Association of NEF2L2 Rs35652124 Polymorphism with Nrf2 Induction and Genotoxic Stress Biomarkers in Autism

Abstract

Increased oxidative/genotoxic stress is known to impact the pathophysiology of ASD (autism spectrum disorder). Clinical studies, however, reported limited, heterogeneous but promising responses to treatment with antioxidant remedies. We determined whether the functional polymorphism of the Nrf2 gene, master regulator of anti-oxidant adaptive reactions to genotoxic stress, links to the genotoxic stress responses and to an in vitro effect of a NRF2 inductor in ASD children. Oxidative stress biomarkers, adaptive responses to genotoxic/oxidative stress, levels of master antioxidant regulator Nrf2 and its active form pNrf2 before and after inducing by dimethyl fumarate (DMF), and promotor rs35652124 polymorphism of NFE2L2 gene encoding Nrf2 were studied in children with ASD (n = 179). Controls included healthy adults (n = 101). Adaptive responses to genotoxicity as indicated by H2AX and cytoprotection by NRF2 contents positively correlated in ASD children with a Spearman coefficient of R = 0.479 in T+, but not CC genotypes. ASD children with NRF2 rs35652124 CC genotype demonstrated significantly higher H2AX content (0.652 vs. 0.499 in T+) and pNrf2 induction by DMF, lowered 8-oxo-dG concentration in plasma and higher cfDNA/plasma nuclease activity ratio. Our pilot findings suggest that in ASD children the NEF2L2 rs35652124 polymorphism impacts adaptive responses that may potentially link to ASD severity. Our data warrant further studies to reveal the potential for NEF2L2 genotype-specific and age-dependent repurposing of DMF and/or other NRF2-inducing drugs.

Central Causation of Autism/ASDs via Excessive [Ca2+]i Impacting Six Mechanisms Controlling Synaptogenesis during the Perinatal Period: The Role of Electromagnetic Fields and Chemicals and the NO/ONOO(-) Cycle, as Well as Specific Mutations

“…Subasi Turgat et al [250] found that ASD patients had lower levels of Nrf2 and higher levels of Keap1 than normal controls, suggesting but not proving that lowered Nrf2 may have a role in ASD causation. Such causation is also suggested by the Porokhovnik et al [251] study, in which there were no significant differences shown in autism incidence in patients carrying a genetic polymorphism in the Nrf2 gene compared to those carrying the more common Nrf2 gene, but some significant differences in oxidative DNA effects and another stress response in ASD patients were shown. That study, although an interesting one, may be limited because of its insufficient size.…”

Autism Spectrum Disorder: Brain Areas Involved, Neurobiological Mechanisms, Diagnoses and Therapies

“…Moreover, high levels of nitrosative stress biomarkers and NO synthase inhibitors were found to induce changes of behavioral ASD-associated phenotype [53]. Analogous increases of oxidative stress were found to induce a polymorphism of the NRF2 gene, which is a master regulator of antioxidant stress [54]. Additional known stresses were found effective in the expression of ASD genes [55,56].…”

Fragments of Oxidized Extracellular DNA Affect the Development of Oxidative Stress in the Peripheral Blood Mononuclear Cells in vitro in Patients with Childhood Autism

“…Существует множество гипотез развития ДА, однако в настоящее время считается, что ключевую роль в развитии ДА играет сочетание двух факторов: генетической предрасположенности и воздействия факторов окружающей среды [4][5][6]. Выделяют три физиологические и метаболические причины ДА: иммунную дисфункцию, окислительный стресс и митохондриальную дисфункцию [7][8][9][10].…”