Our study highlights the role of gender and age in hypertension within the Qatari population. We found that men generally had higher MAP than women, and MAP increased with age as shown in Fig. 1. These findings, consistent with global hypertension trends, emphasize the importance of demographic factors in understanding and managing hypertension [12]. However, it’s essential to note that individual variations and other factors can influence this trend, so it’s a general observation and not a rule for every individual. Notably, the interaction between gender and age did not significantly affect blood pressure. The regression model suggests that sex, age, BMI, total cholesterol, and triglyceride levels are all statistically significant predictors for MAP. Gender has a negative relationship with MAP, while age, BMI, total cholesterol, and triglyceride levels have positive relationships with MAP. However, it’s important to note that the model only explains a portion of the variance in MAP, which is about 30.8%, and there may be other factors not included in the model that also influence MAP.

We further investigated the correlation between 1,305 circulating protein biomarkers and blood pressure regulation within 778 Qatari participants. Among these proteins, we have identified 25 significant protein associations with mean arterial pressure in the Qatari cohort: The analysis identified the following significant proteins: QORL1, MMP-7, Renin, E-Selectin, SHBG, BMP-1, HSP70, TFPI, ApoE, C9, ApoE3, ApoE4, RBP4, Growth Hormone Receptor, Notch 1, GDF-11/8, MMP-2, TGF-β Receptor III, Protein S, C3b, MFRP, Cadherin-5, IL-17 RC, TNF sR-II, and Serum Amyloid P Component (Fig. 2).

Additionally, 13 proteins were significantly associated with hypertension: QORL1, SHBG, Renin, ApoE, MMP-7, Protein C, RBP4, ApoE3, E-Selectin, IL1RAP, ApoE4, Ghrelin, and Protein S (Fig. 3). Notably, ten of these proteins overlapped with those identified in the initial analysis, emphasizing their potential relevance.

From both analyses, QORL1 and BMP1 emerged as novel candidate biomarkers for further investigation in the context of hypertension. Detailed summary statistics, along with the full names and gene symbols of these proteins, are provided in Supplementary Tables 1 and 2.

Our findings not only corroborate six previously known associations in hypertension research but also introduce new potential genes that might be involved in its pathogenesis. These macromolecular interactions, particularly those involving complex protein assemblies, underscore the proteins' roles in pathways linked to conditions like coronary artery disease and arteriosclerosis, highlighting their potential as targets in the broader clinical spectrum of hypertension.

One of the top associations found in our analysis is Renin, a well-known blood pressure regulator due to its crucial role in the renin–angiotensin–aldosterone system (RAAS), which is implicated in hypertension and kidney disease. Renin’s primary function is to catalyze the conversion of angiotensinogen into angiotensin I, which subsequently leads to the production of angiotensin II—a potent vasoconstrictor that increases blood pressure. Dysregulation of the RAAS, including overactivity of renin, can result in elevated angiotensin II levels, leading to hypertension [13].

Many of the other significant proteins have gained attention in hypertension research, each shedding light on its unique role in this complex condition. For example, MMP2 (Matrix Metalloproteinase 2) and MMP7 (Matrix Metalloproteinase 7), are recognized for their involvement in hypertension due to their potent extracellular matrix-degrading capabilities, which can impact blood vessel architecture. MMPs regulatory influence extends to cardiovascular diseases like coronary artery disease and atherosclerosis, closely intertwined with hypertension. Genetic investigations have pinpointed a specific variation in the MMP7 gene promoter strongly associated with hypertension; individuals carrying the AG genotype exhibit elevated blood pressure levels [14]. Interestingly, we observed that BMP1 is also involved in the degradation of the extracellular matrix pathway (Fig. 7). Another notable protein, E-selectin, a cell adhesion molecule expressed in endothelial cells lining blood vessels, has emerged as a correlate of hypertension. Studies reveal elevated E-selectin levels in hypertensive individuals compared to controls, possibly a consequence of chronic blood pressure elevation that subjects the endothelial lining to sustained mechanical stress, thereby triggering molecular responses, including E-selectin upregulation [15]. Furthermore, HSP70, an essential member of the heat shock protein family, has piqued interest. While a clear causal relationship has not been established, increased levels of HSP70 in people with hypertension was observed in multiple studies, suggesting its potential involvement as a protective response to vascular stress [16].

The correlation analysis revealed significant information about potential protein interaction networks (Fig. 4). Our newly identified key factor, QORL1, has emerged as a novel candidate gene associated with hypertension. Notably, it exhibits a positive correlation with various isoforms of the Apo E protein, such as Apo E2, Apo E, Apo E3, and Apo-E4 (Fig. 4A). The proteins listed represent distinct isoforms of the Apo E gene, a key player in lipid metabolism in the body. The clinical significance of Apo E in patients with hypertension has been the focus of numerous studies. These investigations have consistently demonstrated an association between Apo E and hypertension. The findings strongly support the hypothesis that Apo E serves as a susceptibility locus for systolic hypertension and carotid artery atherosclerosis [17]. Apo E2, Apo E3, and Apo E4 are variations of this gene, each characterized by slightly different amino acid sequences, leading to varied effects on lipid metabolism and associated health outcomes. Specifically, Apo E4 stands out as a contributing factor to neurodegeneration. It plays crucial roles in redistributing lipids among central nervous system cells to maintain normal lipid homeostasis, repair injured neurons, sustain synapto-dendritic connections, and scavenge toxins [18]. These Apo E isoforms, recognized as crucial players in lipid metabolism, have established correlations with QORL1 and are clinically significant in patients with hypertension.

