Characterization of a unique genetic variant in the beta(1)-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 bene ficial 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 gen e was first performed. The organization and sequence of the human beta(1)-a drenoceptor gene were established using polymerase chain reaction, single-s trand conformation polymorphism analysis and sequencing. The gene comprises 1434 bp and no intron was observed. We found a unique and frequent polymor phism (C1165G) which predicts an Arg389Gly substitution. The association of this polymorphism with IDCM was then analysed using the PCR-restriction fr agment length polymorphism method in the CARDIGENE population, a clinically well-characterized population of IDCM. Genotypic distribution was in agree ment 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). Withi n the patient group. no association was observed with the severity of the d isease, In conclusion, the genomic organization of beta(1)-adrenoceptor is described here for the first time. We found a unique and frequent polymorph ism in the coding sequence of the gene. No association was observed between IDCM and the genetic variant. Its possible involvement in other cardiac di seases related to the beta(1)-adrenoceptor remains to be analysed. (C) 1999 Academic Press.