Our results showed that both of the studied variants caused an increase in the risk of T2DM by the C allele. The P2RX7 gene is located on chromosome 12q24.31, including 13 exons translated to the P2X7R protein. The P2X7R, as the most prominent member of the P2XR group, is a trimeric ATP-gated cation channel consisting of three subunits, including a bulky carboxy-terminal chain, an intracellular N-terminal head, and transmembrane chain that have been specialized for its function [16]. The P2X7R plays a dual role in the selective transport of Ca2+, Na+, and K+ and the non-selective transport of macromolecules in cases of overstimulation [17, 18]. P2X7R is expressed by macrophages, natural killer cells, and lymphocytes as a result of some cytokine promotion, including IL-2, IL-4, IL-6, and TNF-α [19]. To date, different functions of P2X7R have been elucidated, including apoptosis, activation, and development of T cells and diverse signaling pathways. [20].

In T2DM, inflammation contributes to the insulin resistance state through the interaction of IL-β with its receptor, which phosphorylates the insulin receptor substrate (IRS) protein and blocks insulin signaling [21]. Moreover, IL-1β promotes the decrease in pancreatic β-cell apoptosis, resulting in the elimination of insulin production [21]. The activation of P2X7R induces the production of IL-1 and its biological antagonist, the IL-1Ra cytokine. The document implied that the activation of P2X7R causes the release of IL-1β and IL-1Ra from β-cells by ATP [22]. While IL-1β has a deleterious effect on β-cells, IL-1Ra has a protective role. Accordingly, it seems that the balance between IL-1β and IL-1Ra plays a pivotal role in the onset of T2DM. P2X7R plays a pivotal role in activating T lymphocytes, mast cells, macrophages, and dendritic cells. So, the activation of P2X7R can promote apoptosis due to the activation of the caspase signaling cascade by the NLRP3 inflammasome. Interestingly, activation of P2X7R may have a deleterious effect on autoimmune disease and was hypothesized to influence the pathophysiology of multiple sclerosis (MS). The association study performed on a population of individuals affected by MS showed that rs1718119C > T increased the risk of MS compared to a healthy sample [23]. Moreover, the documents showed that rs1718119T > C increased the risk of Gout disease. This variant resulted in a rise in the level of IL-1β mRNA in the serum of affected subjects with Gout disease compared to the healthy group. Furthermore, the expression level of NLRP3 mRNA in individuals who carried the rs1718119T > C variant showed a higher level than the normal group [24]. Another study performed on a Chinese population revealed that the T allele of rs1718119 had a protective role in systemic lupus erythematosus (SLE) [25]. Most of the genetic variants in the P2RX7 gene showed a loss of function role regarding downstream events. At the same time, rs1718119T > C, located on the transmembrane domain 2 of P2X7R, causes an increased response compared to the P2X7R function of normal cells. In addition, the study revealed that affected subjects who carried minor alleles of rs1718119 showed an increased level of IL-1β secretion compared to IL-1β levels in healthy subjects [26]. The research confirmed the presence of P2X7R in the membrane of adipocyte cells. It seems that P2X7R has a significant role in the regulation of adipocyte apoptosis, which is a critical stage in the development of obesity [27]. The loss of function of P2X7R can likely result in the abnormal gathering of fat due to a reduction in the apoptosis of mature fat cells or an increase in adipogenesis in mesenchymal stem cells (MSCs) [28]. A study conducted on postmenopausal women of Chinese ethnicity revealed that the rs1718119 variant was associated with a higher probability of obesity [28].

As with any qualified biochemical carrier, extracellular ATP (eATP) must be degraded to prevent excess signaling responses. The primary sensor of eATP is purinergic receptors 2 and 1 (P2Rs and P1Rs, respectively) [29]. P1Rs are targeted by adenosine only; while, P2Rs are ligated and activated by different ligands, including ATP, ADP, UTP, and UDP. Purinergic receptor two is divided into two subgroups, namely (i) P2XRs and (ii) P2YRs [30]. To date, eight members of P2YR are recognized in humans (P2Y1-2R, P2Y4R, P2Y6R, and P2Y11-14R). While P2YRs are activated by different nucleotides, P2XRs are activated by eATP solely [31]. The documents revealed that seven subtypes of P2XR are identified, named P2X1R to P2X7R [32]. The P2XRs have an N-terminal domain, a C-terminal domain, and two transmembrane domains. Based on its unique function and molecular characteristics, the P2X7R act as a therapeutic target [33].