Refined Mapping of a Hypertension Susceptibility Locus on Rat Chromosome 12

Prisco, Sasha Z.; Prokop, Jeremy W.; Sarkis, Allison B.; Yeo, Nan Cher; Hoffman, Matthew J.; Hansen, Colin; Jacob, Howard J.; Flister, Michael J.; Lazar, Jozef

doi:10.1161/hypertensionaha.114.03550

Cited by 10 publications

(4 citation statements)

References 48 publications

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“…A key goal in animal studies is to identify relevant models of human disease. Syntenic genome regions between humans and rodents often regulate a number of infectious and chronic diseases, and our analysis of HrS26 extends this important pattern [42][43][44] to sarbecovirus infections. All told, the synteny between human Chr3 and mouse Chr9, the effect sizes of the loci identified in this F2 (between 5-15% of the population-wide phenotypic variation in this F2, Table 1), as well as the prevalence of loci impacting multiple aspects of SARS-MA associated disease, highlight how sorting of multiple susceptibility alleles into individual CC strains model unique aspects of the genetic control of disease responses.…”

Section: Identification Of Ccr9 As a Major Susceptibility Allele During Sars-cov-2 Infectionsupporting

confidence: 54%

Common Mechanism of SARS-CoV and SARS-CoV-2 Pathogenesis across Species

Schäfer

Gralinski

Leist

et al. 2021

Preprint

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Sarbecovirus (CoV) infections, including Severe Acute Respiratory CoV (SARS-CoV) and SARS-CoV-2, are considerable human threats. Human GWAS studies have recently identified loci associated with variation in SARS-CoV-2 susceptibility. However, genetically tractable models that reproduce human CoV disease outcomes are needed to mechanistically evaluate genetic determinants of CoV susceptibility. We used the Collaborative Cross (CC) and human GWAS datasets to elucidate host susceptibility loci that regulate CoV infections and to identify host quantitative trait loci that modulate severe CoV and pan-CoV disease outcomes including a major disease regulating loci including CCR9. CCR9 ablation resulted in enhanced titer, weight loss, respiratory dysfunction, mortality, and inflammation, providing mechanistic support in mitigating protection from severe SARS-CoV-2 pathogenesis across species. This study represents a comprehensive analysis of susceptibility loci for an entire genus of human pathogens conducted, identifies a large collection of susceptibility loci and candidate genes that regulate multiple aspects type-specific and cross-CoV pathogenesis, and also validates the paradigm of using the CC platform to identify common cross-species susceptibility loci and genes for newly emerging and pre-epidemic viruses.

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Section: Identification Of Ccr9 As a Major Susceptibility Allele During Sars-cov-2 Infectionsupporting

confidence: 54%

Common Mechanism of SARS-CoV and SARS-CoV-2 Pathogenesis across Species

Schäfer

Gralinski

Leist

et al. 2021

Preprint

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“…108 A role for narrower DNA segments was investigated by the creation of congenic strains with introgressed overlapping regions of these chromosomes. A combination of these experiments and the study of differential expression of genes between the congenic and parental strains, detection of nonsynonymous single nucleotide polymorphisms in the regions of interest, and transcriptomic analysis has revealed a number of possible candidate genes, 96,97,100,101,109,110 the majority of which have no previously known cardiovascular regulatory function. However, even with high-resolution substitution mapping, there are usually additional variants flanking a substituted candidate gene, requiring genetic engineering to sort out the significance of the finding.…”

