Rosuvastatin Can Block Pro-Inflammatory Actions of Transgenic Human C-Reactive Protein Without Reducing its Circulating Levels

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Dissection of chromosome 18 blood pressure and salt-sensitivity quantitative trait loci in the spontaneously hypertensive rat

Hypertension in humans and experimental models has a strong hereditary basis, but identification of causative genes remains challenging. Quantitative trait loci (QTLs) for hypertension and salt sensitivity have been reported on rat chromosome 18. We set out to genetically isolate and prioritise genes within the salt sensitivity and hypertension QTLs on the spontaneously hypertensive rat (SHR) chromosome 18, by developing and characterising a series of congenic strains derived from the SHR and normotensive Brown Norway (BN) rat strains. The SHR.BN-D18Rat113/D18Rat82 (SHR-18) congenic strain exhibits significantly lower blood pressure and is salt-resistant compared to SHR. Transplantation of kidneys from SHR-18 donors into SHR recipients is sufficient to attenuate increased blood pressure but not salt sensitivity. Derivation of congenic sublines allowed separation of salt sensitivity from hypertension QTL regions. Renal expression studies with microarray and Solexa-based sequencing in parental and congenic strains identified four differentially expressed genes within the hypertension QTL region, one of which is an unannotated transcript encoding a previously undescribed, small non-coding RNA. Sequencing selected biological candidate genes within the minimal congenic interval revealed a non-synonymous variant in SHR Transcription factor 4. The minimal congenic interval is syntenic to a region of human chromosome 18 where significant linkage to hypertension was observed in family-based linkage studies. These congenic lines provide reagents for identifying causative genes that underlie the chromosome 18 SHR QTLs for hypertension and salt sensitivity. Candidate genes identified in these studies merit further investigation as potentially causative hypertension genes in SHR and human hypertension

Mapping genetic determinants of coronary microvascular remodeling in the spontaneously hypertensive rat

The mechanisms underlying coronary microvascular remodeling and dysfunction, which are critical determinants of abnormal myocardial blood flow regulation in human hypertension, are poorly understood. The spontaneously hypertensive rat (SHR) exhibits many features of human hypertensive cardiomyopathy. We demonstrate that remodeling of intramural coronary arterioles is apparent in the SHR already at 4 weeks of age, i.e. before the onset of systemic hypertension. To uncover possible genetic determinants of coronary microvascular remodeling, we carried out detailed histological and histomorphometric analysis of the heart and coronary vasculature in 30 weeks old SHR, age-matched Brown Norway (BN-Lx) parentals and BXH/HXB recombinant inbred (RI) strains. Using previously mapped expression quantitative trait loci (eQTLs), we carried out a genome-wide association analysis between genetic determinants of cardiac gene expression and histomorphometric traits. This identified 36 robustly mapped eQTLs in the heart which were associated with medial area of intramural coronary arterioles [false discovery rate (FDR) ~5 %]. Transcripts, which were both under cis-acting genetic regulation and significantly correlated with medial area (FDR <5 %), but not with blood pressure indices, were prioritized and four candidate genes were identified (Rtel1, Pla2g5, Dnaja4 and Rcn2) according to their expression levels and biological functions. Our results demonstrate that genetic factors play a role in the development of coronary microvascular remodeling and suggest blood pressure independent candidate genes for further functional experiments. © 2012 Springer-Verlag Berlin Heidelberg

Systems-level approaches reveal conservation of trans-regulated genes in the rat and genetic determinants of blood pressure in humans

AIMS: Human genome-wide association studies (GWAS) of hypertension identified only few susceptibility loci with large-effect that were replicated across populations. The vast majority of genes detected by GWAS have small-effect and the regulatory mechanisms through which these genetic variants cause disease remain mostly unclear. Here, we used comparative genomics between human and an established rat model of hypertension to explore the transcriptional mechanisms mediating the effect of genes identified in 15 hypertension GWAS. METHODS AND RESULTS: Time-series analysis of radiotelemetric blood pressure (BP) was performed to assess eleven parameters of BP-variation in recombinant inbred strains derived from the Spontaneously Hypertensive Rat. BP-data were integrated with ∼27,000 expression QTLs (eQTLs) mapped across seven tissues, detecting >8,000 significant associations between eQTL genes and BP-variation in the rat. We then compiled a large catalogue of human genes from GWAS of hypertension and identified a sub-set of 2,292 rat-human orthologous genes. Expression levels for 795 (34%) of these genes correlated with BP-variation across rat tissues: 51 genes were cis-regulated, whereas 459 were trans-regulated and enriched for 'calcium signalling pathway' (P=9.6x10-6) and 'ion channel' genes (P=3.5x10-7), which are important determinants of hypertension. We identified 158 clusters of trans-eQTLs, annotated the underlying 'master regulator' genes and found significant over-representation in the human hypertension gene-set (enrichment P=5x10-4). CONCLUSION: We showed extensive conservation of trans-regulated genes and their master regulators between rat and human hypertension. These findings reveal that small-effect genes associated with hypertension by human GWAS are likely to exert their action through coordinate regulation of pathogenic pathways

Integrated transcriptional profiling and linkage analysis for identification of genes underlying disease.

Integration of genome-wide expression profiling with linkage analysis is a new approach to identifying genes underlying complex traits. We applied this approach to the regulation of gene expression in the BXH/HXB panel of rat recombinant inbred strains, one of the largest available rodent recombinant inbred panels and a leading resource for genetic analysis of the highly prevalent metabolic syndrome. In two tissues important to the pathogenesis of the metabolic syndrome, we mapped cis- and trans-regulatory control elements for expression of thousands of genes across the genome. Many of the most highly linked expression quantitative trait loci are regulated in cis, are inherited essentially as monogenic traits and are good candidate genes for previously mapped physiological quantitative trait loci in the rat. By comparative mapping we generated a data set of 73 candidate genes for hypertension that merit testing in human populations. Mining of this publicly available data set is expected to lead to new insights into the genes and regulatory pathways underlying the extensive range of metabolic and cardiovascular disease phenotypes that segregate in these recombinant inbred strains