive linkage in genome scans for hypertension in humans.

Figure 3

Human chromosomal regions implicated in hypertension based on rat–human comparative maps for 67 QTLs identified in seven different progenies from genetically hypertensive rats. Distribution of the 26 predicted genomic regions in the human genome located on 16 different autosomes based on cytogenetics. Human chromosomes 6, 12, 14, 20, 21, and 22 do not contain positional candidate loci predicted by the rat studies, and the sex chromosomes were not evaluated in this study. Regions of the genome in which multiple blood pressure-related phenotypes cluster from more than one cross are designated first priority regions. There are 20 of 26 regions that fall into this category (boxed regions). We predict six “second priority regions” based on QTLs identified in a single rat cross that may represent either areas of interest for a distinct subtype of hypertension or areas harboring modifier genes for blood pressure (nonboxed regions). Confidence level for placement of syntenic regions designated by vertical bars: (Red) Highest, (blue) high, (black) moderate. Numbers: (Black) SHR × BN, (purple) SS/MCW × BN, (blue) SHR × WKY, (red) SHR × DRY, (dark green) ACI × FHH, (light green) GH × BN, (magenta) LH × LN. Mouse syntenic QTLs are represented by the vertical bars to the left of the human idiograms. (Star) Genomic region reported with significant or suggestive linkage in genome scans for hypertension in humans.

Figure 3

Human chromosomal regions implicated in hypertension based on rat–human comparative maps for 67 QTLs identified in seven different progenies from genetically hypertensive rats. Distribution of the 26 predicted genomic regions in the human genome located on 16 different autosomes based on cytogenetics. Human chromosomes 6, 12, 14, 20, 21, and 22 do not contain positional candidate loci predicted by the rat studies, and the sex chromosomes were not evaluated in this study. Regions of the genome in which multiple blood pressure-related phenotypes cluster from more than one cross are designated first priority regions. There are 20 of 26 regions that fall into this category (boxed regions). We predict six “second priority regions” based on QTLs identified in a single rat cross that may represent either areas of interest for a distinct subtype of hypertension or areas harboring modifier genes for blood pressure (nonboxed regions). Confidence level for placement of syntenic regions designated by vertical bars: (Red) Highest, (blue) high, (black) moderate. Numbers: (Black) SHR × BN, (purple) SS/MCW × BN, (blue) SHR × WKY, (red) SHR × DRY, (dark green) ACI × FHH, (light green) GH × BN, (magenta) LH × LN. Mouse syntenic QTLs are represented by the vertical bars to the left of the human idiograms. (Star) Genomic region reported with significant or suggestive linkage in genome scans for hypertension in humans.

Figure 3

Human chromosomal regions implicated in hypertension based on rat–human comparative maps for 67 QTLs identified in seven different progenies from genetically hypertensive rats. Distribution of the 26 predicted genomic regions in the human genome located on 16 different autosomes based on cytogenetics. Human chromosomes 6, 12, 14, 20, 21, and 22 do not contain positional candidate loci predicted by the rat studies, and the sex chromosomes were not evaluated in this study. Regions of the genome in which multiple blood pressure-related phenotypes cluster from more than one cross are designated first priority regions. There are 20 of 26 regions that fall into this category (boxed regions). We predict six “second priority regions” based on QTLs identified in a single rat cross that may represent either areas of interest for a distinct subtype of hypertension or areas harboring modifier genes for blood pressure (nonboxed regions). Confidence level for placement of syntenic regions designated by vertical bars: (Red) Highest, (blue) high, (black) moderate. Numbers: (Black) SHR × BN, (purple) SS/MCW × BN, (blue) SHR × WKY, (red) SHR × DRY, (dark green) ACI × FHH, (light green) GH × BN, (magenta) LH × LN. Mouse syntenic QTLs are represented by the vertical bars to the left of the human idiograms. (Star) Genomic region reported with significant or suggestive linkage in genome scans for hypertension in humans.