Section: Genetics and Ss Phenotype In Rodentsmentioning

confidence: 99%

Salt Sensitivity of Blood Pressure

Elijovich¹,

Weinberger²,

Anderson³

et al. 2016

Hypertension

387

230

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The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on January 23, 2016, and the American Heart Association Executive Committee on February 23, 2016. A copy of the document is available at http://professional.heart.org/statements by using either "Search for Guidelines & Statements" or the "Browse by Topic" area. To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay@ wolterskluwer.com.The American Heart Association requests that this document be cited as follows: Elijovich F, Weinberger MH, Anderson CAM, Appel LJ, Bursztyn M, Cook NR, Dart RA, Newton-Cheh CH, Sacks FM, Laffer CL; on behalf of the American Heart Association Professional and Public Education Committee of the Council on Hypertension; Council on Functional Genomics and Translational Biology; and Stroke Council. Salt sensitivity of blood pressure: a scientific statement from the American Heart Association. Hypertension. 2016;68:e7-e46. doi: 10.1161/HYP.0000000000000047.Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit http://professional.heart.org/statements. Select the "Guidelines & Statements" drop-down menu, then click "Publication Development."Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.heart.org/HEARTORG/General/CopyrightPermission-Guidelines_UCM_300404_Article.jsp. A link to the "Copyright Permissions Request Form" appears on the right side of the page. Figure 2 shows the major effect of aging in increasing the prevalence of SSBP in both normotensive and hypertensive subjects. An important and encouraging observation is that the multiple phenotypic characteristics described in pure SS strains of rodents reproduce those observed in humans, indicating that the phenotypic cluster of SSBP can be brought out in humans by the current techniques used in carefully controlled research. Additionally, despite the unquestionable influence of environmental factors in the determination of SSBP in humans, estimates of its heritability have been as high as 74% in blacks 9 and 50% in Chinese subjects, 10 both higher than those for hypertension. Salt Sensitivity of Blood PressureAn important issue is the clinical significance of the SSBP phenotype. There was increasing understanding that it represents an abnormality. The reasons w...

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“…Additionally, two human genomewide association studies in individuals of European ancestry (11,43) have suggestively associated a single-nucleotide polymorphism (rs2969070 [G]) that is intergenic of CHST12 and GRIFIN to hypertension. Interestingly, previous whole genome sequencing analysis of overlapping rat blood pressure loci within our candidate region found an ϳ86-kb region (chr12: 14,541,567-14,627,442 bp) containing single nucleotide variants near Chst12 and Grifin that were unique to the hypertensive SS strain compared with the normotensive BN, Dahl salt-resistant, and Wistar-Kyoto strains, suggesting that the SS-derived variant(s) within this region may be involved in BP regulation (38). Thus our studies may provide insights into the potential role(s) of CHST12 and GRIFIN in the development of vascular-dependent human hypertension.…”

Section: Discussionmentioning

confidence: 97%

Vascular dysfunction precedes hypertension associated with a blood pressure locus on rat chromosome 12

Prisco

Priestley

Weinberg

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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dysfunction precedes hypertension associated with a blood pressure locus on rat chromosome 12. Am J Physiol Heart Circ Physiol 307: H1103-H1110, 2014. First published August 22, 2014; doi:10.1152/ajpheart.00464.2014.-We previously isolated a 6.1-Mb region of SS/Mcwi (Dahl salt-sensitive) rat chromosome 12 (13.4 -19.5 Mb) that significantly elevated blood pressure (BP) (⌬ϩ34 mmHg, P Ͻ 0.001) compared with the SS-12 BN consomic control. In the present study, we examined the role of vascular dysfunction and remodeling in hypertension risk associated with the 6.1-Mb (13.4 -19.5 Mb) locus on rat chromosome 12 by reducing dietary salt, which lowered BP levels so that there were no substantial differences in BP between strains. Consequently, any observed differences in the vasculature were considered BP-independent. We also reduced the candidate region from 6.1 Mb with 133 genes to 2 Mb with 23 genes by congenic mapping. Both the 2 Mb and 6.1 Mb congenic intervals were associated with hypercontractility and decreased elasticity of resistance vasculature prior to elevations of BP, suggesting that the vascular remodeling and dysfunction likely contribute to the pathogenesis of hypertension in these congenic models. Of the 23 genes within the narrowed congenic interval, 12 were differentially expressed between the resistance vasculature of the 2 Mb congenic and SS-12 BN consomic strains. Among these, Grifin was consistently upregulated 2.7 Ϯ 0.6-fold (P Ͻ 0.05) and 2.0 Ϯ 0.3-fold (P Ͻ 0.01), and Chst12 was consistently downregulated Ϫ2.8 Ϯ 0.3-fold (P Ͻ 0.01) and Ϫ4.4 Ϯ 0.4-fold (P Ͻ 0.00001) in the 2 Mb congenic compared with SS-12 BN consomic under normotensive and hypertensive conditions, respectively. A syntenic region on human chromosome 7 has also been associated with BP regulation, suggesting that identification of the genetic mechanism(s) underlying cardiovascular phenotypes in this congenic strain will likely be translated to a better understanding of human hypertension.

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Refined Mapping of a Hypertension Susceptibility Locus on Rat Chromosome 12

Cited by 10 publications

References 48 publications

Common Mechanism of SARS-CoV and SARS-CoV-2 Pathogenesis across Species

Common Mechanism of SARS-CoV and SARS-CoV-2 Pathogenesis across Species

Salt Sensitivity of Blood Pressure

Vascular dysfunction precedes hypertension associated with a blood pressure locus on rat chromosome 12

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