Gene-Environment Interaction: Impact of MET Gene on Traffic Exposure From Freeways As a Risk Factor for Autism

Background:  Although gene-environment interactions are widely believed to contribute to autism, the evidence for specific gene-environment interactions is sparse.  In independent studies, we recently identified (1) increased autism risk among individuals exposed to high levels of traffic related air pollution (TRP) near the time of birth; and (2) increased autism risk among individuals with the C allele of MET gene promoter variant rs1858830.  Association of the MET rs1858830 C allele has been replicated in 5 independent samples, and the allele is known to be functional, decreasing expression of MET protein in brain and peripheral blood.  

Objectives:  In this study we investigated the relationship between TRP exposure, genotype at the MET rs1858830 locus, and autism.  Based on animal model studies showing decreased MET protein in brain following prenatal exposure to the TRP component benzo(a)pyrene, we hypothesized a potential gene-environment interaction that could be detected in a human sample. 

Methods:  This study analyzed data on 165 autism simplex cases and 149 typically developing controls enrolled in the Childhood Autism Risks from Genetics and the Environment (CHARGE) Study. Autism diagnosis was confirmed based on both the ADOS and ADIR while controls were those that scored below the cut-off of 15 on the Social Communications Questionnaire and who did not meet criteria for developmental delay using the Mullen's Scales of Infant Development and the Vineland Adaptive Behavior Scales.  The mother’s address from the birth certificate was geo-coded and TRP estimates assigned to each location using the CALINE4 line-source air-quality dispersion model.  Genotype at the MET rs1858830 locus was determined by direct re-sequencing of DNA obtained from blood samples.  We examined genotype and TRP associations using logistic regression models comparing autism vs. typically developing controls.  

Results:  Cases were more likely to live at residences with the highest quartile of TRP exposure, as compared to controls (OR 1.62, 95%CI (0.95-2.79)).  Consistent with previous reports in simplex cohorts, no main effect of genotype was observed (OR 0.94, 95% CI (0.56-1.59)). Examination of joint TRP and gene effects indicated that subjects with both the MET rs1858830 CC genotype and high TRP exposure were at increased risk of autism compared to subjects with the GG genotype and unexposed to TRP (OR 4.16, 95% CI (1.29-16.21)).  

Conclusions: These findings suggest that the joint effects of MET rs1858830 CC genotype and TRP exposure increase autism risk among simplex families, demonstrating a gene-environment interaction.