Epistatic genetic determinants of blood pressure and mortality in a salt-sensitive hypertension model.
Although genetic determinants protecting against the development of elevated blood pressure (BP) are well investigated, less is known regarding their impact on longevity. We concomitantly assessed genomic regions of rat chromosomes 3 and 7 (RNO3 and RNO7) carrying genetic determinants of BP without known epistasis, for their independent and combinatorial effects on BP and the presence of genetic determinants of survival using Dahl salt-sensitive (S) strains carrying congenic segments from Dahl salt-resistant (R) rats. Although congenic and bicongenic S.R strains carried independent BP quantitative trait loci within the RNO3 and RNO7 congenic regions, only the RNO3 allele(s) independently affected survival. The bicongenic S.R strain showed epistasis between R-rat RNO3 and RNO7 alleles for BP under salt-loading conditions, with less-than-additive effects observed on a 2% NaCl diet and greater-than-additive effects observed after prolonged feeding on a 4% NaCl diet. These RNO3 and RNO7 congenic region alleles had more-than-additive effects on survival. Increased survival of bicongenic compared with RNO3 congenic rats was attributable, in part, to maintaining lower BP despite chronic exposure to an increased dietary salt (4% NaCl) intake, with both strains showing delays in reaching highest BP. R-rat RNO3 alleles were also associated with superior systolic function, with the S.R bicongenic strain showing epistasis between R-rat RNO3 and RNO7 alleles leading to compensatory hypertrophy. Whether these alleles affect survival by additional actions within other BP-regulating tissues/organs remains unexplored. This is the first report of simultaneous detection of independent and epistatic loci dictating, in part, longevity in a hypertensive rat strain.
Cicila
George T
GT
Physiological Genomics Laboratory, Department of Physiology and Pharmacology, University of Toledo College of Medicine, 3000 Arlington Ave, Mail Stop 1008, Toledo, OH 43614, USA.
Morgan
Eric E
EE
Lee
Soon Jin
SJ
Farms
Phyllis
P
Yerga-Woolwine
Shane
S
Toland
Edward J
EJ
Ramdath
Ramona S
RS
Gopalakrishnan
Kathirvel
K
Bohman
Keith
K
Nestor-Kalinoski
Andrea L
AL
Khuder
Sadik A
SA
Joe
Bina
B
D000483:Alleles; D000818:Animals; D020296:Animals, Congenic; D001794:Blood Pressure / Q000235:genetics*; D006332:Cardiomegaly / Q000235:genetics / Q000401:mortality; D004195:Disease Models, Animal; D004843:Epistasis, Genetic / Q000502:physiology*; D006973:Hypertension / Q000235:genetics* / Q000401:mortality*; D008136:Longevity / Q000235:genetics; D008137:Longitudinal Studies; D051381:Rats; D020303:Rats, Inbred Dahl; D017673:Sodium Chloride, Dietary / Q000494:pharmacology; D013045:Species Specificity; D016019:Survival Analysis
D017673:Sodium Chloride, Dietary