(1) Endothelial constitutive NO synthase (ecNOS) gene may be involved in the pathogenesis of essential hypertension (EH). We investigated the possible association between a variable number of tandem repeats (VNTR) polymorphism in intron 4 of the ecNOS gene and EH. The overall distributions of allele frequencies differed significantly between the two groups, with the four-repeat allele more frequent in the EH group than in the normotensive group (p=0.00027, odds ratio=4.0). The four-repeat allele of the ecNOS gene was thus associated with EH and may be a genetic marker of this disease in Japanese subjects.
(2) The natriuretic peptide (NP) family is involved in regulation of blood pressure and fluid volume. We determined the exon/intron organization of human natiuretic peptide receptor the type A (hNPRA) gene. The gene, which spans more than 16 kilobases, is composed of 22 exons, and we isolated the 5'-flanking region of the gene and identified an insertion/deletion mutation in this regio
n. Our results suggest that this deletion in the hNPRA gene reduces receptor activity and may confer increased susceptibility to developing EH or LVH.
(3) We determined the organization of human natriuretic peptide receptor the type B (NPRB) gene. This gene, which spans approximately 16.5 kilobase (kbp), is composed of 22 exons, and the intron-exon junctions follow the GT-AG rule. Seven hundred fifty basepaires of the 5' flanking region were sequenced using a thermal asymmetric interlaced-PCR (TAIL-PCR) method. This region contains 10 potential Sp1-binding sites and lacks a TATA box. Rapid amplification of cDNA ends (RACE) revealed the transcriptional start site at -14 bp. A CA/GT microsatellite repeat was identified with a hybridization-based method and was converted to sequence tagged site (STS). Association study using a novel GT repeat polymorphism, which associated with EH, was identified. These results suggest that one cause of EH is a mutation in this gene or a closely related gene or region.
(4) The adenosine A2a receptor (A2aAR) gene is thought to be involved in essential hypertension because adenosine elicits vasodilation and decreases arterial blood pressure via this receptor, and because disruption of the A2aAR gene increases blood pressure in mice. Therefore, using a restriction fragment length polymorphism (RFLP) of the A2aAR gene, we performed an association study in patients with EH. Our resullts suggest that the alleles detected by this RFLP polymorphism in the A2aAR gene is not associated with EH.
(5) Defective renal dopamine receptor function have been reported in EH. Using a RFLP of the dopamine D1 redeptor (DRD1) gene, we performed an association study in patients with EH. The alleles detected by this RFLP polymorphism in the DRD1 gene are associated with EH, and they appear to influence diastolic blood pressure of Japanese EH patients. Less