Renin-angiotensin-aldosterone system (RAS) pathway involves several genes such as renin (REN), angiotensinogen (AGT), angiotensin-converting enzyme (ACE), angiotensin II type 1 receptor (AGTR1), angiotensin II type 2 receptor (AGTR2) and aldosterone synthase (CYP11B2), which regulating the homeostasis of arterial pressure, tissue perfusion and extracellular volume (Atlas 2007; Cat et al. 2013). Within the RAS, juxtaglomerular cells release REN in response to the reduction of circulated blood volume, renal perfusion pressure and sodium chloride concentration in the tubular fluid. REN cleaves the circulating AGT to form biologically inert decapeptide Ang I (angiotensin I), further converted to Ang II (angiotensin II) by ACE. Ang II is mediated by AGTR1 and AGTR2 to produce aldosterone. As a feedback inhibition, both Ang II and aldosterone restore renal perfusion, regulate sodium and fluid reabsorption, and inhibit subsequent release of REN, in order to restore circulating homeostasis and mediate BP (Atlas 2007; Cat et al. 2013). As shown in Table 2, it has been hypothesized that single nucleotide polymorphisms (SNPs) of REN, AGT, AGTR1, AGTR2, ACE and CYP11B2 genes can dysregulate RAS and thus influence the pathophysiology of hypertension (Atlas 2007; Cat et al. 2013). SNPs of REN rs12750854, ACE rs4646994, AGT rs699, rs4762 and rs5050 are associated with DBP (Sethi et al. 2003; Fang et al. 2010; Penesova et al. 2006; Vangjeli et al. 2010; Fayyad and Aziz 2015).

In fact, aortic stiffness and left ventricular mass are the predictors for hypertension progression (Kim et al. 2014). Of which, elderly with aortic stiffness and carrying AGTR1 rs5186 and rs275653 polymorphisms may prone to hypertension (Lajemi et al. 2001; Lacolley et al. 2009). AGTR2 rs5194, rs12710567 and rs1403543 polymorphisms may cause hypertension by mediating left ventricular mass (Alfakih et al. 2004; Carstens et al. 2010; Huber et al. 2010). The accumulated plasma ACE disturbs homeostasis control of endothelial function by mediating aortic stiffness (Ljungberg et al. 2011). Moreover, high BP can become severe if an individual is carrying CYP11B2 rs1799998 polymorphism (Matsubara et al. 2004). This SNP increases the aldosterone-to-renin ratio, while reducing the aldosterone production (Matsubara et al. 2004). Low levels of aldosterone induces extra sodium and fluid accumulation, in turn dysregulates BP and causes hypertension (Harrison-Bernard 2009; Mishra et al. 2012).

Vasomotor system consists of endothelin and endothelial nitric oxide that maintain vasoconstriction and vasodilation activities respectively (Table 2). Endothelin converting enzyme 1 (ECE-1) and endothelin converting enzyme 2 (ECE-2) are expressed in vascular endothelium and neuronal tissues, respectively. Among their isoforms, ECE-1b serves as the main player for BP regulation (Valdenaire et al. 1999). ECE1b rs213045 and rs213046 polymorphisms may increase ECE gene and protein expressions (Annapareddy et al. 2016), that subsequently promote ECE bind to vasoconstrictive receptors such as G-protein couple receptors, endothelin receptor A (EDNRA) and endothelin receptor B (EDNRB), to exert its vasoconstrictive effect (Ling et al. 2013). The receptor polymorphisms of EDNRA rs5335 and rs5343 alter EDNRA gene expression and endothelin binding (Rahman et al. 2008) as well as increase DBP and SBP in response to different salt sensitivity i.e. either salt depletion or repletion. On the other hand, a decrease in BP is observed among salt-sensitive individuals who carry EDRNB rs5351 polymorphism (Caprioli et al. 2008). Nonetheless, endothelin 1 (EDN1) rs5370 and endothelin 2 (EDN2) rs5800 polymorphisms increase the production of endothelin, enhance the calcium sensitivity on arteries, and subsequently mediate the progression of hypertension (Iglarz et al. 2002; Panoulas et al. 2008; Dhawan et al. 2014). The endothelial nitric oxide synthase (eNOS) produces nitric oxide and vasodilates the blood vessels to lower BP levels. Dysregulated eNOS may reduce about 50 % of the nitric oxide levels at the basal blood flow, and subsequently restrict endothelial diastolic function (Förstermann and Münzel 2006). This dysregulation is mainly related to eNOS rs1799983 and variable tandem repeat 4a/4b polymorphisms, which also associated with hypertension risk (Tang et al. 2008a; Patkar et al. 2009; Yan-yan 2011).

Genetic polymorphisms of apolipoprotein B (ApoB), apolipoprotein C (ApoC), apolipoprotein E (ApoE) and lipoprotein lipase (LPL) genes within the lipid metabolism pathways have been associated with the variations in BP and the propensity of hypertension (Table 2). ApoB and ApoE are the major constituents for chylomicrons that catabolize triglyceride-rich lipoprotein particles. ApoB rs693 and ApoE E4E4 polymorphisms may impair the clearance of chylomicrons and VLDL remnants, which lead to the higher levels of triglycerides and cholesterol (Tang et al. 2008b; Das et al. 2009; Wei et al. 2015a, 2015b). This phenomenon promotes intimal-medial carotid artery thickening and susceptibility risk to hypertension (Paternoster et al. 2008; Rossi et al. 2001). Meanwhile, ApoC3 is a VLDL protein that inhibits LPL activity while destroying triglyceride-rich remnants catabolism. In particular, ApoC3 rs5128 and rs4225 as well as LPL rs320 and rs328 polymorphisms induce high levels of triglycerides, high BP and thus increase the susceptibility risk of hypertension (Salah et al. 2009; Muñoz-Barrios et al. 2012; Ghattas et al. 2013).

