We conducted the present study to determine whether the angiotensin II type I receptor (AT,) gene might be implicated in human essential hypertension by using case-control and linkage studies. The entire coding and 3' untranslated regions of the AT, receptor gene (2.2 kb) were amplified by polymerase chain reaction and submitted to single-strand conformation polymorphism in 60 hypertensive subjects with a familial susceptibility. We identified five polymorphisms (T 573 -»C, A 1062 -*G, A" 6 6^C , G 1 5 "^T, and A' 878 -»G). However, no mutations that alter the encoded amino acid sequence were detected. A case-control study performed on white hypertensive (n=206; blood pressure, 168±16/103±9 mm Hg) and normotensive (n=298; blood pressure, 122±10/75±9 mm Hg) subjects using three of five polymorphisms showed a significant increase in allelic fre-H uman essential hypertension is thought to result from the interaction of environmental and genetic factors, with approximately 30% of the interindividual variability in blood pressure being genetically determined.1 The renin-angiotensin system is an important component of blood pressure regulation, playing roles in saltwater homeostasis and vascular tone, 2 and has been suspected to be involved in hypertension. Indeed, evidence for a genetic linkage of human essential hypertension to the angiotensinogen locus was recently obtained in an extensive collaborative study.3 However, linkage and association studies of the human renin and angiotensin I (Ang I)-converting enzyme loci have given negative results. 49Ang II receptors, which mediate the vasoconstrictive and salt-conserving actions of the renin-angiotensin system, also represent interesting candidate genes for essential hypertension. Two subtypes of cell surface

Abstract-Anomalies in either of the tightly linked genes encoding the enzymes CYP11B1 (11␤-hydroxylase) or CYP11B2 (aldosterone synthase) can lead to important changes in arterial pressure and are responsible for several monogenically inherited forms of hypertension. Mutations in these genes or their regulatory regions could thus contribute to genetic variation in susceptibility to essential hypertension. To test this hypothesis, we performed 2 complementary studies of the CYP11B1/CYP11B2 locus in essential hypertension. After characterizing a DNA contig containing the CYP11B1 gene and mapping the gene in the Centre d'Etudes du Polymorphisme Humain reference panel of families, we performed a linkage study with 292 hypertensive sibling pairs and a highly informative microsatellite marker near CYP11B1. We also analyzed the association of 2 frequent biallelic polymorphisms of the CYP11B2 gene, 1 in the promoter at position Ϫ344 (Ϫ344C/T) and the other, a common gene conversion in intron 2, with hypertension in 380 hypertensive patients and 293 normotensive individuals. Statistical analyses did not show significant linkage of the CYP11B1 microsatellite marker to hypertension. No positive association with hypertension was found with the gene conversion in intron 2, but a positive association with hypertension was found with the Ϫ344T allele. The hypertensive and normotensive samples differed significantly in both genotype (Pϭ0.023) and allele frequencies (Pϭ0.010). Our data suggest a modest contribution of the CYP11B2 gene to essential hypertension. (Hypertension. 1998;32:198-204.)Key Words: aldosterone synthase Ⅲ steroid 11␤-hydroxylase Ⅲ biallelic polymorphism Ⅲ microsatellite marker Ⅲ association study Ⅲ linkage study T he cytochrome P450, CYP11B1, a steroid 11␤-hydroxylase, catalyzes the terminal step of cortisol biosynthesis.