A unique cluster of 21 interconnected proteins, comprising MMP-2, PAPP-A, VCAM-1, Notch 1, and SDF-1, displayed positive relationships with each other (Fig. 4A). Many of these genes are recognized for their relevance to hypertension and have been proposed as potential biomarkers for cardiovascular diseases. For example, MMP-2 has been implicated in the progression of cardiac and vascular hypertrophy, accompanied by elevated formation of reactive oxygen species [19]. The significance of Pregnancy-Associated Plasma Protein-A (PAPP-A) is underscored by its inclusion in a risk model for predicting hypertensive disorders of pregnancy (HDP). The risk model combines first-trimester maternal MAP, placental growth factor, and PAPP-A. The predictive value of these factors collectively in anticipating HDP is currently uncertain and warrants further investigation [20]. Their relevance to hypertension have been proposed as potential biomarkers for cardiovascular diseases. The correlation network revealed a common pattern with slightly more negative correlations than positive ones. A group of 21 proteins shows predominantly negative correlations with the frequencies of UBC9 and NAGK proteins. A recent investigation aimed to uncover the relationship between UBC9 expression and its potential impact on cardiac hypertrophy and heart failure [21]. UBC9 expression increased in the hearts of individuals with hypertrophic cardiomyopathy and pressure overload-induced mice. Moreover, Neonatal Mouse Cardiomyocytes treated with phenylephrine exhibited elevated UBC9 expression, suggesting its potential as a target for intervention in cardiac hypertrophy. A distinct clustering of proteins with both positive and negative correlations underscores the intricate interplay and potential regulatory relationships among them. This observation suggests that there might be a delicate balance in the regulatory relationships between these proteins. Such correlation profile could be indicative of a sophisticated regulatory mechanism, where subtle shifts in one protein’s expression influence the others. Furthermore, the network distinctly delineates a cluster of proteins characterized by both positive and negative correlations. This distinct clustering underscores the intricate interplay and potential regulatory relationships.

The enrichment analysis validated the importance of associated genes in hypertension. It highlighted genetic pathways and group functions linked to the cardiovascular system. Notable associations: biological pathway with blood vessel maturation, tissue category with blood vessel cells (Fig. 5A). Such information could give us a hint that these blood cell maturation and differentiation processes play a pivotal role in hypertension. Research indicates that an expedited biological maturation is linked to elevated blood pressure, the onset of arterial hypertension, and the emergence of cardiovascular disease in later stages of adulthood [22]. This is a current focal point of discussion in the context of children diagnosed with primary hypertension. Additionally, the gene enrichment analysis provided insights into extensively studied genes with versatility across biological pathways (Fig. 5B), including Well-known genes (C3, ADIPOQ, Notch1, VCAM1) associated with hypertension. For example, the famous Endothelial Notch1, which is known to be crucial in vascular development, appears to be prominent in the gene frequency distribution across diverse biological pathways. In a 2019 article by Babicheva and Yuan, the significance of Notch1 was thoroughly examined. It was revealed that Notch1 is overexpressed in both humans and animals affected by pulmonary hypertension, with a specific emphasis on its crucial role in hyperproliferative and apoptotic-resistant endothelial cells [23]. Furthermore, the gene frequency analysis highlighted the ADIPOQ gene, which is also an important and well-studied factor for hypertension [24], obesity [25], and diabetes [26]. The ADIPOQ gene is linked to plasma adiponectin levels, and reduced adiponectin levels are associated with an increased risk of essential hypertension. Numerous studies have explored the connection between the ADIPOQ gene polymorphisms and factors like insulin resistance, adiponectin levels, and metabolic disorders, such as diabetes [27].

Our subsequent pathway and gene-disease enrichment analyses revealed interesting links between these proteins and cardiovascular health. As illustrated in Fig. 7, many of the identified proteins were further associated with coronary artery disease and atherosclerosis. These findings indicate that these proteins may serve not only as markers of blood pressure regulation but also as key players in the pathophysiology of cardiovascular diseases, potentially elucidating underlying mechanisms.

For example, NOTCH1 is critical for cardiovascular development. Although its direct link to hypertension is unclear, NOTCH1 may influence blood vessel structure and function, thereby contributing to hypertension through vascular abnormalities [23]. Similarly, CDH5, or Cadherin-5, is a protein localized in the endothelial cells lining blood vessels, playing an essential role in maintaining endothelial integrity. Dysfunction or variations in CDH5 may lead to endothelial dysfunction, a recognized risk factor for hypertension and other cardiovascular conditions [28, 29]. Interestingly, we also observed that APOE and BMP1 are intricately linked to the plasma lipoprotein pathway, which can exacerbate hypertension and vascular deterioration [30]. While several members of the peptidase M12A family of bone morphogenetic proteins (BMPs)—such as BMP2, BMP4, and BMP9—have established roles in pulmonary hypertension [31], the specific involvement of the BMP1 protein in this condition remains unclear.