Congenic Mapping and Sequence Analysis of the
            <i>Renin</i>
            Locus

Flister, Michael J.; Hoffman, Matthew J.; Reddy, Prajwal; Jacob, Howard J.; Moreno, Carol

doi:10.1161/hypertensionaha.111.01008

Cited by 12 publications

(10 citation statements)

References 40 publications

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“…Within the region, it is also possible that other nonsynonymous variants and intergenic variants have functional consequences beyond the limitations of prediction software. Thus, validating these candidates genes will likely require further narrowing of the QTL by congenics (26, 50, 51), gene expression analysis, and/or directly testing candidates by gene-editing (20, 52, 53), all of which we have done previously for other disease loci (see below for description).…”

Section: Discussionmentioning

confidence: 99%

CXM: A New Tool for Mapping Breast Cancer Risk in the Tumor Microenvironment

et al. 2014

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The majority of causative variants in familial breast cancer remain unknown. Of the known risk variants, most are tumor cell autonomous and little attention has been paid yet to germline variants that may affect the tumor microenvironment. In this study, we developed a system called the Consomic Xenograft Model (CXM) to map germline variants that impact only the tumor microenvironment. In CXM, human breast cancer cells are orthotopically implanted into immunodeficient consomic strains and tumor metrics are quantified (e.g., growth, vasculogenesis, and metastasis). Because the strain backgrounds vary, whereas the malignant tumor cells do not, any observed changes in tumor progression are due to genetic differences in the non-malignant microenvironment. Using CXM, we defined genetic variant(s) on rat chromosome 3 that reduced relative tumor growth and hematogenous metastasis in the SS.BN3IL2Rγ consomic model compared to the SSIL2Rγ parental strain. Paradoxically, these effects occurred despite an increase in the density of tumor-associated blood vessels. In contrast, lymphatic vasculature and lymphogenous metastasis were unaffected by the SS.BN3IL2Rγ background. Through comparative mapping and whole genome sequence analysis, we narrowed candidate variants on rat chromosome 3 to six genes with a priority for future analysis. Collectively, our results establish the utility of CXM to localize genetic variants affecting the tumor microenvironment which underlie differences in breast cancer risk.

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Section: Discussionmentioning

confidence: 99%

CXM: A New Tool for Mapping Breast Cancer Risk in the Tumor Microenvironment

et al. 2014

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“…29 It is also possible that multiple causative variants co-segregate at the 830 kb locus, as we have demonstrated previously for other hypertension loci. 15, 23, 30 However, future studies targeting specific genes or further reducing the congenic interval will be necessary to localize the causative variant(s).…”

Section: Discussionmentioning

confidence: 99%

“…15 Briefly, kidneys were isolated after 21 days on 8% NaCl diet (AIN-76, Dyets, Bethlehem, PA) and fixed in 10% buffered formalin, sectioned at 4 μm thickness, and stained with Masson's trichrome and H&E.…”

Section: Methodsmentioning

confidence: 99%

Refined Mapping of a Hypertension Susceptibility Locus on Rat Chromosome 12

et al. 2014

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Previously, we found that transferring 6.1 Mb of SS chromosome 12 (13.4-19.5 Mb) onto the consomic SS-12BN background significantly elevated mean arterial pressure in response to an 8% NaCl diet (178±7 vs. 144±2 mmHg; P<0.001). Using congenic mapping, we have now narrowed the blood pressure locus by 86% from a 6.1 Mb region containing 133 genes to an 830 kb region (chr12:14.36-15.19 Mb) with 14 genes. Compared with the SS-12BN consomic, the 830 kb blood pressure locus was associated with a Δ+15 mmHg (P<0.01) increase in blood pressure, which coincided with elevated albuminuria (Δ+32 mg/day; P<0.001), proteinuria (Δ+48 mg/day; P<0.01), protein casting (Δ+154%; P<0.05), and renal fibrosis (Δ+79%; P<0.05). Of the 14 genes residing in the 830 kb locus, 8 were differentially expressed and among these, Chst12 (carbohydrate chondroitin 4 sulfotransferase 12) was the most consistently down-regulated by 2.6 to 4.5-fold (P<0.05) in both the renal medulla and cortex under normotensive and hypertensive conditions. Moreover, whole genome sequence analysis of overlapping blood pressure loci revealed an ∼86 kb region (chr12:14,541,567-14,627,442 bp) containing single nucleotide variants near Chst12 that are unique to the hypertensive SS strain when compared to the normotensive BN, SR, and WKY strains. Finally, the 830 kb interval is syntenic to a region on human chromosome 7 that has been genetically linked to blood pressure, suggesting that insight gained from our SS-12BN congenic strain may be translated to a better understanding of human hypertension.

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“…We recently published that at least 2 other BP loci reside in the line 9 congenic interval using male rats only. 60 One BN locus (chr13:47.2–49.0 Mb; referred to as line9 BP2 ) was hypertensive and the other BN locus, containing Renin (chr13:46.1–47.2; referred to as line9 BP1 ), lowered BP in male rats. 60 At present, it appears that the male BP QTL identified previously 60 and the female BP QTL identified here (Figure 1) are likely not shared.…”

Section: Discussionmentioning

confidence: 99%

“…60 One BN locus (chr13:47.2–49.0 Mb; referred to as line9 BP2 ) was hypertensive and the other BN locus, containing Renin (chr13:46.1–47.2; referred to as line9 BP1 ), lowered BP in male rats. 60 At present, it appears that the male BP QTL identified previously 60 and the female BP QTL identified here (Figure 1) are likely not shared. Although the protective line9 BP1 (male) and line9 BP3 (female) QTL overlapped, the line 9E males were not protective, suggesting that protective BP loci in this region are gender-specific.…”

Section: Discussionmentioning

confidence: 99%

Female-Specific Hypertension Loci on Rat Chromosome 13

et al. 2013

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A 3.7 Mb region of rat chromosome 13 (45.2–49.0 Mb) affects blood pressure (BP) in females only, indicating the presence of gender-specific BP loci in close proximity to the Renin locus. In the present study, we used a series of Dahl salt-sensitive/Mcwi (SS)-13 Brown Norway (BN) congenic rat strains to further resolve BP loci within this region. We identified 3 BP loci affecting female rats only, of which the 2 smaller loci (line9BP3 and line9BP4) were functionally characterized by sequence and expression analysis. Compared with SS, the presence of a 591 Kb region of BN chromosome 13 (line9BP3) significantly lowered BP by 21 mmHg on an 8% NaCl diet (153±7 vs 174±5 mmHg, P<0.001). Unexpectedly, the addition of 23 Kb of BN chromosome 13 (line9BP4) completely erased the female-specific BP protection on 8% NaCl diet, suggesting that BN hypertensive allele(s) reside in this region. The congenic interval of the protective line 9F strain contains 3 genes (Optc, Prelp, and Fmod) and the hypertensive line 9E contains 1 additional gene (Btg2). Sequence analysis of the 2 BP loci revealed a total of 282 intergenic variants, with no coding variants. Analysis of gene expression by RT-qPCR revealed strain- and gender-specific differences in Prelp, Fmod, and Btg2 expression, implicating these as novel candidate genes for female-specific hypertension.

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Congenic Mapping and Sequence Analysis of the Renin Locus

Cited by 12 publications

References 40 publications

CXM: A New Tool for Mapping Breast Cancer Risk in the Tumor Microenvironment

CXM: A New Tool for Mapping Breast Cancer Risk in the Tumor Microenvironment

Refined Mapping of a Hypertension Susceptibility Locus on Rat Chromosome 12

Female-Specific Hypertension Loci on Rat Chromosome 13

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