Gene Silencing and Haploinsufficiency of Csk in GWAS Locus 15q24 Increase Blood Pressure. B. Oh1,2,3, H. Lee2, S. Ji2, S. Park2, M. Kim3, B. Jigden1, J. Lim1, Y. Lee4 1) Biomedical Engineering, Sch Med, Kyung Hee Univ, Seoul, South Korea; 2) Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul, Korea; 3) Department of Medicine, Graduate School, Kyung Hee University, Seoul, Korea; 4) Department of Physiology, College of Medicine, BK 21 Project for Medical Sciences, Yonsei University, Seoul, Korea.
Recent genomewide association studies have identified 33 genetic loci that influence blood pressure. The 15q24 locus is one such locus that has been confirmed in Asians and Europeans. There are 21 genes in the locus within a 1-Mb boundary, but a functional link of these genes to blood pressure has not been reported. We aimed to identify a causative gene in the 15q24 locus by siRNA in vivo delivery in mice. CYP1A1, CYP1A2, CSK, and ULK3 were selected as candidate genes, based on their functions and proximity to the lead SNP (rs1378942). The siRNA for each gene was injected into mouse tail vein. Of the 4 genes, Csk and Cyp1a2 siRNA reduced their mRNA levels in injected mice. Thus, the blood pressure of Csk and Cyp1a2 siRNA-injected mice was measured in the carotid artery. Whereas Cyp1a2 siRNA did not change blood pressure, Csk siRNA increased it. Further, blood pressure in Csk+/- heterozygotes was higher than in wild-type, consistent with what we observed in Csk siRNA-injected mice. These results suggest that CSK is a causative gene in the 15q24 locus. After ATP2B1 in 12q21, CSK is the second gene in a blood pressure GWAS locus to be identified as a causative gene. CSK, c-src tyrosine kinase, is a negative regulator of SRC that is involved in angiogenesis and the CSK knockout embryo has an abnormal vascular network. This study may provide a new genetic pathway that underlies the development of hypertension and a novel therapeutic target for the treatment of hypertension.
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