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 ma lignant 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 F-1 populations with (a) 100% penetrance of MH in progeny hete rozygous for the Fischer F344 genetic background and (b) 58.5% penetrance i n progeny heterozygous for the Lewis genetic background. To identify the mo difier loci affecting the phenotype, a cohort of 252 males was produced by breeding the same single male with Fischer-Lewis F-1 females. The progeny w ere phenotyped for clinical and pathological features of MH. Results. Genome-wide screening and quantitative trait loci (QTL) analysis i dentified 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 le thal MH phenotype. Their influence on mortality was consistent with a multi plicative effect of the two loci. In addition, we found higher plasma angio tensin-converting enzyme activity in progeny receiving the Fischer allele t han 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 enz yme and MH. Conclusions. Our study demonstrates the application of a transgene as a "ma jor gene" to facilitate the identification of modifier loci, which can affe ct the phenotype of MH, and reveals Ace and At1 as candidate genes involved in the manifestation of the MH phenotype.