Objectives: To investigate gene-environment interaction between glutathione-related genes and potentially stressful fetal environments as measured via maternal conditions known to cause oxidative stress.
Methods: Glutathione genes were ranked by weighted criteria that addressed each gene’s biological relationship with glutathione, location in autism linkage regions, levels of expression in brain, and degree with which their expression correlated with expression of other glutathione genes. SNPs were then selected for the top scoring genes by selecting tag-SNPs, functional SNPs as well as SNPs in conserved regions. Two domains of stressful fetal environments, altered mitochondrial function (AMF) and impaired immune function (IIF) were characterized based on maternal health conditions known to relate to oxidative stress. The AMF category included conditions that may stress mitochondrial function, leading to an increased production of oxidants and included: endocrine disorders, respiratory disorders, cardiovascular disease (CVD), and hypertension. The IIF category included: migraines, asthma, allergies, immune deficiencies, autoimmune disorders as well as irritable bowel syndrome and disease. Tests of genetic associations in the presence of gene-environment interactions with either of these environmental domains (AMF and IIF) were performed in case-parent trios from the AGRE sample for 308 SNPs in 41 glutathione-related genes using a nested likelihood ratio test (LRT) comparing models with SNP and environment and interaction terms to those with only environment terms. Odds ratios for interaction between gene variants and stressful fetal environments were estimated using conditional logistic regression (CLR) models. Genotype odds ratios for groups stratified by environment were also estimated for those SNPs with significant LRT results.Results: Statistically significant associations in the context of stressful fetal environments were observed for a number of SNPs in genes related to glutathione metabolism, including DPEP1, ADH5, ABCC6, CTH, and multiple isoforms of GGTLA and GSTs. The maternal conditions that contributed most to these joint gene-environment effects were those associated with AMF, including endocrine disorders, respiratory disorders, CVD and hypertension. Of note, SNPs in DPEP1, LTC4S, GGTLA1, GGTLA4 each had significantly interacting SNPs. In addition to their role in glutathione metabolism, they are each involved in cysteinyl Leukotriene synthesis. Cysteinyl leukotrienes have a role in inflammation in addition to serving as messengers and modulators during development.
Conclusions: These results suggest that risk associated with variation in glutathione genes may interact synergistically with a fetal environment resulting from medical conditions and/or exogenous factors experienced by mothers of affected children. Genes related to cysteinyl leukotriene synthesis emerged as potential candidate genes for autism, given their role in oxidative stress, inflammation as well as messengers during neuronal development.