ANTXR2 is a potential causative gene in the genome-wide association study of the blood pressure locus 4q21

Abstract

Hypertension is the most prevalent cardiovascular disease worldwide, but its genetic basis is poorly understood. Recently, genome-wide association studies identified 33 genetic loci that are associated with blood pressure. However, it has been difficult to determine whether these loci are causative owing to the lack of functional analyses. Of these 33 genome-wide association studies (GWAS) loci, the 4q21 locus, known as the fibroblast growth factor 5 (FGF5) locus, has been linked to blood pressure in Asians and Europeans. Using a mouse model, we aimed to identify a causative gene in the 4q21 locus, in which four genes (anthrax toxin receptor 2 (ANTXR2), PR domain-containing 8 (PRDM8), FGF5 and chromosome 4 open reading frame 22 (C4orf22)) were near the lead single-nucleotide polymorphism (rs16998073). Initially, we examined Fgf5 gene by measuring blood pressure in Fgf5-knockout mice. However, blood pressure did not differ between Fgf5 knockout and wild-type mice. Therefore, the other candidate genes were studied by in vivo small interfering RNA (siRNA) silencing in mice. Antxr2 siRNA was pretreated with polyethylenimine and injected into mouse tail veins, causing a significant decrease in Antxr2 mRNA by 22% in the heart. Moreover, blood pressure measured under anesthesia in Antxr2 siRNA-injected mice rose significantly compared with that of the controls. These results suggest that ANTXR2 is a causative gene in the human 4q21 GWAS-blood pressure locus. Additional functional studies of ANTXR2 in blood pressure may identify a novel genetic pathway, thus increasing our understanding of the etiology of essential hypertension.

Plasma proteomic profile of frailty

“…But there are a number of previous studies pointing toward its possible role in frailty. Recent genetic studies have implicated ANTXR2 gene coding for ANTR2 protein associated with hypertension (Park et al, 2014) as well as grip strength (Tikkanen et al, 2018). Grip strength is an important component of the frailty definition and hypertension is a known risk factor for frailty (Fried et al, 2001).…”

Genomic analysis of the domestication and post-Spanish conquest evolution of the llama and alpaca

“…Intriguingly, the HSA4q21 locus has been linked using GWAS, to blood pressure homeostasis in Asians and Europeans. A mouse model has been used to identify the causative gene in humans, which was found to be ANTXR2, whereas blood pressure did not differ between FGF5 knockout and wild-type mice [17,62]. Systematic studies have identified a positive link between altitude (and thus hypoxia) with the frequency of hypertension in humans [63] and PRDM8 belongs to a family of histone methyltransferases that are known as negative regulators of transcription.…”

Gene Silencing and Haploinsufficiency of Csk Increase Blood Pressure

“…The selection and in vivo delivery of siRNA have been previously described [ 19 – 21 ]. In brief, more than 3 siRNAs per gene ( Csk , Ulk3 , and Cyp1a2 ) were synthesized by Genolution (Seoul, Korea), and only one of them was selected for in vivo injection.…”

“…The protocol for blood pressure measurement has been previously described [ 19 – 21 ]. In brief, blood pressure was recorded intra-arterially with a computerized data acquisition system (AD Instruments, Bella Vista, Australia).…”