Published Online
on September 27, 2004

A more recent version of this article appeared on November 1, 2004

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Submitted on July 13, 2004
Revised on August 2, 2004

Mapping the Genetic Determinants of Hypertension, Metabolic Diseases, and Related Phenotypes in the Lyon Hypertensive Rat

Marijo Bilusic; Alain Bataillard; Michael R. Tschannen; Li Gao; Nadia E. Barreto; Madeleine Vincent; Tao Wang; Howard J. Jacob; Jean Sassard; and Anne E. Kwitek^*

From the Department of Physiology (M.B., M.R.T., L.G., N.E.B., H.J.J., A.E.K.), the Human and Molecular Genetics Center (M.B., M.R.T., L.G., N.E.B., T.W., H.J.J., A.E.K.), and the Division of Biostatistics (T.W.), Medical College of Wisconsin, Milwaukee, and the Faculte de Pharmacie-Université Lyon 1 (A.B., M.V., J.S.), Lyon, France.

^* To whom correspondence should be addressed. E-mail: akwitek{at}mcw.edu.

Abstract--The complex nature of hypertension makes identifying the pathophysiology and its genetic contributions a challenging task. One powerful approach for the genetic dissection of blood pressure regulation is studying inbred rat models of hypertension, as they provide natural allele variants but reduced heterogeneity (both genetic and etiologic). Furthermore, the detailed physiologic studies to which the rat is amenable allow for the determination of intermediate phenotypes. We have performed a total genome scan in offspring of an F₂ intercross between the Lyon hypertensive (LH) and Lyon normotensive rat strains to identify linkage of anthropometric, blood pressure, renal, metabolic, and endocrine phenotypes. Quantitative trait locus (QTL) regions involved in blood pressure regulation, end-stage organ damage, body and organ weight, and lipid metabolism in the LH rat were identified on chromosomes 1, 2, 3, 5, 7, 10, 13, and 17, with 2 phenotypes associated with the metabolic syndrome identified on chromosomes 1 and 17. Regions on chromosomes 2, 13, and 17 were revealed to be important for blood pressure regulation. Regions on chromosome 17 were found to significantly contribute to both metabolic homeostasis and blood pressure regulation; 2 aggregates of a total of 23 QTLs were identified, including several "intermediate phenotypes." These intermediate phenotypes may be used as closer surrogates to the mechanisms leading to hypertension and metabolic dysfunction in the LH rat.

Key words: genetics • linkage analysis • metabolism • hypertension, genetic • rats, inbred strains • cardiovascular diseases

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