A meta-analysis of pro-inflammatory cytokines in autism spectrum disorders: Effects of age, gender, and latitude. (August 2019) - Saghazadeh, Amene
Abstract: Background: Autism spectrum disorders (ASD) occur in 1.5% of the general population worldwide. Studies suggest that ASD might have more costs than diabetes and attention deficit and hyperactivity disorder by 2025. Dysregulation of the cytokine system is well-documented in ASD. We conducted a meta-analysis of studies providing data on circulating concentrations of pro-inflammatory cytokines in people with ASD compared with control subjects without ASD. Methods: We identified potentially eligible studies by systematically searching electronic databases from inception to February 2018. Results: Thirty-eight studies with total of 2487 participants (1393 patients with ASD and 1094 control subjects) were included in the meta-analysis; 13 for interferon (IFN)-γ, 17 for interleukin (IL)-1β, 22 for IL-6, 19 for tumor necrosis factor (TNF)-α, 4 for IL-1α, 6 for IL-2, 4 for IL-7, 8 for IL-8, 14 for IL-12, 3 for IL-15, 12 for IL-17, 3 for IL-18, 3 for IL-2 receptor, 3 for TNF-β, and 3 for IL-23. We found medium increases in levels of plasma IFN-γ (standardized mean difference, SMD = 0.53) and serum IL-1β (SMD = 0.56) and small increases in levels of blood IL-1β (SMD = 0.35), serum IL-6 (SMD = 0.30) and serum TNF-α (SMD = 0.31) for patients with ASD. Meta-regression analyses identified latitude as a negative moderator of the effect size (ES) of difference in mean levels of IFN-γ (R 2 = 0.26) and TNF-α (R 2 = 0.74). Also, difference in the mean age between patients and controls had a negative interaction with the ES of difference in mean levels of IL-1β. In contrast, there was a positive effect of the moderator of difference in the proportion of male subjects between patients and controls on the ES of difference in mean levels of IL-1β. We found no significant alterations in peripheral levels of other pro-inflammatory cytokines including IL-1α, IL-2, IL-2R, IL-3, IL-7, IL-8, IL-12, IL-12p40, IL-12p70, IL-15, IL-17, IL-18, IL-23, TBF-β, and TNFRI/II in patients with ASD. Conclusions: This meta-analysis provides evidence for higher concentration of pro-inflammatory cytokines IFN-γ, IL-1β, IL-6, and TNF-α in autistic patents compared with control subjects. Also, meta-regression analyses point to the interaction of latitude, age, and gender with peripheral alterations of associated pro-inflammatory cytokines. Highlights: There are many concerns surrounding a child with autism spectrum disorder (ASD) ranging from the high prevalence of comorbidities to the lack of definitive diagnosis and treatment. In the search for the causes of ASD, inflammatory markers have emerged as potential candidates. Numerous studies have determined circulating concentrations of cytokines in people with ASD compared to people without ASD and provided inconsistent results. This meta-analysis provides evidence for higher concentration of pro-inflammatory cytokines IFN-γ, IL-1β, IL-6, and TNF-α in autistic patents compared with control subjects. Meta-regression analyses point to the interaction of latitude, age, and gender with peripheral alterations of associated pro-inflammatory cytokines.