title: Evidence of gene-gene interactions in the genetic susceptibility to renal impairment after unilateral nephrectomy.
abstract: The number of patients with hypertension-associated end-stage renal failure (ESRF) continues to increase despite improved antihypertensive management and early detection programs. Variation for the development of renal complications in hypertension may reflect independent genetic susceptibility to ESRF. The genetically hypertensive fawn-hooded rat is characterized by the early presence of systolic hypertension, glomerular hypertension, progressive proteinuria (UPV), and focal glomerulosclerosis (FGS), resulting in premature death as a result of renal failure. In the present study, the genetic basis of hypertension-associated ESRF in an F2 intercross consisting of 337 animals, in which systolic BP, UPV, albuminuria, and FGS, were studied at 8 wk after a unilateral nephrectomy performed at 5 to 6 wk of age. A total genome scan, consisting of 418 markers, was used to identify regions that contribute to the pathogenesis of UPV and FGS. Linkage analysis revealed five loci involved in the development of renal impairment. Of these five, two (Rf-1, Rf-2) had been identified previously. There seems to be strong interactive effects between the various loci and their impact on UPV and the other parameters of renal impairment, as well as an interaction with BP. In particular, Rf-1 seems to play a major role in determining the severity of the disease. This study is the first to report the interaction of more than two loci to produce progressive renal failure, suggesting that the genetic dissection of renal failure in humans will require understanding of how multiple genes interact with each other and BP to produce ESRF.
authors.affiliation: Laboratory for Genetics Research, Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Masahide
authors.initials: M
authors.lastname: Shiozawa
authors.affiliation: Department of Pediatric Surgery, Erasmus University, Rotterdam, The Netherlands.
authors.forename: Abraham P
authors.initials: AP
authors.lastname: Provoost
authors.affiliation: Department of Pediatric Surgery, Erasmus University, Rotterdam, The Netherlands.
authors.forename: Richard P E VAN
authors.initials: RPEV
authors.lastname: Dokkum
authors.affiliation: Laboratory for Genetics Research, Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Rebecca R
authors.initials: RR
authors.lastname: Majewski
authors.affiliation: Laboratory for Genetics Research, Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Jacob
mesh_terms: D000818:Animals; D002874:Chromosome Mapping; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007674:Kidney Diseases / Q000209:etiology* / Q000235:genetics*; D009392:Nephrectomy / Q000009:adverse effects*; D019655:Quantitative Trait, Heritable; D051381:Rats; D011912:Rats, Inbred ACI; D011919:Rats, Inbred Strains; D017385:Sequence Homology; D013045:Species Specificity