Linkage Studies in Essential Hypertension.

Essential hypertension is a multifactorial and polygenic disease. The absence of hypotheses concerning inheritance imposes critical limits on strategies to define its genetic determinants. Genetic linkage studies in multiple affected hypertensive sibships are usually performed with an affected sib-pair method, and rely on the use of highly polymorphic markers located near potential candidate genes. Such markers are frequently found in the genome and can be identified by cloning methods. Candidate genes to be studied in human hypertensive pedigrees are determined from human or animal physiological studies or from animal genetic studies employing experimental models. Linkage and case-control studies of candidate genes have been done recently with a unique sample of 200 French hypertensive pedigrees. Using highly informative genetic markers in hypertensive sibships, the angiotensinogen, angiotensin II type I (AT1) receptor, endothelial nitric oxide synthase, and SA loci have all been studied. It was shown that the angiotensinogen locus, and possibly the AT1 receptor, are implicated in hypertension. No linkage of the endothelial NO synthase or SA genes was noted. A gene common to human and experimental animal models of hypertension has yet to be found. Such studies demonstrate the usefulness of this approach to unravel the genetic determinants of essential hypertension. Future linkage studies will combine candidate gene and “total genome” approaches, although the effect of a major gene on blood pressure variability is unlikely.