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

Attilio Cannata,Liudmila G Korkina,Riccardo Ientile,Monica Currò,Chiara De Luca,Daniela Caccamo,Giulia Andolina,Nadia Ferlazzo

doi:10.3390/ijms21051858

Attilio Cannata, Liudmila G Korkina + Show 6 more

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https://doi.org/10.3390/ijms21051858

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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.

Highlights

Multiple chemical sensitivity (MCS), called environmental sensitivity illness (ESI) or toxicant-induced loss of tolerance (TILT), involves an aberrant susceptibility response to a broad range of chemical substances present in daily life [1]
Genotype distributions in the control group were in concordance with the Hardy–Weinberg equilibrium (HWE) (p = 0.928), and with those reported for Italian population in the 1000 Genomes project, while they were found to deviate from the expected value by HWE (p = 0.000000) in the group of MCS patients
The T mutated allele was more frequent among MCS patients than among healthy subjects, and was predominant in homozygous state, while in controls it was more frequently found in heterozygous state (Table 1)

Summary

Introduction

Multiple chemical sensitivity (MCS), called environmental sensitivity illness (ESI) or toxicant-induced loss of tolerance (TILT), involves an aberrant susceptibility response to a broad range of chemical substances present in daily life [1]. Much attention has been paid to this disorder because of the potential pathogenic role of increased pollution and stressful lifestyles. Disease onset occurs especially in adult life and in women, but the frequency of pediatric cases is increasing [5], and a possible role of in-utero sensitization has been proposed [6]. Despite the absence of validated diagnostic biomarkers, the epidemiological evidence has led the individual countries to at least partially recognize MCS as a pathological state. In Europe, in particular, Germany and Austria classified MCS under the ICD-10 code T78.4 (unspecified allergies, Nitrous Oxide System-hypersensitivity, NOS-idiosyncrasy) [1], while in Japan, where particular attention is paid to environmental pollution, MCS is classified under ICD code T65.9 (unspecified respiratory conditions due to inhalation of fumes, gas, and chemical vapors) [7]. In US and Australia several medical associations have long recognized chemical hypersensitivity as a disability that deserves thorough investigations

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