Original Article
Kidney International (1999) 56, 414–420; doi:10.1046/j.1523-1755.1999.00571.x
Genetic mapping of modifier loci affecting malignant hypertension in TGRmRen2 rats
Surasak Kantachuvesiri, Chris S Haley, Stewart Fleming, Katarna Kurian, Caroline E Whitworth, Philip Wenham, Yuri Kotelevtsev and John J Mullins
Centre for Genome Research, University of Edinburgh; Roslin Institute; Department of Pathology, University of Edinburgh Medical School; Department of Renal Medicine, Royal Infirmary of Edinburgh; and Department of Clinical Biochemistry, Western General Hospital, Edinburgh, Scotland, United Kingdom
Correspondence: John J. Mullins, Ph.D., Department of Medical and Radiological Sciences, Wilkie Building, University of Edinburgh Medical School, Teviot Place, Edinburgh EH8 9AG, United Kingdom. E-mail: J.Mullins@ed.ac.uk
Received 13 November 1998; Revised 18 March 1999; Accepted 28 March 1999.
Abstract
Genetic mapping of modifier loci affecting malignant hypertension in TGRmRen2 rats.
Background
Genetic background has a major influence on the manifestation of multifactorial diseases such as hypertension in which severe complications may be caused through an interaction with additional factors, which may be genetically determined. We have previously described a genetic model of malignant hypertension (MH) in rats carrying the mouse Ren2 gene (TGRmRen2-27), in which the phenotype is dependent on the genetic background.
Methods
Using a single homozygous TGRmRen2-27 male as transgene donor, we produced two F1 populations with (a) 100% penetrance of MH in progeny heterozygous for the Fischer F344 genetic background and (b) 58.5% penetrance in progeny heterozygous for the Lewis genetic background. To identify the modifier loci affecting the phenotype, a cohort of 252 males was produced by breeding the same single male with Fischer-Lewis F1 females. The progeny were phenotyped for clinical and pathological features of MH.
Results
Genome-wide screening and quantitative trait loci (QTL) analysis identified two loci, on chromosome 10 (LOD 4.4) and on chromosome 17 (LOD 3.9) close to the Ace and At1 genes, respectively, which contribute to the lethal MH phenotype. Their influence on mortality was consistent with a multiplicative effect of the two loci. In addition, we found higher plasma angiotensin-converting enzyme activity in progeny receiving the Fischer allele than in progeny receiving the Lewis allele (123.5 
9.5 vs. 91.8 4.9 U/liter, P < 0.01), suggesting the association of angiotensin-converting enzyme and MH.
Conclusions
Our study demonstrates the application of a transgene as a "major gene" to facilitate the identification of modifier loci, which can affect the phenotype of MH, and reveals Ace and At1 as candidate genes involved in the manifestation of the MH phenotype.
Keywords:
gene mapping, hypertension, cardiovascular, transgenic rat, renin-angiotensin system
