The SNP rs2298383 Reduces ADORA2A Gene Transcription and Positively Associates with Cytokine Production by Peripheral Blood Mononuclear Cells in Patients with Multiple Chemical Sensitivity

Abstract

Systemic inflammation and immune activation are striking features of multiple chemical sensitivity (MCS). The rs2298383 SNP of ADORA2A gene, coding for adenosine receptor type 2A (A2AR), has been involved in aberrant immune activation. Here we aimed to assess the prevalence of this SNP in 279 MCS patients and 238 healthy subjects, and its influence on ADORA2A, IFNG and IL4 transcript amounts in peripheral blood mononuclear cells of randomly selected patients (n = 70) and controls (n = 66) having different ADORA2A genotypes. The ADORA2A rs2298383 TT mutated genotype, significantly more frequent in MCS patients than in controls, was associated with a three-fold increased risk for MCS (O.R. = 2.86; C.I. 95% 1.99-4.12, p < 0.0001), while the CT genotype, highly prevalent among controls, resulted to be protective (O.R. = 0.33; C.I. 95% 0.224-0.475, p < 0.0001). Notably, ADORA2A mRNA levels were significantly lower, while IFNG, but not IL4, mRNA levels were significantly higher in TT MCS patients compared with controls. A significant negative correlation was found between ADORA2A and both IFNG and IL4, while a significant positive correlation was found between IFNG and IL4. These findings suggest that A2AR defective signaling may play a relevant role in PBMC shift towards a pro-inflammatory phenotype in MCS patients.

Genetic Polymorphisms of P2RX7 but Not of ADORA2A Are Associated with the Severity of SARS-CoV-2 Infection

“…Although the role of A2AR in the severity of SARS-CoV-2 infection has been hypothesized [32][33][34] and preliminary clinical data indicate that the infusion of either adenosine or of a selective A2AR agonist may dampen inflammation in COVID-19 patients [35,36], our study did not reveal any association between SARS-CoV-2 infection and the rs2298383 SNP of A2AR, a loss-of-function polymorphism associated with bolstered immune response [28]. We have previously shown in the context of brain diseases that the altered role of A2AR depends both on the up-regulation of A2AR as well as an increased formation of extracellular adenosine [40][41][42][43].…”

“…ADORA2A, the gene encoding A2AR, has several polymorphisms that have been associated with anxiety, depression or cardiovascular disorders [ 27 ]. In particular, the rs2298383 SNP of ADORA2A is associated with higher production of pro-inflammatory cytokines and with aberrant immune activation [ 28 ].…”

“…To fill this gap of knowledge, we now investigated if the rs2298383 SNP of ADORA2A, associated with decreased A2AR activity [ 28 ], and the rs208294 SNP of P2RX7, associated with increased P2X7R activity [ 19 , 20 , 21 ], were linked to the severity of COVID-19.…”

Italian Expert Consensus on Clinical and Therapeutic Management of Multiple Chemical Sensitivity (MCS)

“…Metabolism perturbations due to or provoked by environmental exposures are currently under evaluation and the preliminary data suggest abnormalities in the detoxification metabolism (i.e., glutathione transferase, catalase, superoxide dismutase), energetic metabolism (i.e., intracellular adenosine triphosphate (ATP) in erythrocytes and platelets) and inflammatory response (pro-inflammatory serum cytokines) [ 43 , 87 , 105 , 109 , 110 , 111 , 112 , 113 , 114 ]. These promising biomarkers evaluated on serum, whole blood and peripheral blood mononuclear cells (PBMCs) are detected with methods validated only in experimental conditions and are not applicable to daily clinical practice.…”

Analysis of ADORA2A rs5760423 and CYP1A2 rs762551 Genetic Variants in Patients with Alzheimer’s Disease

“…ADORA2A is implicated in several pathophysiological processes, including neurogenesis, caffeine metabolism, and synaptic plasticity in glutamatergic synapses [11]. Moreover, the loss of adenosinereceptor-mediated modulation on immune cells has an impact on oxidative-stress-mediated inflammation [12,13]. Cytochrome P450 1A2 (CYP1A2) is an inducible enzyme, and it is considered to be the main caffeine-metabolizing enzyme, while it is implicated in several drugs' metabolisms as well [14,15].…”