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

Langley, Sarah R. ORCID: https://orcid.org/0000-0003-4419-476X, Bottolo, Leonardo, Kunes, Jaroslav, Zicha, Josef, Zidek, Vaclav, Hubner, Norbert, Cook, Stuart A., Pravenec, Michal, Aitman, Timothy J. and Petretto, Enrico 2013. Systems-level approaches reveal conservation of trans-regulated genes in the rat and genetic determinants of blood pressure in humans. Cardiovascular Research 97 (4) , pp. 653-665. 10.1093/cvr/cvs329

Full text not available from this repository.

Abstract

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 has 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 11 parameters of BP variation in recombinant inbred strains derived from the spontaneously hypertensive rat. BP data were integrated with ∼27 000 expression quantative trait loci (eQTLs) mapped across seven tissues, detecting >8000 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 subset of 2292 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 = 9.6 × 10−6) and ‘ion channel’ genes (P = 3.5 × 10−7), 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 = 5 × 10−4). 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	Oxford University Press
ISSN:	0008-6363
Date of Acceptance:	26 October 2012
Last Modified:	05 Sep 2023 12:45
URI:	https://orca.cardiff.ac.uk/id/eprint/162159

Actions (repository staff only)

Edit Item