Mapping of quantitative trait loci for blood pressure and cardiac mass in the rat by genome scanning of recombinant inbred strains.

Pravenec, Michal; Guyader, Dominique; Schott, Jean‐Jacques; Buard, Jérǒme; Křen, Vladimı́r; Bı́lá, V; Szpirer, Claude; Szpirer, Josiane; Wang, J M; Huang, Hongdong

doi:10.1172/jci118244

Cited by 151 publications

(96 citation statements)

References 42 publications

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“…On the other hand, genetic loci for cardiac mass that are independent of the influence of blood pressure have been found on rat chromosomes 2, 20 3, 9 10, 23 12, 24,25 and 17. 26 The latter QTL was close to the Edn1 and Drd1A genes on the short arm of rat chromosome 17 (17p14), at least 40 cM away from the QTL we describe in the present study. It is important to emphasize that none of the above studies provided substantive evidence of functional differences or genetic sequence variation implicating a particular gene in the control of cardiac mass.…”

Section: Discussionsupporting

confidence: 63%

Right Ventricular Hypertrophy Secondary to Pulmonary Hypertension Is Linked to Rat Chromosome 17

et al. 2001

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Background-Fischer 344 (F344) rats are relatively resistant to hypoxia-induced right ventricular (RV) hypertrophy compared with the Wistar-Kyoto (WKY) strain. These 2 strains were used to examine the genetic basis for the differential response. Methods and Results-Male F 2 offspring from an F344ϫWKY intercross were exposed to hypoxia (10% O 2 ) for 3 weeks, and pulmonary artery pressure and cardiac chamber weights were measured. Genomic DNA was screened by use of polymorphic microsatellite markers across the whole genome (excluding the sex chromosomes). A quantitative trait locus (QTL) for RV weight was identified on rat chromosome 17 (lod score 6.5) that accounted for 22% of the total variance of RV weight in the F 2 population and was independent of pulmonary artery pressure. The peak was centered over marker D17Rat41, close to Chrm3, with a 1-lod support interval of 5 cM. Comparison of homologous regions in mice and humans suggested that Ryr2, the cardiac isoform of the ryanodine receptor, colocalizes with our QTL. A panel of somatic cell hybrids and fluorescence in situ hybridization mapped Ryr2 close to the gene Chrm3 within our QTL.

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Section: Discussionsupporting

confidence: 63%

Right Ventricular Hypertrophy Secondary to Pulmonary Hypertension Is Linked to Rat Chromosome 17

et al. 2001

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“…A genome-wide QTL analysis undertaken in another laboratory, using 500 genetic markers to genotype recombinant inbred strains of rats (HBX and BXH) derived from a spontaneously hypertensive strain and a normotensive strain, 11 indicated the presence of blood-pressure regulatory loci on rat chromosomes 2, 4, and 19. The IL-6 marker on chromosome 4 showed the strongest correlation with mean arterial pressure.…”

Section: Discussionmentioning

confidence: 99%

Allelic variants in the interleukin-6 gene and essential hypertension in Japanese women

et al. 1999

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Genes that can be implicated in hypertension in experimental animals are plausible candidates in the pathogenesis of human hypertension. A recent genome-wide search for quantitative-trait loci (QTL) in hypertensive rats revealed a strong correlation between the interleukin-6 (IL-6) locus on rat chromosome 4 and systolic, diastolic, and mean arterial pressure in this mammalian species. To investigate a possible association between genetic variations of the IL-6 gene and hypertension in humans, we identified two novel single-nucleotide sequence variations, a C/G substitution at −634 in the promoter region and a G/A substitution at 4391 in a 3 ′ non-coding portion of exon 5, and a previous reported sequence variant, an A/T variation in the composition of the A n T n tract around −447 in the promoter region ( Fishman D et al. J Clin Invest 1998; 102: 1369-1376, within a test population of 96 Japanese subjects. Allelic associations involving these variations were analyzed in 150 hypertensive and 143 normotensive Japanese women. The distribution of alleles of the three polymorphisms, as well as a dinucleotide repeat present at the IL-6 locus, was similar in the two groups. Therefore, the IL-6 gene appears to play a minimal role in the genetic etiology of essential hypertension in Japanese women.

