A meta-analysis of pro-inflammatory cytokines in autism spectrum disorders: Effects of age, gender, and latitude

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 (R² = 0.26) and TNF-α (R² = 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.

Keywords: Autism spectrum disorder; Cytokine; Inflammation; Latitude; Meta-analysis; Systematic review.