Relationships between TLR4 pathway Single Nucleotide Polymorphisms, Distance to Roadway, and Asthma Diagnosis and Severity

Asthma is a complex chronic health condition estimated to affect 25 million people in the United States alone. Gene by environment interactions may play a role in determining asthma incidence or severity. Previous work indicates that specific gene polymorphisms on the TLR4 pathway are associated with asthma incidence.  We examine four common single nucleotide polymorphisms (SNPs) that have functional effects on TLR4 signaling: two gain-of-function SNPs, CD14 and TNFa; and two loss-of-function SNPs, TLR4 and TIRAP.  Our objective was to explore possible gene-environment interactions by examining SNP combinations, residential distance to roadway as a proxy for traffic-related air pollution exposure, and asthma outcomes.

We obtained individual-level data from the Environmental Polymorphisms Registry, including SNP data, residential address, and asthma diagnosis and symptoms. Subjects (n=1,823) were divided into three “responder type” groups based on genetic profiles: (1) hyper-responders (carriers of CD14 and TNFa and wild-type TLR4 and TIRAP); (2) hypo-responders (carriers of TLR4 and/or TIRAP and wild-type CD14 and TNFa); and (3) others. We geocoded addresses and calculated the distance between each subject’s residence and nearest road, considering highways, major roads, and secondary/connecting roads. We classified each subject’s proximity to the nearest road as either <250m or >250m; in a sensitivity analysis, we used this distance classification but only considered proximity to highways and major roads (i.e., excluding secondary/connecting roads). Asthma outcomes were examined separately using a logistic regression model (asthma diagnosis) and cumulative logit model (asthma-related sleeplessness, activity limitations, emergency room [ER] visits). Covariates included sex, smoking status, race, and home environmental tobacco smoke.

Over half of the subjects (n=1,016, 55.7%) lived >250m from the nearest road; 807 subjects (44.3%) lived <250m from the nearest road. Whites were more likely than blacks/African Americans to report asthma diagnosis (OR=1.33, CI: 1.07, 1.65), and men were less likely to report asthma diagnosis (OR=0.53, CI: 0.43, 0.64) and symptoms. Individuals closer to roads (<250m) were more likely to report asthma diagnosis (OR=1.25, CI: 1.03, 1.52).  Hypo responders were less likely than hyper responders to report asthma-related activity limitations (OR=0.58, CI: 0.36, 0.98).  Sensitivity analysis results were consistent with the main analysis findings; additionally, for subjects <250 from a road, regular responders were less likely than hyper responders to report more severe asthma, as indicated by asthma-related ER visits (OR=0.37, CI: 0.14, 0.97).