Prenatal Smoke Exposure, Tyrosirse Receptor Kinase Methylation, and Childhood Respiratory Health

摘要

Background: Prenatal tobacco smoke exposure (PTS) may increase risk for poor childhood respiratory outcomes through induced epigenetic changes in immune response genes. The receptor tyrosine kinase AXL and its closely related family members, TYRO3 and MER (aka TAM), play a crucial role in inhibition of inflammation by preventing unrestrained signaling by Toll-like receptors and were recently described as the ultimate and previously unrecognized missing link in the tri-partite cycle of inflammation. Aims: We hypothesized that PTS affects TAM gene DNA methylation in a manner that alters key innate immune pathways involved in asthma and normal lung development. Methods: We investigated the association between CpG methylation in TAM genes using the Illumina HumanMethylation450 array in newborn blood spots and lung function level and prevalence of asthma assessed at age 11 in 252 children from the Children's Health Study. We related respiratory-associated CpG loci with PTS in a subset of 85. Linear and logistic regression models were used to evaluate FEV1, FVC and asthma. Beta regression models were used to evaluate PTS and CpG methylation. All analyses were conducted in the R software package. Results: 8 TAM CpG targets were associated with FEV1, FVC and an additional 5 with asthma, using a threshold p ＜0.1. Of these, 2 were also associated with PTS. A 1 % increase in CpG methylation in cgl7354880 (MERTK) and in cgl9270050 (AXL) was associated with decreased childhood FEV1 (β = -6 ml, p=0.07 and β = -49 ml, p=0.1) and FVC (β = -8 ml, p=0.05 and β = -55 ml, p=0.12) and with PTS exposure (β = 0.9%, p=0.08 and β = 0.3%, p=0.02). Conclusions: These associations are consistent with the hypothesis that PTS-related increased methylation may silence TAM genes, potentially leading to overstimulation of the immune system and negative effects on childhood respiratory health.