ANALYSIS OF AN EXON-1 POLYMORPHISM OF THE B2 BRADYKININ RECEPTOR GENEAND ITS TRANSCRIPT IN NORMAL SUBJECTS AND PATIENTS WITH C1 INHIBITOR DEFICIENCY

The B2 bradykinin receptor (B2BKR) mediates most of the inflammatory a ctions of bradykinin. To evaluate its potential role in allergic disea ses, we assessed the structure of the human B2BKR gene. Screening a hu man placenta genomic DNA library identified only clones containing exo ns 2 and 3. Human placenta and colon tissues were used for 5' rapid am plification of complementary DNA ends to identify nine exon 1 clones, each containing one 9 bp and two 1 bp deletions compared with publishe d sequences. Exon 1 genomic polymerase chain reaction of human leukocy te DNA revealed two distinct products, which were shown to differ by t he presence of absence of the 9 bp deletion. Alleles with the 9 bp del etion were designated as (-)(21-29), whereas alleles without the delet ion were designated as (+)(21-29). Genomic polymerase chain reaction i n 39 Caucasian, 31 African-American, and 32 Asian normal subjects reve aled a highly significant difference in the allelic frequency of the t wo genotypes, primarily because of an absence of the (+)(21-29) allele in Asian subjects. Analysis of steady-state B2BKR messenger RNA level s by reverse-transcription polymerase chain reaction in heterozygous n ormal subjects revealed consistently higher expression of (-)(21-29) t ranscripts. To investigate the potential clinical significance of the exon 1 polymorphism, 21 patients with angioedema and C1 inhibitor defi ciency were genotyped. None were homozygous for the (+)(21-29) allele (p = 0.0088 compared with normal subjects). In contrast, two patients with immunochemical evidence of hereditary angioedema without history of clinical angioedema were (+)(21-29) homozygous. These results sugge sts that the B2BKR genotype may influence clinical status in diseases characterized by involvement of bradykinin.