Genome-wide identification of allelic expression in hypertensive rats.

TitleGenome-wide identification of allelic expression in hypertensive rats.
Publication TypeJournal Article
Year of Publication2009
AuthorsDmitrieva, RI, Hinojos, CA, Grove, ML, Bell, RJ, Boerwinkle, E, Fornage, M, Doris, PA
JournalCirc Cardiovasc Genet
Volume2
Issue2
Pagination106-15
Date Published2009 Apr
ISSN1942-3268
KeywordsAlleles, Animals, Blood Pressure, Disease Models, Animal, Female, Gene Expression Profiling, Genome-Wide Association Study, Humans, Hypertension, Kidney, Male, Pedigree, Polymorphism, Single Nucleotide, Rats, Rats, Inbred SHR, Rats, Inbred WKY
Abstract

BACKGROUND: Identification of genes involved in complex cardiovascular disease traits has proven challenging. Inbred animal models can facilitate genetic studies of disease traits. The spontaneously hypertensive rat (SHR) is an inbred model of hypertension that exists in several closely related but genetically distinct lines.METHODS AND RESULTS: We used renal gene-expression profiling across 3 distinct SHR lines to identify genes that show different expression in SHR than in the genetically related normotensive control strain, Wistar-Kyoto. To ensure robust discovery of genes showing SHR-specific expression differences, we considered only those genes in which differential expression is replicated in multiple animals of each of multiple hypertensive rat lines at multiple time points during the ontogeny of hypertension. Mutation analysis was performed on the identified genes to uncover allelic variation. We identified those genes in which all SHR lines share a single allele of the gene when normotensive controls (Wistar-Kyoto) have fixed the alternative allele. We then identified which of the differentially expressed genes show expression that is controlled by the alleleic variation present in and around the gene. Allelic expression was demonstrated by observing the effect on gene expression of alleles inherited in the freely segregating F(2) progeny of a cross between SHR and Wistar-Kyoto animals.CONCLUSIONS: The result of these studies is the identification of several genes (Ptprj, Ela1, Dapk-2, and Gstt2) in which each of 4 SHR lines examined have fixed the same allele and in which each of 2 Wistar-Kyoto lines have a contrasting allele for which the inherited allele influences the level of gene expression. We further show that alleles of these genes lie in extensive haplotype blocks that have been inherited identical by descent in the hypertensive lines.

DOI10.1161/CIRCGENETICS.108.809509
Alternate JournalCirc Cardiovasc Genet
PubMed ID20031574
PubMed Central IDPMC2760851
Grant ListHL69126 / HL / NHLBI NIH HHS / United States
R01 DK045538 / DK / NIDDK NIH HHS / United States
R01 DK045538-10 / DK / NIDDK NIH HHS / United States
DDK74680 / / PHS HHS / United States
R01 DK069632-02 / DK / NIDDK NIH HHS / United States
R01 HL069126-03 / HL / NHLBI NIH HHS / United States
R37 HL051021-15 / HL / NHLBI NIH HHS / United States
R37 HL051021 / HL / NHLBI NIH HHS / United States
NS41466 / NS / NINDS NIH HHS / United States
R01 NS041466 / NS / NINDS NIH HHS / United States
HL51021 / HL / NHLBI NIH HHS / United States
DDK45538 / / PHS HHS / United States
R01 DK069632 / DK / NIDDK NIH HHS / United States
R01 NS041466-04 / NS / NINDS NIH HHS / United States
R01 HL069126 / HL / NHLBI NIH HHS / United States