title: 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.
authors.affiliation: Physiological Genomics and Medicine Group, MRC Clinical Sciences Centre, Department of Epidemiology and Public Health, Faculty of Medicine, Imperial College, London, United Kingdom.
authors.forename: Catherine
authors.initials: C
authors.lastname: Morrissey
authors.forename: Ian C
authors.initials: IC
authors.lastname: Grieve
authors.forename: Matthias
authors.initials: M
authors.lastname: Heinig
authors.forename: Santosh
authors.initials: S
authors.lastname: Atanur
authors.forename: Enrico
authors.initials: E
authors.lastname: Petretto
authors.forename: Michal
authors.initials: M
authors.lastname: Pravenec
authors.forename: Norbert
authors.initials: N
authors.lastname: Hubner
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Aitman
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000378:metabolism*; D020869:Gene Expression Profiling; D056726:Genetic Association Studies / Q000379:methods*; D020022:Genetic Predisposition to Disease; D023281:Genomics / Q000379:methods*; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D015203:Reproducibility of Results; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D020121:5' Untranslated Regions; D012333:RNA, Messenger; D014157:Transcription Factors