Synergic Effect of GSTP1 and Blood Manganese Concentrations in Autism Spectrum Disorder

Background:  Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that impairs social interaction and communication. It has been reported that the development and clinical manifestation of ASD may contribute to impaired capacity for methylation and increased oxidative stress. Manganese (Mn) is an essential element for human health and development but its neurotoxic effects are well established. Glutathione-S-transferase (GST) genes, including GST pi 1 (GSTP1), GST mu 1 (GSTM1), and GST theta 1 (GSTT1) encode enzymes that can protect cells from oxidative stress. 

Objectives: To investigate whether there is an interaction between the aforementioned GST genes and blood manganese concentrations (BMC) in relation to ASD.

Methods: We used data from 100 ASD cases and their 1:1 age- and sex-matched typically developing (TD) controls (age 2-8 years) from Jamaica. We administered the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview-Revised (ADI-R) to confirm the diagnosis of ASD. We administered the Lifetime form of the Social Communication Questionnaire (SCQ) to the parents/guardians of potential control children to rule out symptoms of ASD. We also administered a questionnaire to the parents/guardians of both ASD cases and TD controls to collect their demographic and socioeconomic status information, such as ownership of a car by the family, parental education levels, and potential exposure to manganese through drinking water sources and food, especially the types and frequency of fruits, vegetables, and seafood consumed by the children.  At the end of interview, about 5 mL of venous whole blood and 2mL of saliva were obtained from each child. Michigan Department of Community Health analyzed 2mL of whole blood for assessment BMC, while the remaining samples were used for genetic analysis in the Center for Human Genetics at University of Texas School of Public Health at Houston.   

Results: Using conditional logistic regression with ASD status as a binary dependent variable, we did not find any significant additive effects for GSTT1, GSTM1, GSTP1, and a binary BMC (BMC < 12µg/L, BMC ≥ 12µg/L) in ASD. However, we observed a significant interaction between GSTP1 and binary BMC in relation to ASD, with and without controlling for several potential confounding variables that included parental education, place of child’s birth (Kingston parish vs. other parishes), consumption of root vegetables (“yam, sweet potato, or dasheen”), “cabbage”, salt water fish, and cakes/buns. Our findings from both co-dominant and recessive genetic models, indicate that among children who had the Ile/Ile genotype for GSTP1, those with BMC ≥ 12µg/L had about 4 times higher odds of ASD than those with BMC < 12µg/L, (Recessive model: Unadjusted Matched Odds Ratio (MOR)=4.02, 95%CI: 1.19-13.64; P=0.03). After adjusting for the aforementioned potential confounders, among the subgroup of children with genotype Ile/Ile, those with BMC ≥ 12µg/L had about six times higher odds of ASD than those with BMC < 12µg/L, (Recessive model: Adjusted MOR=5.92, 95%CI: 1.05-33.32; P=0.04).  

Conclusions: These findings suggest a possible synergic effect of BMC and GSTP1 in ASD. Further investigation of the mechanism through which increased manganese levels may be related to ASD is warranted.