Abstract
DIAPH1 is a formin protein involved in actin polymerization with important roles in vascular remodeling and thrombosis. To investigate potential associations of DIAPH1 single-nucleotide polymorphisms (SNPs) with hypertension and stroke, 2,012 patients with hypertension and 2,210 controls, 2,966 stroke cases [2,212 ischemic stroke (IS), 754 hemorrhagic stroke (HS)] and 2,590 controls were enrolled respectively in the case-control study. A total of 4,098 individual were included in the cohort study. DIAPH1 mRNA expression was compared between 66 IS [43 small artery occlusion (SAO) and 23 large-artery atherosclerosis (LAA)] and 58 controls. Odds ratio (OR), hazard ratio (HR) and 95% confidence interval (CI) were calculated by logistic and cox regression analysis. Rs7703688 T>C variation was significantly associated with an increased risk of IS [OR (95% CI) was 1.721 (1.486-1.993), P=4.139×10-12]. Association of rs7703688 with stroke risk was further validated in the cohort study [adjusted HRs (95% CIs) for additive and recessive models were 1.385 (1.001-1.918), P=0.049, and 2.882 (1.038-8.004), P=0.042, respectively)]. DIAPH1 mRNA expression was significantly downregulated in IS. In SAO stroke subtype, DIAPH1 expression has an increased trend among rs251019 genotypes (Ptrend=0.048). These novel findings suggest that DIAPH1 variation contributes to genetic susceptibility to stroke risk, especially the SAO subtype of IS.
Highlights
Stroke ranks as the first leading cause of death in China, with bearing the highest stroke burden in the world [1]
Clinic-demographic characteristics of participants in the hypertension case-control study are summarized in Supplementary Table 1
The current study conducted case-control and cohort studies to investigate the associations of diaphanous 1 (DIAPH1) polymorphisms with hypertension and stroke
Summary
Stroke ranks as the first leading cause of death in China, with bearing the highest stroke burden in the world [1]. Hypertension is a major risk factor for cerebrovascular disease, including ischemic stroke (IS) and hemorrhagic stroke (HS) [2]. Characterization of the mechanisms underlying stroke is still incomplete. Chronic hypertension induces vascular remodeling of cerebral arteries, an essential risk factor for stroke. At play in this phenomenon is activation of the Rho/Rhokinase pathway, a crucial modulator of proliferation, motility, and contractility of smooth muscle cells (SMCs) [3,4,5]. Supporting a key association between Rho/Rhokinase pathway and cardiovascular diseases via vascular remodeling, our previous studies showed that genetic variations in Rho kinases (ROCK1 and ROCK2) modulate susceptibility to hypertension and stroke [6]
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