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

BACKGROUND Bundle branch block (BBB) has been regarded as a disease of the conduction system, but occurs in mice lacking connexin 40 (expressed in atria, proximal conduction system) or connexin 43 (expressed in Purkinje cells, cardiomyocytes). OBJECTIVE The aim of this paper is to explore whether BBB is heritable, and whether polymorphisms at connexin 40 and connexin 43 loci are associated with BBB. METHODS To assess BBB heritability, we screened descendants of men with BBB in the population cohort 'The Study of Men Born 1913'. DNA samples from 80-year-old men with extreme QRS-duration phenotypes were used to search for polymorphisms at connexin 40 and 43 loci. Associations between identified polymorphisms and BBB were evaluated in an independent cohort (INTERGENE). RESULTS Seventy-seven men from 'The Study of Men Born 1913' with BBB had 116 descendants. Among the 76 participating descendants, 2 sons (6.4%) had BBB at 54 years of age. At the same age, 0.9% of men born in 1913 had BBB. We identified 6 single nucleotide polymorphisms (SNPs) in connexin 40 and 1 polymorphism in connexin 43. In the INTERGENE cohort, the connexin 43 polymorphism was associated with left BBB (LBBB) (4 of 35 LBBB vs 16 of 232 without BBB, χ(2)=7.4, p=0.03), but not with right BBB (RBBB) or overall BBB. None of the connexin 40 SNPs or haplotypes were associated with LBBB or RBBB. CONCLUSIONS These findings indicate that conduction by connexin 43 within the ventricular muscle distal to the specialised conduction system may be important for LBBB development.