High-Resolution Identity by Descent Mapping Uncovers the Genetic Basis for Blood Pressure Differences Between Spontaneously Hypertensive Rat Lines

Abstract

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 SHR-A3 (SHRSP, SHR-stroke prone) line and the injury-resistant SHR-B2 line. This revealed that that the two 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 16–18wk old animals fed a normal diet, systolic blood pressure (SBP, mm Hg) in SHR-A3 was 205.7 ± 3.86 (mean ± SEM, n = 26), while 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). In order 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 less than 10Mb 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.

Hypertensive Renal Injury Is Associated With Gene Variation Affecting Immune Signaling

“…The origin of these inbred lines has been previously reported 2, 9 . Animals were housed in an AAALAC-approved animal facility and provided a standard rodent chow diet and drinking water ad libitum.…”

“…The two lines are derived from a single pair of founders common to both lines 11 . The ~87% of the genome shared identical by descent (IBD) across these lines is partitioned into discrete haplotype blocks 9 . SHR-A3 (males) and SHR-B2 (females) were crossed to generate an F1 progeny.…”

“…SHR-A3 (males) and SHR-B2 (females) were crossed to generate an F1 progeny. The F1 progeny was further crossed to generate a freely-segregating F2 progeny (n=210), as previously reported 9 . All animal use was prospectively reviewed and approved by the University’s Animal Welfare Committee.…”

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

“…It is thus expected that these strains will share the same alleles in much of their genome. Doris and his colleagues 23 used such identity-by-decent areas to exclude the genomic regions that do not contribute to BP differences between SHR/B2 and SHRSP/A3. Combining the identity-by-decent information with a QTL analysis, they identified a small non-identity-by-decent area on Chr 17, which could harbor a gene (or genes) contributing to the BP difference between the two strains.…”

“…On the basis of comprehensive gene expression data, they further suggested that Slc34a1, a sodium/phosphate co-transporter expressed in renal tubules, was a candidate gene. 23 This is a unique strategy in that they took advantage of the common genetic backgrounds shared between SHR and SHRSP.…”