Cytokine Polymorphisms and Their Potential Role in Autism

Background: Cytokines are a diverse group of soluble regulatory proteins that play an essential role in the regulation of inflammatory responses and are involved in the regulation of both innate and acquired immunity. Cytokines and their receptors are often encoded by highly polymorphic genes; and some of these polymorphisms are responsible for the observed inter-individual differences in cytokine production and likely impact the immune response. In the last 10 years, evidence has accumulated that increased levels of some pro-inflammatory cytokines are present in the peripheral blood mononuclear cells of children with autism spectrum disorders (ASD); fueling the hypothesis that an abnormal immune response could be another component of this multifactorial disorder. It may be useful to hypothesize that there are phenotypes of the immune system predisposed to stronger or weaker inflammatory immune responses, and these phenotypes can manifest from several different combinations of genotypes of different cytokine genes with variable expression. Since cytokines are able to cross the placenta the maternal immunogenetic make up may also be associated with fetal pathogenesis of autism. Objectives: The main objective of the current study is to characterize different single nucleotide polymorphisms (SNPs) in selected cytokine genes in autistic subjects and their mothers. Methods: DNA samples from two different sources were included in this study: a) ASD patients and their mothers (n=20) from Coriell Cell Repositories (http://ccr.coriell.org/ autism/); b) ASD patients and their mothers (n=17) recruited at the Department of Pediatrics (University of Louisville). Cytokine genotypes were determined using a cytokine genotype kit (Invitrogen, Carlsbad, CA). A broad cytokine single nucleotide polymorphism panel was targeted: IL-1α, IL-1β, IL-1R, IL-1RA, IL-4, IL-4Rα, IFNγ, TGFβ1, TNFα, IL-2, IL-4, IL-6, IL-10, and IL-12. Results: Analyses revealed that frequencies of certain genotypes for specific cytokines document significant differences in the following groups: mothers vs. controls and autistics vs. controls, for IL-6, IL-12, IFNγ, and IL-4R. Significant differences were also detected between autistics vs. controls for IL-4 and IL-1RA specific genotypes. Conclusions: This study shows that some genotypes likely affecting the overall balance of pro- and anti-inflammatory components of the immune response may be more prevalent in autistic patients and their mothers. Furthermore, the assaying of cytokine genotypes may permit characterization of immune endophenotypes within the autistic spectrum.