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

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)-gamma, 17 for interleukin (IL)-1 beta, 22 for IL-6, 19 for tumor necrosis factor (TNF)-alpha, 4 for IL-1 alpha, 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-beta, and 3 for IL-23. We found medium increases in levels of plasma IFN-gamma (standardized mean difference, SMD = 0.53) and serum IL-1 beta (SMD = 0.56) and small increases in levels of blood IL-1 beta (SMD = 0.35), serum IL-6 (SMD = 0.30) and serum TNF-alpha (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-gamma (R-2 = 0.26) and TNF-alpha (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-1 beta. 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-1 beta. We found no significant alterations in peripheral levels of other proinflammatory cytokines including IL-1 alpha, 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-beta, and TNFRI/II in patients with ASD. Conclusions: This meta-analysis provides evidence for higher concentration of pro-inflammatory cytokines IFN-gamma, IL-1 beta, IL-6, and TNF-alpha 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.