Abstract
ObjectiveRecent 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.Methods and ResultsCSK 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.ConclusionsOur 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.
Highlights
Blood pressure is influenced by a variety of mechanisms that involve many genetic factors
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
Both mouse homologs Csk and Ulk3 were selected as comparably strong candidate genes among nearby genes on the 15q24 locus based on Expression Quantitative Trait Loci (eQTL) analysis studies (S1 Table)
Summary
Blood pressure is influenced by a variety of mechanisms that involve many genetic factors. In the 15q24 locus, there are at least 21 genes near the lead SNP (rs1378942) within a 1-Mb boundary Among these genes, several Expression Quantitative Trait Loci (eQTL) analysis studies have shown that the expression levels of CSK (c-src tyrosine kinase) and ULK3 (unc51-like kinase3) are significantly associated with polymorphism of rs1378942 in blood, lymphoblastoid cell lines (LCLs), and monocytes (CSK, P = 1.97×10−45, P = 1.27×10−129 in blood, P = 2.386×10−13 in LCLs; ULK3, P = 3.17×10−17 in blood, P = 1.043×10−20 in LCLs, P = 3.21×10−35 in monocytes) (S1 Table) [10,11,12,13]. Activation of Csk by angiotensin II (Ang II; a vasoconstrictor) is reduced in vascular smooth muscle cells (VSMCs) from Spontaneously Hypertensive Rats (SHR), leading to activation of Src, a target of Csk [16]
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