The renin-angiotensin system is involved in control of blood pressure and salt and fluid homeostasis. Genes for components of this system have been of major focus in research on the causation of the common, complex, polygenic trait, essential hypertension (HT). Association of an A-->C variant at nucleotide 1166 of the angiotensin II type 1 receptor (AT1R) gene with HT, but an absence of linkage of this locus with this disease, has been reported recently. Since confirmation in a different setting is imperative, we performed a cross-sectional case-control study of the A1166C variant in a well-characterized group of 108 Caucasian HT subjects with a strong family history (two affected parents) and early onset disease. Genotyping was by mismatch polymerase chain reaction/BfrI restriction fragment length polymorphism analysis. Frequency of the C1166 allele was 0.40 in HTs and 0.29 in normotensives. The difference in genotype (chi 2 = 13, P = 0.0015) and allele (chi 2 = 5.3, P = 0.02) frequencies between the two groups was significant (odds ratio for CC vs AA + AC = 7.3 [95% CI, 1.9-31.9). The present results implicate the AT1R gene, or a locus in linkage disequilibrium with the variant tested, in the causation of essential HT.