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“…Other studies have reported BP QTLs in the same region in 3 different F 2 intercrosses (Table 2). [22][23][24][25][26][27][28][29][30][31][32][33] We found that the angiotensin receptor 1a gene (Atr1a) is in this putative QTL region. All published heart weight/hypertrophy QTLs on chromosome 17 harbor a common interesting candidate gene, Drd1a (dopamine receptor 1a).…”

Section: Bilusic Et Al Genetic Analysis In the Lyon Hypertensive Ratmentioning

confidence: 99%

Mapping the Genetic Determinants of Hypertension, Metabolic Diseases, and Related Phenotypes in the Lyon Hypertensive Rat

et al. 2004

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Abstract-The complex nature of hypertension makes identifying the pathophysiology and its genetic contributions a challenging task. One powerful approach for the genetic dissection of blood pressure regulation is studying inbred rat models of hypertension, as they provide natural allele variants but reduced heterogeneity (both genetic and etiologic). Furthermore, the detailed physiologic studies to which the rat is amenable allow for the determination of intermediate phenotypes.We have performed a total genome scan in offspring of an F 2 intercross between the Lyon hypertensive (LH) and Lyon normotensive rat strains to identify linkage of anthropometric, blood pressure, renal, metabolic, and endocrine phenotypes. Quantitative trait locus (QTL) regions involved in blood pressure regulation, end-stage organ damage, body and organ weight, and lipid metabolism in the LH rat were identified on chromosomes 1, 2, 3, 5, 7, 10, 13, and 17, with 2 phenotypes associated with the metabolic syndrome identified on chromosomes 1 and 17. Regions on chromosomes 2, 13, and 17 were revealed to be important for blood pressure regulation. Regions on chromosome 17 were found to significantly contribute to both metabolic homeostasis and blood pressure regulation; 2 aggregates of a total of 23 QTLs were identified, including several "intermediate phenotypes." These intermediate phenotypes may be used as closer surrogates to the mechanisms leading to hypertension and metabolic dysfunction in the LH rat. Key Words: genetics Ⅲ linkage analysis Ⅲ metabolism Ⅲ hypertension, genetic Ⅲ rats, inbred strains Ⅲ cardiovascular diseases H uman essential hypertension and associated cardiovascular diseases are multifactorial disorders with a complex etiology, resulting from the interaction between multiple genes and environmental factors. Despite development of new genetic and genomic technologies, the genetic determinants of multifactorial disorders remain unclear. The study of animal models in discovering pathophysologic and genetic determinants of polygenetic disorders such as hypertension provides a platform of reduced heterogeneity. Currently, there exist several different genetically hypertensive rat and mouse selection models. 1 Numerous linkage studies in rats have shown that each rat chromosome contains at least 1 blood pressure (BP) quantitative trait locus (QTL; http://rgd.mcw.edu/qtls).The Lyon hypertensive (LH) rat has many features common to the human metabolic syndrome, a group of metabolic risk factors including central obesity, atherogenic dyslipidemia, elevated BP, insulin resistance or glucose intolerance, and prothrombotic and proinflamatory states. 2 Interestingly, a control strain, the Lyon normotensive (LN) rat, has been simultaneously derived from a common ancestor of the LH; the LN is genetically quite similar to the LH (85% identical based on characterization of 4328 microsatellite markers; data not shown) but phenotypically very distinct. Compared with the LN, LH rats have mild salt-sensitive hypertension and reduced life ...

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Mapping of quantitative trait loci for blood pressure and cardiac mass in the rat by genome scanning of recombinant inbred strains.

Cited by 151 publications

References 42 publications

Right Ventricular Hypertrophy Secondary to Pulmonary Hypertension Is Linked to Rat Chromosome 17

Right Ventricular Hypertrophy Secondary to Pulmonary Hypertension Is Linked to Rat Chromosome 17

Allelic variants in the interleukin-6 gene and essential hypertension in Japanese women

Mapping the Genetic Determinants of Hypertension, Metabolic Diseases, and Related Phenotypes in the Lyon Hypertensive Rat

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