BP is influenced by the efficiency of sodium reabsorption. Increase in sodium channel activity promotes sodium reabsorption and sodium retention, thereby elevating BP (Sun et al. 2011). Gene polymorphisms encoded for renal ion channels and sodium reabsorption transporters were summarized in Table 2.

Being the pertinent component in sodium reabsorption, epithelial sodium channel (ENaC) is involved in the first step of active sodium reabsorption in urinary bladder and renal collecting duct, which maintains the water and electrolyte homeostasis. ENaC consists of α-, β- and γ-subunits that encodes sodium channel non voltage gated 1 alpha subunit (SCNN1A), sodium channel non voltage gated 1 beta subunit (SCNN1B) and sodium channel non voltage gated 1 gamma subunit (SCNN1G) genes, respectively (Sun et al. 2011). It has been reported that SCNN1A rs4149623 may decrease SCNN1A gene expression and subsequently reduce sodium reabsorption efficiency in the kidney (Iwai et al. 2002). SCNN1A rs4149623 may prevent individuals from the risk of hypertension, however, this SNP is a risk marker for hypertension among Japanese population (Iwai et al. 2002). SCNN1B rs1799979 alters β-ENaC protein structure and causes protein kinase C phosphorylation, which inhibits sodium channel activity and thus increases sodium retention and elevates BP (Yang et al. 2014). SCNN1G rs5718 reduces pulse pressure and SBP, in which dropping of pulse pressure (8 mmHg) and SBP (11 mmHg) have been observed among hypertensive patients (Iwai et al. 2001). Sodium reabsorption efficiency may also be regulated by thiazide sensitive Na⁺ Cl⁻ cotransporter (TSC) 2736G > A and 1420C > T polymorphisms. These SNPs up-regulate TSC gene expression and promote sodium reabsorption in thick ascending limb and distal convoluted tubule, which induce BP before and during the early phase of hypertension development (Manning et al. 2002; Keszei et al. 2007).

The absorbed sodium ions are transported across cell membrane to maintain electrolytes homeostasis (Sun et al. 2011). Several lines of evidence suggested that rs2901029, rs3766031, rs12079745, rs1138486, rs3766032 and rs2982468 polymorphisms in both ATPase, Na⁺/K⁺ transporting, alpha 2 polypeptide (ATP1A2) and ATPase, Ca⁺⁺ transporting, plasma membrane 1 (ATP1B1) genes are deviating the electrochemical gradients of sodium and potassium ions across plasma membrane, and lead to higher BP (Chang et al. 2007; Xiao et al. 2009; Faruque et al. 2011). In addition, alpha-adducin (ADD) gene polymorphisms, such as ADD1 rs4961, ADD2 rs4984 and ADD3 rs3731566 may dysregulate TSC and enhance constitutive tubular sodium reabsorption, which lead to higher salt-sensitivity (Tikhonoff et al. 2003; Zafarmand et al. 2008; Seidlerová et al. 2009; Dimke et al., 2011). Increased salt sensitivity is also associated with neural precursor cell expressed developmentally down-regulated 4-like E3 ubiquitin protein ligase (NEDD4L) rs4149601 polymorphism through ENaC regulation. All in all, dysregulation of genes associated with sodium regulating system are contributed to the susceptibility risk of hypertension (Russo et al. 2005; Fava et al. 2006; Luo et al. 2009).

Sympathetic nervous system (SNS) is controlled by α- and β-adrenergic receptors that actively interact with G-proteins (Table 2). Among the available adrenergic receptors, the associations between β1-adrenergic receptor (ADRB1) and β2-adrenergic receptor (ADRB2) with hypertension risk are discussed. Both subunits that control BP by mediating cardiac output and peripheral resistance are believed to play a major role in hypertension (Soualmia 2012). ADRB1 belong to G-coupled receptor superfamily that located at the intracellular cytoplasmic tail. ADRB1 rs1801253 polymorphism decreases it’s receptor activity, affects the binding of ADRB1 on G-proteins, and is associated with lower mean values of SBP and DBP as well as the risk of hypertension (Johnson et al. 2011b). The ADRB2 regulates the vasodilation of smooth muscle cells via activation of cyclic adenosine monophosphate (cAMP) signalling pathway (Snyder et al. 2008). The risk of hypertension is multiplied among ADRB2 rs1042713 carriers in an elderly population (Soudani et al. 2014).

In addition, the health status of vasculature also mediated by insulin-like growth factor 1 (IGF-1), a strong promoter for the growth of cardiomyocyte. Genetic polymorphisms of IGF-1 receptor (IGF-1R) have been associated with atherosclerosis, hypertension, angiogenesis, and diabetes (Higashi et al. 2012). Specifically, IGF-1R rs8034564 polymorphism contributes to abnormal left ventricular hypertrophy geometry changes that deteriorates the hypertension progression (Horio et al. 2010).