Abstract
Previous studies have showed that insulin-like growth factor (IGF) axis is involved in the development of hypertension. It is unclear whether genetic variants in the IGF-binding proteins (IGFBPs) contribute to the susceptibility to hypertension. Three single-nucleotide polymorphisms (SNPs) in IGFBP1 and four SNPs in IGFBP3 were selected for genotyping in 2,012 hypertension cases and 2,210 healthy controls and 4,128 subjects were followed up for a median of 5.01 years. Multiple logistic regression and Cox regression were performed to evaluate the association of these seven SNPs with hypertension and cardio-cerebral vascular disease (CCVD). In the case-control study, rs2132572 and rs3110697 at IGFBP3 were significantly associated with hypertension, and the odds ratios (ORs) of rs2132572 (CT+TT vs. CC) and rs3110697 (GA+AA vs. GG) were 1.235 (P=0.002) and 1.176 (P=0.013), respectively (PFDR<0.05). The association of rs2132572 (TT vs. CT+CC) with hypertension was further replicated in the follow-up population, with a hazard ratio (HR) of 1.694 (P=0.014). rs1874479 at IGFBP1 was significantly associated with CCVD, particularly with stroke, and the HRs of the additive model were 1.310 (P=0.007) and 1.372 (P=0.015). Moreover, the hypertension cases presented with lower serum IGFBP1 levels than the controls (P=0.011). The serum levels of IGFBP1 significantly varied among the genotypes of rs1065780, rs2854843 and rs13223993, both in the controls and in the hypertension cases (P<0.05). These findings suggest that the genetic variants of IGFBP1 and IGFBP3 were associated with an increased risk of stroke and hypertension, respectively. Lower serum IGFBP1 levels may predict an increased risk of hypertension.
Highlights
Hypertension is a global public health challenge due to its high prevalence
The serum IGFBP1 levels linearly decreased with the variations in rs2854843 and rs13223993 in the controls (Ptrend
Previous studies have indicated that rs3110697 and rs2132572 polymorphisms are associated with decreased circulating levels of IGFBP3 [23, 24], but this association was not replicated in the current study
Summary
Hypertension is a global public health challenge due to its high prevalence. The total number of hypertensive cases in adults is predicted to reach 1.5 billion by 2025 [1]. The severe outcome of hypertension is primarily due to its driving role in the development of cardio-cerebral vascular disease (CCVD), including coronary heart disease (CHD) and stroke [2]. Insulin-like growth factor-1 (IGF-1) promotes the somatic growth, proliferation and migration of vascular smooth muscle cells (VSMC), and cellular survival [4]. IGF-binding proteins (IGFBP1~6) inhibit IGF-1 interactions with their receptors and prolong the half-lives of IGF-1 [5]. IGFBP1 expression was significantly upregulated in induced acute hypotension rats [6]. Animal experiment suggested that IGFBP1 stimulates nitric oxide production by activating the PI3K/Akt/phospho-eNOS pathway and subsequently reducing blood pressure [7]
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