Date Published: January 11, 2016
Publisher: Public Library of Science
Author(s): Hyeon-Ju Lee, Ji-One Kang, Sung-Moon Kim, Su-Min Ji, So-Yon Park, Marina E. Kim, Baigalmaa Jigden, Ji Eun Lim, Sue-Yun Hwang, Young-Ho Lee, Bermseok Oh, Zhanjun Jia.
Recent genome-wide association studies have identified 33 human 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 for blood pressure change in the 15q24 locus.
CSK and ULK3 were selected as candidate genes based on eQTL analysis studies that showed the association between gene transcript levels and the lead SNP (rs1378942). Injection of siRNAs for mouse homologs Csk, Ulk3, and Cyp1a2 (negative control) showed reduced target gene mRNA levels in vivo. However, Csk siRNA only increased blood pressure while Ulk3 and Cyp1a2 siRNA did not change it. Further, blood pressure in Csk+/- heterozygotes was higher than in wild-type, consistent with what we observed in Csk siRNA-injected mice. We confirmed that haploinsufficiency of Csk increased the active form of Src in Csk+/- mice aorta. We also showed that inhibition of Src by PP2, a Src inhibitor decreased high blood pressure in Csk+/- mice and the active Src in Csk+/- mice aorta and in Csk knock-down vascular smooth muscle cells, suggesting blood pressure regulation by Csk through Src.
Our study demonstrates that Csk is a causative gene in the 15q24 locus and regulates blood pressure through Src, and these findings provide a novel therapeutic target for the treatment of hypertension.
Blood pressure is influenced by a variety of mechanisms that involve many genetic factors. To detect genetic markers for blood pressure, genome-wide association studies (GWASs) have been performed using large human samples from various ethnic groups and have identified many genetic loci that are associated with blood pressure and hypertension. The Korean Association REsource (KARE) , the Global Blood Pressure Genetics (GlobalBPgen) , Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) , the Asian Genetics Epidemiology Network Blood Pressure (AGEN-BP) , and International Consortium for Blood Pressure (ICBP)  have conducted GWASs on blood pressure and hypertension, identifying 33 independent loci that have reached a genome-wide significance level.
It has been a challenging task to identify a causative gene in a locus that is associated with blood pressure. Therefore, there are very few genes identified as causative so far despite of multiple candidates associated with blood pressure GWASs. For that reason, we utilized two-step approaches. First, we selected the most relevant candidate genes in a locus by using the eQTL analysis studies. Then, we tested the effect of gene knock-down on blood pressure after the in vivo delivery of candidate gene siRNA into mice.