Genetic variation at the human connexin 43 locus but not connexin 40 locus is associated with left bundle branch block

Abstract

Purpose: Bundle branch block has previously been regarded as a disease of the conduction system. Evolving evidence, including data from knock-out mice, suggest that Bundle Branch Block (BBB) also can be the result of impaired conduction distal to the conduction system. Connexin 40 is expressed in atria and the proximal conduction system. Connexin 43 is expressed in cardiomyocytes. We wanted to explore if bundle branch block is a heritable trait and if genetic variation at the loci for connexin 40 and 43 are associated with bundle branch block. Methods: To assess heritability of bundle branch block we screened descendants from men with bundle branch blocks participating in Study of Men Born 1913. To assess genetic variation at the connexin 40 and 43 loci DNA samples from twenty 80 year old men (representing extreme phenotypes regarding long/short QRS) and two sons with BBB were used as a screening panel. The coding exons and 5' and 3-UTR part of the genes for connexin 40 and connexin 43 were sequenced in search for polymorphisms. Association between the identified polymorphisms and bundle branch block were then evaluated in an independent cohort sampled from INTERGENE with 108 BBB (70 RBBB, 38 LBBB) and 266 controls without BBB. Results: Seventyseven men from Study of Men Born 1913 with BBB and families had 116 offspring, of these 76 (66%) were willing to participate. Offspring had a mean age of 53 years on examination. Seventeen of all men (41%) had a QRS >95 ms, which is longer than expected at that age, and two sons had BBB. 6 Single Nucleotide Polymorphisms (SNPs) were identified in Connexin 40 and one insertion/deletion polymorphism in connexin 43. The INTERGENE cohort was genotyped for identified polymorphisms and an association between the Cx43 insertion/deletion polymorphism and Left Bundle Branch Block was observed, (chi-square 8.6, p=0.02) but no association to RBBB or overall BBB. None of the connexin 40 SNPs or haplotypes were associated with LBBB nor RBBB. Conclusions: In conclusion, we identified an insertion/deletion polymorphism in connexin 43 associated with left bundle branch block. No association was seen between genetic variation in Connexin 40 and LBBB nor RBBB. These findings suggest that conduction within the ventricular muscle distal to the specialised conduction system can be of importance for bundle branch block development.