Abstract 177: Association Mapping of Phosducin in Inbred Rat Models of Hypertension and Response to Chronic Stress
Background: Hypertension and its complications represent a leading cause of morbidity and mortality. Numerous lines of evidence suggest that a significant portion of the disease risk is determined by genetic factors. The phosducin gene (PDC) emerged as a novel candidate since a knockout mouse model develops profound hypertension, particularly during stress. Furthermore, in 3 independent human populations we have shown an association of SNPs in a haplotype block containing PDC with blood pressure and stress responses. In order to investigate the role of PDC, we utilized an association mapping approach in inbred rat models to determine regions of PDC affecting blood pressure phenotypes.
Methods: We fully resequenced PDC in 9 normotensive and 5 hypertensive inbred rat strains. For further physiological studies, we selected rat strains representing haplotypes with likely functional effects (SS, BN, F344). Rats were implanted with telemetry transmitters at 8 weeks of age (n=8 /group), and blood pressure was measured during 1 week of recovery and 2 weeks of stress.
Results: We identified 26 SNPs and 2 hypertensive strains, FHH and SHR, contained unique SNPs. Comparing hypertensive and normotensive rat strains, we identified a significant difference for a two SNP haplotype in the 3′ untranslated region of PDC (p<0.05). In our chronic stress protocol, we found that stress negatively affects body weight (p<0.0001) and causes increase in adrenal (p<0.01) and decrease in thymus weight (p<0.01). Also, SS and F344 require more time than BN to recover resting blood pressure following surgery. F344 and SS stress rats had significantly higher heart rates when compared to controls (p<0.01; 0.05). We noted several differences between blood pressure profiles that suggest a rise in systolic blood pressure for SS rats, and sensitivity to stress in F344.
Conclusion: The PDC gene sequence differs between hypertensive and other inbred strains in a 2-SNP haplotype in the 3′ untranslated region. Strains representing these haplotypes show significant differences for hypertension and stress related phenotypes, suggesting that SNPs in the 3′region of PDC have a functional effect. This expands the evidence for the influence of PDC on blood pressure previously found in human and mouse.