SELECTED CANDIDATE GENES IN HUMAN HYPERTENSION

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Familial aggregation of essential hypertension (EH) implies genetic factors in its etiology. We propose to test specific genetic hypotheses through three distinct strategies applied to familial material at hand. We will use 148 multiplex EH sibships with a total of 296 EH siblings and 15 pedigrees each with at least 4 EH subjects (4 to 10) among 20 sampled relatives already ascertained under other, non-overlapping support. Two classes of hypotheses will be tested: (1) the renin angiotensin system may be directly involved in the etiology of EH through mutations of the renin, angiotensinogen or angiotensin-I converting (ACE) enzyme genes. (2) Peripheral and central adrenergic systems have been implicated in the pathogenesis of EH. We will test the involvement of 4 adrenergic receptors subtypes, alpha1, alpha2, beta1 and beta2 receptors. These hypotheses will be tested either by linkage analysis or, in the select case of renin, by direct search for DNA variants. A. Linkage analysis will include three components: (1) The development of highly polymorphic genetic systems based on tandem repeats of simple sequence motifs, as the information content of marker loci critically determine the power to detect linkage; (2) Joint analysis of biochemical measurements and genotypes at three loci of the RAS (REN, ANG and ACE) in pedigrees and sib-pairs of hypertensive subjects; (3) Sib-pair analysis of linkage between EH and RFLPs of the renin- angiotensin system and adrenergic receptors genes in hypertensive sib- pairs. B. Direct search for DNA variants at the renin locus will be performed in 20 hypertensive subjects selected on the basis of immunoreactive renin in the extreme range of recorded values, through a combination of chemical mismatch detection and direct DNA sequencing.