High-resolution identity by descent mapping uncovers the genetic basis for blood pressure differences between spontaneously hypertensive rat lines.

TitleHigh-resolution identity by descent mapping uncovers the genetic basis for blood pressure differences between spontaneously hypertensive rat lines.
Publication TypeJournal Article
Year of Publication2011
AuthorsBell, R, Herring, SM, Gokul, N, Monita, M, Grove, ML, Boerwinkle, E, Doris, PA
JournalCirc Cardiovasc Genet
Date Published2011 Jun
KeywordsAnimals, Blood Pressure, Chromosome Mapping, Female, Gene Expression, Genetic Predisposition to Disease, Genotype, Haplotypes, Lod Score, Male, Molecular Sequence Data, Polymorphism, Single Nucleotide, Rats, Rats, Inbred SHR

BACKGROUND: The recent development of a large panel of genome-wide single nucleotide polymorphisms (SNPs) provides the opportunity to examine genetic relationships between distinct SHR lines that share hypertension but differ in their susceptibility to hypertensive end-organ disease.METHODS AND RESULTS: We compared genotypes at nearly 10,000 SNPs obtained for the hypertension end-organ injury-susceptible spontaneously hypertensive rat (SHR)-A3 (SHRSP, SHR-stroke prone) line and the injury-resistant SHR-B2 line. This revealed that that the 2 lines were genetically identical by descent (IBD) across 86.6% of the genome. Areas of the genome that were not IBD were distributed across 19 of the 20 autosomes and the X chromosome. A block structure of non-IBD comprising a total of 121 haplotype blocks was formed by clustering of SNPs inherited from different ancestors. To test the null hypothesis that distinct SHR lines share a common set of hypertension susceptibility alleles, we compared blood pressure in adult SHR animals from both lines and their F1 and F2 progeny using telemetry. In 16- to 18-week-old animals fed a normal diet, systolic blood pressure (SBP, mm Hg) in SHR-A3 was 205.7 ± 3.86 (mean ± SEM, n = 26), whereas in similar SHR-B2 animals, SBP was 186.7 ± 2.53 (n = 20). In F1 and F2 animals, SBP was 188.2 ± 4.23 (n = 19) and 185.6 ± 1.1 (n = 211), respectively (P<10(-6), ANOVA). To identify non-IBD haplotype blocks contributing to blood pressure differences between these SHR lines, we developed a high-throughput SNP genotyping system to genotype SNPs marking non-IBD blocks. We mapped a single non-IBD block on chromosome 17 extending over <10 Mb, at which SHR-A3 alleles significantly elevate blood pressure compared with SHR-B2.CONCLUSIONS: Thus hypertension in SHR-A3 and -B2 appears to arise from an overlapping set of susceptibility alleles, with SHR-A3 possessing an additional hypertension locus that contributes to further increase blood pressure.

Alternate JournalCirc Cardiovasc Genet
PubMed ID21406686
PubMed Central IDPMC3116070
Grant ListR01 DK081866 / DK / NIDDK NIH HHS / United States
R01 DK069632-05 / DK / NIDDK NIH HHS / United States
R01 DK069632 / DK / NIDDK NIH HHS / United States
R01 DK081866-01 / DK / NIDDK NIH HHS / United States
R01-DK069632 / DK / NIDDK NIH HHS / United States
R01-DK08186 / DK / NIDDK NIH HHS / United States
R01 DK081866-02 / DK / NIDDK NIH HHS / United States

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