Background: Lack of connexin40, a gap junction protein expressed in endothelial and renin-producing cells, results in hypertension and cardiac hypertrophy in mice due to unleashed renin production caused by disruption of the pressure-induced feedback inhibition. We analysed human GJA5 consisting of two exons (exon1A or 1B and exon2) in a selected cohort identified by a single nucleotide polymorphism (SNP) in the GJA5 intron for polymorphisms and putative association with hypertension and left ventricular hypertrophy (LVH).
Methods: Individuals carrying a SNP in the intron of GJA5 (rs791295) were selected from the MONICA/KORA cohort (n = 1677) and searched for GJA5 polymorphisms. We accessed DNA of 178 probands, of which 26 suffered from LVH, 112 were hypertensive and 29 normotensive (unknown: 11).
Results: Sequencing of the GJA5 coding region did not reveal alterations suggesting the expression of functional connexin40 in all probands. Sequencing of the upstream region of transcript 1A including exon1A revealed two previously described linked SNPs (rs35594137 -44G>A; rs11552588 + 71A>G) at an increased frequency. Moreover, the rare genotype was significantly associated with hypertension and LVH with a preponderance in men. Functional analysis in a reporter gene assay verified promoter activity, however, it was unchanged by the identified SNPs after expressing respective reporter constructs in HeLa and human endothelial cells.
Conclusion: We suggest to consider the -44G>A SNP upstream of the connexin40 transcript 1A indeed as a risk factor for hypertension in men. However, the underlying mechanisms remain unclear but animal data suggest that renin-producing cells may be involved and contribute to hypertension.
Keywords: Cx40 transcript 1A; connexin40 gene (GJA5); hypertension; polymorphisms; renin-producing cells.