© 1999 American Heart Association, Inc.
Original Contribution |
Structure of the Type B Human Natriuretic Peptide Receptor Gene and Association of a Novel Microsatellite Polymorphism With Essential Hypertension
From the Second Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.
Correspondence to Masayoshi Soma, MD, PhD, Second Department of Internal Medicine, Nihon University School of Medicine, 30-1 Ooyaguchi-kamimachi, Itabashi-ku, Tokyo 173, Japan. E-mail msoma{at}med.nihon-u.ac.jp
Abstract—The
natriuretic peptide (NP) system may play a crucial role in
development of essential hypertension (EH). C-type NP dilates arteries
and lowers blood pressure and inhibits proliferation of vascular smooth
muscle cells via the type B NP receptor (NPR-B). However, the
association of the human NPR-B gene with EH has not been studied,
because little is known about the genomic organization of this gene. We
designed oligonucleotide primers based on the cDNA
sequence of the human NPR-B gene, and long-range polymerase chain
reaction (PCR) was performed. The amplified fragments were sequenced
directly, and the exon/intron organization of the human NPR-B gene was
determined. The gene, which spans 
16.5 kbp, is composed of 22 exons,
and the intron-exon junctions follow the GT-AG rule. Seven hundred
fifty base pairs 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 a sequence-tagged site
(STS). The GT microsatellite repeat was localized to intron 2 150 bp
downstream of the exon-intron junction. Two alleles, (GT)10 and
(GT)11, were detected in both EH patients and age-matched normotensive
(NT) controls. Multiple logistic linear regression analysis
indicated that the NPR-B genotype is associated significantly
with EH (odds ratio 1.55; 95% confidence interval, 1.02 to 2.35). The
(GT)11 frequency was 0.316 (65/206) for the EH group and 0.218 (44/202)
for the NT group and differed significantly between the EH and NT
groups (
2=4.97, P=0.026). The structural
organization of the human NPR-B gene was determined, and 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.
Key Words: natriuretic peptide • receptor, type B • gene structure • association • essential hypertension
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