An endothelial regulatory module links blood pressure regulation with elite athletic performance

by Kim Fegraeus, Maria K. Rosengren, Rakan Naboulsi, Ludovic Orlando, Magnus Åbrink, Ahmad Jouni, Brandon D. Velie, Amanda Raine, Beate Egner, C Mikael Mattsson, Karin Lång, Artemy Zhigulev, Hanna M. Björck, Anders Franco-Cereceda, Per Eriksson, Göran Andersson, Pelin Sahlén, Jennifer R. S. Meadows, Gabriella Lindgren

The control of transcription is crucial for homeostasis in mammals. A previous selective sweep analysis of horse racing performance revealed a 19.6 kb candidate regulatory region 50 kb downstream of the Endothelin3 (EDN3) gene. Here, the region was narrowed to a 5.5 kb span of 14 SNVs, with elite and sub-elite haplotypes analyzed for association to racing performance, blood pressure and plasma levels of EDN3 in Coldblooded trotters and Standardbreds. Comparative analysis of human HiCap data identified the span as an enhancer cluster active in endothelial cells, interacting with genes relevant to blood pressure regulation. Coldblooded trotters with the sub-elite haplotype had significantly higher blood pressure compared to horses with the elite performing haplotype during exercise. Alleles within the elite haplotype were part of the standing variation in pre-domestication horses, and have risen in frequency during the era of breed development and selection. These results advance our understanding of the molecular genetics of athletic performance and vascular traits in both horses and humans.