title: Association of CT dinucleotide repeat polymorphism in the 5'-flanking region of the guanylyl cyclase (GC)-A gene with essential hypertension in the Japanese.
abstract: Guanylyl cyclase (GC)-A (natriuretic peptide receptor [NPR]-1), the receptor for atrial and brain natriuretic peptide, is important in the regulation of blood pressure in animal models and, possibly, in humans. In this study, we examined the association between dinucleotide repeat polymorphism within the 5'-flanking region of the GC-A gene and essential hypertension in a group of Japanese subjects. By genotyping 177 hypertensive and 170 normotensive subjects, we identified 5 allele types with 6, 9, 10, 11 and 12 CT dinucleotide repeats, respectively, around position -293, upstream of the ATG codon in the human GC-A gene. The frequency of the (CT)n=6 allele was significantly higher among hypertensive than normotensive subjects, while the frequencies of the other allele types did not differ between the two groups. We also examined the linkage between G/A polymorphism at position -77 (rs13306004), downstream of the (CT)n polymorphism, and found that the (CT)n=6 allele was tightly linked to an A at position -77, while all other (CT)n alleles were linked to G. Promoter-reporter analyses carried out in cultured human aortic smooth muscle cells using a luciferase gene fused to the 5'-flanking region of the GC-A gene revealed that the promoter containing (CT)n=6 drove less transcriptional activity than that containing (CT)n=10. Finally, site-directed mutation showed that the (CT)n and G/A polymorphisms act synergistically to affect GC-A promoter activity. Our results thus define the (CT)n polymorphism in the 5'-flanking region of the GC-A gene as a potent and novel susceptibility marker for hypertension.
authors: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Japan.
authors: Satoru
authors: S
authors: Usami
authors: Ichiro
authors: I
authors: Kishimoto
authors: Yoshihiko
authors: Y
authors: Saito
authors: Masaki
authors: M
authors: Harada
authors: Koichiro
authors: K
authors: Kuwahara
authors: Yasuaki
authors: Y
authors: Nakagawa
authors: Michio
authors: M
authors: Nakanishi
authors: Shinji
authors: S
authors: Yasuno
authors: Kenji
authors: K
authors: Kangawa
authors: Kazuwa
authors: K
authors: Nakao
mesh_terms: D024506:5' Flanking Region / Q000235:genetics*; D000368:Aged; D000483:Alleles; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics; D018900:Dinucleotide Repeats / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D017930:Genes, Reporter / Q000235:genetics; D005838:Genotype; D006162:Guanylate Cyclase / Q000235:genetics*; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000453:epidemiology* / Q000235:genetics*; D007564:Japan / Q000453:epidemiology; D008156:Luciferases / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D010957:Plasmids / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D004247:DNA; D008156:Luciferases; D006162:Guanylate Cyclase