Research Centre, Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada.
Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
J Hypertens. 2019 Apr;37(4):775-789. doi: 10.1097/HJH.0000000000001948.
We investigated the association of genetic variants of EPHA4, a receptor tyrosine kinase, with hypertension, and its role in vascular smooth muscle cell (VSMC) contractility.
Data from two human genetic studies, ADVANCE and HCHS/SOL, were analyzed for association of EPHA4 single nucleotide variants (SNVs) with hypertension risks. The effect of EPHA4 signalling on mouse VSMC contractility was assessed.
We identified a SNV (rs75843691 hg19 chr2:g.222395371 C>G), located in the third intron of EPHA4 gene, being significantly associated with hypertension in human female patients (P value = 8.3 × 10, below the Bonferroni-corrected critical P value) but not male patients with type 2 diabetes from the ADVANCE clinical trial. We found that EPHA4 was expressed in VSMCs and its stimulation by anti-EPHA4 antibody led to reduced VSMC contractility. Estrogen enhanced the contractility-lowering effect of EPHA4 stimulation. Conversely, siRNA knockdown of Epha4 expression in VSMCs resulted in increased contractility of VSMCs from female mice but not from male mice.
EPHA4 appears to be a sex-specific hypertension risk gene in type 2 diabetic patients. Forward EPHA4 signalling reduces VSMC contractility, and estrogen is a modifier of this effect. The effect of EPHA4 on VSMCs contractility explains the association of EPHA4 gene with hypertension risks in female patients.
我们研究了受体酪氨酸激酶 EPHA4 的遗传变异与高血压的关联，以及其在血管平滑肌细胞（VSMC）收缩性中的作用。
分析了 ADVANCE 和 HCHS/SOL 两项人类遗传研究的数据，以评估 EPHA4 单核苷酸变异（SNV）与高血压风险的关联。评估了 EPHA4 信号对小鼠 VSMC 收缩性的影响。
我们鉴定出一个位于 EPHA4 基因第三个内含子中的 SNV（rs75843691 hg19 chr2:g.222395371 C>G），与女性 2 型糖尿病患者的高血压显著相关（P 值=8.3×10，低于 Bonferroni 校正的临界 P 值），但与 ADVANCE 临床试验中的男性 2 型糖尿病患者无关。我们发现 EPHA4 在 VSMCs 中表达，其刺激物抗-EPHA4 抗体导致 VSMC 收缩性降低。雌激素增强了 EPHA4 刺激的这种降低收缩性的作用。相反，在 VSMCs 中敲低 Epha4 表达导致来自雌性小鼠的 VSMCs 收缩性增加，但来自雄性小鼠的 VSMCs 则没有。
EPHA4 似乎是 2 型糖尿病患者中一种性别特异性的高血压风险基因。正向 EPHA4 信号降低 VSMC 收缩性，而雌激素是这种作用的修饰因子。EPHA4 对 VSMCs 收缩性的影响解释了 EPHA4 基因与女性患者高血压风险的关联。
