Abstract-The natriuretic peptide (NP) family is involved in the regulation of blood pressure and fluid volume. We isolated the 5Ј-flanking region of the type A human NP receptor gene and identified an insertion/deletion mutation in this region. We then assessed whether there is a genetic association between this mutation and essential hypertension (EH). The deletion allele lacks 8 nucleotides and alters binding sites for the activator protein-2 (AP-2) and Zeste transcriptional factors. We genotyped 200 EH and 200 normotensive (NT) individuals and found 9 subjects with the deletion (8 in the EH group and 1 in the NT group). All 9 individuals were heterozygous. The NT subject with the mutation had left ventricular hypertrophy without hypertension. Transcriptional activity of the deletion allele was Ͻ30% that of the wild-type allele. The plasma levels of brain NP in EH patients with the deleted allele were significantly higher than the levels in the EH patients with the wild-type allele, and plasma brain NP levels were significantly higher in subjects with the deleted allele than in subjects with the wild-type allele, despite comparable blood pressures. These findings suggest that in Japanese individuals, this deletion in the human NP receptor gene reduces receptor activity and may confer increased susceptibility to developing EH or left ventricular hypertrophy. Key Words: natriuretic peptides Ⅲ type A receptors Ⅲ 5Ј-flanking region Ⅲ essential hypertension T hree types of natriuretic peptides (NPs) have been isolated: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). The NP family elicits a number of vascular, renal, and endocrine effects that help maintain blood pressure and extracellular fluid volume. 1-3 These effects are mediated by specific binding of NP to cell surface receptors that have been characterized, purified, and cloned from the vasculature, kidney, adrenal gland, and brain. 4 -7 There are 3 subtypes of NP receptors: type A NP receptor (NPRA), 4 type B NP receptor (NPRB), 8 and type C NP receptor (NPRC). 5 All 3 influence cellular second messengers. NPRA and NPRB are guanylyl cyclase receptors, and their activation increases cGMP levels. 9 Activation of NPRC results in the inhibition of adenylyl cyclase activity. 10 Human NPRA (hNPRA) has high structural homology with human NPRB (hNPRB) and also contains a highly conserved guanylyl cyclase domain. 5 ANP and BNP bind primarily to NPRA, which exerts its effect on the vasculature, causing vasodilation and inhibition of the proliferation of vascular smooth muscle cells. 11 Essential hypertension (EH) is thought to be a multifactorial disorder, and there are only a few reports of candidate genes associated with EH. 12 Mice with a targeted deletion of NPRA showed hypertension, cardiac hypertrophy, and sudden death. 13 These findings suggest that NPRA may play key roles in vasodilation, maintenance of blood pressure, and cardiac remodeling and that lack of it may lead to hypertension and other cardiov...