Pulse pressure (PP) refers to the difference between systolic and diastolic blood pressure, of which the normal range is 30–50 mmHg [1]. As an independent risk factor of cardiovascular disease, PP is attracting more attention from doctors, and its forecast value may be larger than systolic blood pressure (SBP) or diastolic blood pressure (DBP) [2]. Hypertension and cardiocerebrovascular diseases caused by vascular diseases are often accompanied by elevated PP [3‐5]. Therefore, a comprehensive understanding of the molecular basis of high PP is crucial for the development of potential therapeutic strategies.

The decrease in vascular elasticity is an important factor for the increase in pulse differential pressure and may result from inflammation and vascular endothelial cell dysfunction. Many novel loci related to blood pressure (BP) adjustment have been identified by researchers. However, it is suggested that there is a possible presence of allelic heterogeneity in BP regulation between Europeans and Asians, which provide new mechanistic insights into cardiovascular disease [6]. A previous study has reported that BRD4 and PIN1 are involved in inflammation and vascular endothelial cell dysfunction. As a transcription regulatory factor, BRD4 may lead to extracellular calcium deposition, and BRD4 may cooperate with seven specific transcription factors to promote calcification [7]. BRD4 silencing results in a significant reduction in inflammatory cytokine expression [8]. Multiple studies have shown that PIN1 binds to endothelial nitric oxide (NO) synthase and enables dephosphorylation of serine, which increases NO production and endothelium-dependent dilation, leading to BP maintenance [9]. Inhibiting Brd4 and Pin1 expression alleviates enhancer-mediated inflammatory transcription and atherosclerosis, which indicates that BRD4 and PIN1 play a vital role in the development of vascular inflammation and atherosclerosis [10‐13]. Therefore, it is possible that variants in BRD4 and PIN1 genes may lead to decreased vascular elasticity by destroying endothelial cells and causing atherosclerosis.

The aim of this study was to investigate the association between BRD4 and PIN1 gene polymorphisms and high PP in a Chinese population.

Scholars are paying more attention to heredity as an important factor in high pulse differential pressure [18, 19]. To investigate a potential association between five promising polymorphisms in the BRD4 and PIN1 genes and high PP risk in a southeastern Chinese population, we designed this pilot case–control study that includes 666 hypertensive patients and 232 normotensive subjects according to exclusion and inclusion criteria. After excluding one SNP (rs2233679) that was not in HWE, we analyzed the remaining four SNPs. There was no statistically significant correlation between the four SNPs and hypertension risk, but we unexpectedly found that rs4808278 in BRD4 was associated with high PP risk, suggesting that BRD4 may play an important role in high PP progression. This discovery may provide a new therapeutic target gene.

BRD4, a member of the bromo and extra-terminal family, plays a role in various vascular pathologies. Knocking down Brd4 with siRNA mitigates neointima formation and vascular remodeling [20, 21]. The protein also regulates vascular endothelial growth factor (VEGF)-induced angiogenesis by activating phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) and P21 activated kinase 1 (PAK1) [22, 23]. To some extent, these pathologies are related to changes in vascular elasticity, which may affect PP variation. Through binding with acetylated RelA, BRD4 enhances activation of NF-κB signaling to induce natriuretic peptide precursor A (NPPA) and natriuretic peptide precursor B (NPPB) transcription [24]. Our previous research also found that a SNP in the NPPB gene is associated with high PP [14]. BRD4 plays a critical role in propagating inflammation and promoting vascular calcification in particular [7, 8]. More importantly, BRD4, a transcriptional regulator, mediates inflammatory transcription, atherogenic endothelial response, and atherosclerosis [10, 11]. Vascular damage, an antecedent to atherosclerosis, leads to an increase in PP and to atherosclerosis, which in turn results in large-vessel stiffening and increased wave reflection. While it is not clear what is the incipient event in this cycle, it is clear that, once initiated, a vicious cycle promoting disease progression ensues. The association analysis of PP with different genotypes show that rs4808278 genotype TT carriers have a lower risk than AT and AA genotypes carriers to have higher PP (OR = 0.405; 95% CI: 0.220–0.745; P = 0.004), which indicates that the T allele has a protective effect. Although rs4808278 is located in an intron of BRD4, the RegulomeDB score of rs4808278 in BRD4 is 4, which suggests that rs4808278 may be part of a TF binding site or DNase hypersensitive region. This suggests that rs4808278 may affect PP by regulating BRD4 expression. Few studies have reported on SNPs in BRD4 and high PP. Our results may provide new research directions on high PP.

High PP, diabetes mellitus, and atherosclerosis are closely related, and PP is considered an independent predictor of new-onset diabetes [25, 26]. Therefore, diabetes and the four SNPs were included in the GMDR analysis. We found a significant three-locus model (P = 0.0010) involving rs4808278, rs2233678, and diabetes after adjusting the covariates. The detailed mechanism underlying this interaction is unknown, but all of them are associated with vascular elasticity, which may be the basis for high PP.

There are several limitations in the present work. Firstly, only five SNPs were studied. Secondly, this is a retrospective case–control study. Our original intention was to look for the relationship between SNPs in BRD4/PIN1 and hypertension, but we did not find any association. Thirdly, the presence of atherosclerosis, an important factor causing an increase in PP, was not recorded in the patients.