Nature 353, 521 - 529 (10 October 1991); doi:10.1038/353521a0

Chromosomal mapping of two genetic loci associated with blood-pressure regulation in hereditary hypertensive rats

P. Hilbert^*†, K. Lindpaintner^‡§, J. S. Beckmann^*, T. Serikawa, F. Soubrier^¶, C. Dubay^*, P. Cartwright^£, B. De Gouyon^*, C. Julier^*, S. Takahasi^§, M. Vincent^**, D. Ganten^§††, M. Georges^‡‡ & G. M. Lathrop^*§§

^* Centre d'Etude du Polymorphisme Humain, 27 rue Juliette Dodu, 75010 Paris, France
^† IRIBNH, Campus Erasme, Brussels 1070, Belgium
^‡ Department of Cellular and Molecular Physiology, Harvard Medical School, Boston, Massachusetts 02115, USA
^§ German Institute for High Blood Pressure, and Department of Pharmacology, University of Heidelberg, D-6900 Heidelberg, Germany
Institute of Laboratory Animals, Faculty of Medicine, Kyoto University, Kyoto 606, Japan
^¶INSERM U. 36, Laboratoire de Médicine Expérimental, Collége de France, Paris 75005, France
^£ Department of Human Genetics, University of Utah, Salt Lake City, Utah 84132, USA
^** Laboratoire de Physiologie, Université Claude Bernard, Lyon 69373, France
^†† Centre for Molecular Medicine, Berlin-Buch 0-1115, Germany
^‡‡ Genmark Inc., 417 Wakara Way, Salt Lake City, Utah 84108, USA
^§§ To whom correspondence should be addressed.

The spontaneously hypertensive rat and the stroke-prone spontaneously hypertensive rat are useful models for human hypertension. In these strains hypertension is a polygenic trait, in which both autosomal and sex-linked genes can influence blood pressure^1–7. Linkage studies in crosses between the stroke-prone spontaneously hypertensive rat and the normotensive control strain Wistar-Kyoto have led to the localization of two genes, BP/SP-1 and BP/SP-2, that contribute significantly to blood pressure variation in the F₂ population. BP/SP-1and BP/SP-2 were assigned to rat chromosomes 10 and X, respectively. Comparison of the human and rat genetic maps indicates that BP/SP-1 could reside on human chromosome 17q in a region that also contains the angiotensin l-converting enzyme gene (ACE)⁸. This encodes a key enzyme of the renin-angiotensin system⁹, and is therefore a candidate gene in primary hypertension. A rat microsatellite marker of ACE was mapped to rat chromosome 10 within the region containing BP/SP-1.

References

1.	Tanase, H. et al. Jap. Circ. J. 51, 1184−1190 (1987).
2.	Louis, W. J. et al. Lancet i, 1035−1036 (1969).
3.	Yen, T. T. et al. Heredity 33, 309−316 (1974).
4.	Harrap, S. B. Hypertension 8, 572−582 (1986).
5.	Pravenec, M. et al. J. Hypertension 7, 217−221 (1989).
6.	Ely, D. L. & Turner, M. E. Hypertension 16, 277−281 (1990).
7.	Lindpaintner, K., Takahashi, S. & Ganten, D. J. Hypertension 8, 763−773 (1990).
8.	Mattei, M. G. et al. Cyto. cell. Genet. 51, 1041 (1989).
9.	Yang, H. Y. T., Erdös, E. G. & Levin, Y. Biochim. biophys. Acta 214, 374−376 (1970).
10.	Dannenberg, A. L. et al. Hypertension 10, 266−233 (1987).
11.	Pickering, G. Am. J. Med. 52, 570−583 (1972).
12.	Ward, R. in Hypertension: Pathophysiology, Diagnosis and Management (eds Laragh, J. H. & Brenner, B. M.) 81−100 (Raven, New York, 1990).
13.	Tanase, H. et al. Jap. Circ. J. 34, 1197−1212 (1970).
14.	Yamori, Y. & Okamoto, K. Lab. Invest. 22, 206−211 (1970).
15.	Rapp, J. P. Hypertension 4, 459−467 (1982).
16.	Rapp, J. P., Wang, S. M. & Dene, H. Science 243, 542−544 (1989).
17.	Kurtz, T. W. et al. J. Clin. Invest 85, 1328−1332 (1990).
18.	Pravnec, M. et al. Genomics 9, 466−472 (1991).
19.	Aoki, K., Yamori, Y., Ooshima, A. & Okamoto, K. Jap. Circ. J. 36, 539−545 (1972).
20.	Dietz, R. et al. J. Cardiovasc. Pharmac. 6, s230−s235 (1984).
21.	Gradin, K. & Persson, B. Acta physiol. Scand. 131, 273−281 (1987).
22.	Luft, F. C. et al. J. Cli. Sci. 74, 577−585 (1988).
23.	Dietz, R. et al. Hypertension 4, 773−781 (1982).
24.	Julier, C. et al. Proc. natn. Acad. Sci. U.S.A. 87, 4585−4589 (1990).
25.	Weber, J. L. & May, P. E. Am. J. hum. Genet. 44, 388−396 (1989).
26.	Litt, M. & Luty, J. A. Am. J. hum. Genet 44, 397−401 (1989).
27.	Todd, J. A. et al. Nature 351, 542−546 (1991).
28.	Cooke, N., Szpirer, C. & Levan, G. Endocrinology 119, 2451−2454 (1986).
29.	Hillyard, A. et al. Locus Map of Mouse with Comparative Map Points of Human on Mouse (The Jackson Laboratory, Bar Harbor, 1991).
30.	Solomon, E. & Barker, D. F. Cytogenet. Cell Genet. 51, 319−337 (1989).
31.	Guyton, A. C. Arterial Pressure and Hypertension (Saunders, Philadelphia, 1980).
32.	Biollaz, J. et al. Hypertension 8, 117−121 (1986).
33.	Hall, J. E. Am. J. Physiol. 19, R960−R972 (1986).
34.	Pravenec, M. et al. Hypertension 17, 242−246 (1991).
35.	Pravenec, M. et al. J. Hypertension 7, 217−221 (1989).
36.	van de Ven, C. M. J. & Boln, D. F. Pfluger's Arch. Eur. J. Physiol. 399, 74−78 (1983).
37.	Yasue, Y. et al. Cytogenet cell. Genet. (in the press).
38.	Lathrop, G. M. & Lalouel, J. M. Am. J. hum. Genet. 36, 460−465 (1984).
39.	Levan, G. et al. Genomics (in the press).
40.	Lathrop, G. M. et al. Genomics 2, 157−164 (1988).
41.	Dixon, W. J. et al. BMDP Statistical Software Manual (University of California Press, Los Angeles, 1988).
42.	Falconer, D. S. Introduction to Quantitative Genetics 2nd edn (Oliver and Boyd, Edinburgh, 1982).
43.	Georges, M. et al. Cytogenet. cell. Genet 47, 127−131 (1988).
44.	Rychlik, W. & Rhoads, R. E. Nucleic Acids Res. 17, 8543−8551 (1989).
45.	Howard, T. E. et al. Molec. cell. Biol. 10, 4294−4302 (1990).