Integrated genomic approaches to identification of candidate genes underlying metabolic and cardiovascular phenotypes in the spontaneously hypertensive rat

Abstract

The spontaneously hypertensive rat (SHR) is a widely used rodent model of hypertension and metabolic syndrome. Previously we identified thousands of cis-regulated expression quantitative trait loci (eQTLs) across multiple tissues using a panel of rat recombinant inbred (RI) strains derived from Brown Norway and SHR progenitors. These cis-eQTLs represent potential susceptibility loci underlying physiological and pathophysiological traits manifested in SHR. We have prioritized 60 cis-eQTLs and confirmed differential expression between the parental strains by quantitative PCR in 43 (72%) of the eQTL transcripts. Quantitative trait transcript (QTT) analysis in the RI strains showed highly significant correlation between cis-eQTL transcript abundance and clinically relevant traits such as systolic blood pressure and blood glucose, with the physical location of a subset of the cis-eQTLs colocalizing with “physiological” QTLs (pQTLs) for these same traits. These colocalizing correlated cis-eQTLs (c3-eQTLs) are highly attractive as primary susceptibility loci for the colocalizing pQTLs. Furthermore, sequence analysis of the c3-eQTL genes identified single nucleotide polymorphisms (SNPs) that are predicted to affect transcription factor binding affinity, splicing and protein function. These SNPs, which potentially alter transcript abundance and stability, represent strong candidate factors underlying not just eQTL expression phenotypes, but also the correlated metabolic and physiological traits. In conclusion, by integration of genomic sequence, eQTL and QTT datasets we have identified several genes that are strong positional candidates for pathophysiological traits observed in the SHR strain. These findings provide a basis for the functional testing and ultimate elucidation of the molecular basis of these metabolic and cardiovascular phenotypes.

Genomic variability and protein species — Improving sequence coverage for proteogenomics

“…Previous genomic and physiological studies generated large lists of candidate genes [86][87][88]. The inherited hypertension phenotype in this model suggests that disease is caused by a genetic defect that should manifest itself at the transcriptome and proteome levels.…”

The stroke-prone spontaneously hypertensive rat: still a useful model for post-GWAS genetic studies?

“…50 A similar bioinformatics strategy may be able to dissect the network underlying hypertension in SHR/SHRSP. 19,51 In addition to such bioinformatics studies, another tool may be useful to promote physiological, cell biological and biochemical studies: a 'reconstructed' SHR with a few genomic fragments of SHR/SHRSP on the WKY background.…”

Genome-Wide Identification of Long Noncoding RNAs in Rat Models of Cardiovascular and Renal Disease

“…Chac2 gene is significantly associated with age-related deterioration of normal physiological function as reported through the analysis of two independent cohorts, the SardiNIA and the TwinsUK cohort studies 43 . Similarly, in the context of the S and SHR rats also presenting with features of metabolic syndrome 44–50 , it is interesting to note that Pex11b is correlated with fat metabolism, insulin and blood sugar-related traits in rats 51 and Sp5 , through regulation of Wnt signaling, is implicated in metabolic diseases 52, 53 .…”