Characterization of a unique genetic variant in the β1-adrenooeptor gene and evaluation of its role in idiopathic dilated cardiomyopathy

The genetic factors that underlie idiopathic dilated cardiomyopathy (IDCM) have not yet been elucidated. Since beta(1)-adrenoceptors are downregulated in patients with IDCM, and since beta-blocker therapy is consistently beneficial in this setting, we hypothesized that genetic variation in the beta(1)-adrenoceptor might affect susceptibility to and/or severity of IDCM. As no intragenic polymorphism was available, a systematic screening of the gene was first performed. The organization and sequence of the human beta(1)-adrenoceptor gene were established using polymerase chain reaction, single-strand conformation polymorphism analysis and sequencing. The gene comprises 1434 bp and no intron was observed. We found a unique and frequent polymorphism (C1165G) which predicts an Arg389Gly substitution. The association of this polymorphism with IDCM was then analysed using the PCR-restriction fragment length polymorphism method in the CARDIGENE population, a clinically well-characterized population of IDCM. Genotypic distribution was in agreement with Hardy-Weinberg equilibrium. There were no differences in the beta(1)-adrenoceptor allele frequencies between IDCM (n = 426; C/G = 0.76/0.24) and age- and sex-matched control subjects (n = 395; C/G =0.78/0.22). Within the patient group. no association was observed with the severity of the disease, In conclusion, the genomic organization of beta(1)-adrenoceptor is described here for the first time. We found a unique and frequent polymorphism in the coding sequence of the gene. No association was observed between IDCM and the genetic variant. Its possible involvement in other cardiac diseases related to the beta(1)-adrenoceptor remains to be analysed. (C) 1999 Academic Press.